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SEPTEMBER 3, 2019

The Wonder Years – Gene Therapy Enters the Age of Adolescence

Christopher J. RaymondSR. RESEARCH ANALYST

+1 312 267-5086 | [email protected]

Tyler M. Van BurenSR. RESEARCH ANALYST


Danielle C. Brill, Pharm.D.SR. RESEARCH ANALYST


Piper Jaffray does and seeks to do business with companies covered in its research reports. As a result, investors should be aware that the firm may have a conflict of interestthat could affect the objectivity of this report. Investors should consider this report as only a single factor in making their investment decisions. This report should be read inconjunction with important disclosure information, including an attestation under Regulation Analyst certification, found on pages 160 - 161 of this report or at the following site:http://www.piperjaffray.com/researchdisclosures.

http://www.piperjaffray.com/researchdisclosures

David Amsellem

Sr. Research Analyst

Danielle Brill, Pharm.D.


Joseph Catanzaro, Ph.D.


Christopher Raymond


Edward Tenthoff


Tyler Van Buren


Piper Jaffray Investment Research

At Piper Jaffray, our biopharma investment research team delivers to clients market-driven and

actionable insights across the biotech and pharmaceutical sectors. We build strong partnerships

with clients, and they trust our unique perspective to guide their investment strategies.

2 | BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence Piper Jaffray Investment Research

Contents

01. Executive Summary

02. Introduction to Gene Therapy

03. Gene Therapy Product Design Considerations

04. Targeting Indications of Interest With Gene Therapy

05. Emerging Gene Therapies

06. Appendix

Piper Jaffray Investment Research BioInsights: The Wonder Years – Gene Therapy Enters the Age of Adolescence | 3

01.Executive Summary


Executive Summary (Page 1/12): Viral Gene Therapy Company Landscape

Market Cap >$10B

Source: Company Websites. Piper Jaffray Research.

Market Cap $1–10B

Companies per GlobalData.



Market Cap <$1B





Private




Gene therapy has experienced a renaissance in the last 5 years. It’s been

roughly five years since gene therapy as a field has re-entered the collective

conscience of biotech investors, as a deeper understanding of virology, advances

in vector and capsid design, and innovation in manufacturing all converged,

resulting in an explosion of promising data and concomitant regulatory

advancement. Indeed, after an almost 15 year “nuclear winter” (from ~1999 –

marked by the tragic death of Jesse Gelsinger as a result of gene therapy

treatment – to 2014), the industry had the first approved gene therapy (QURE’s

Glybera – approved by EMA in 2012), as well as meaningful human proof of

concept data across a number of disease indications. Since then, this innovation

has only accelerated, as the FDA and/or EMA have now approved five gene

therapies (QURE’s Glybera, ORTX’s Strimvelis, ONCE’s Luxterna, AVXS/NVS’

Zolgensma, and BLUE’s Zynteglo) and the number of annual AAV-based trial

initiations has ballooned from a handful in 2014 to ~40 today, with approximately

300 active programs ongoing (Exhibit 1). Despite this innovation and resultant

value creation, we still view the field as very early in terms of fulfilling its potential.

Sizeable value creation with likely more to come. While pure-play gene therapy

companies have been around for decades, as one might expect, the collective

market cap of these names has followed a trajectory very similar to that we would

expect for a space undergoing tremendous innovation.

Executive Summary (Page 4/12): As a Therapeutic Class, Gene Therapy Has Already Delivered a Great Deal

of Value, But in Terms of Potential, it’s Still Just an Adolescent

Source: Clinicaltrials.gov. Piper Jaffray Research.

EXHIBIT 1

Clinical Trial Initiations for AAV-based Treatments

EXHIBIT 2

Collective Market Cap of All Pure Play Gene Therapy Companies over Time

0

5

10

15

20

25

30

35

2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Num

ber

of C

linic

al tr

ial In

itia

tio

ns

Year

Phase I Phase II Phase III

$0

$5,000

$10,000

$15,000

$20,000

$25,000

$30,000

$35,000

$40,000

$45,000

2005 2010 2015 2019

Mark

et C

ap (

in $

M)

Year


As one might expect, with innovation comes acquisition. As gene therapies have made their way out of academic institutions and into the hands of biotech companies

via licensing deals and academic spinouts, the field seems poised to enter a new era wherein the pace of gene therapy company acquisitions may begin to increase.

One could argue that it has already, as we've witnessed a number of large-cap names acquire public smid-cap and private gene therapy companies over the last 5 years.

These include Pfizer (Bamboo Therapeutics in 2016), Novartis (AveXis in 2018), Biogen (Nightstar Therapeutics this year), and Roche (Spark, in process), and as these

companies build out their manufacturing capabilities to support ongoing therapeutic development, it is likely only a matter of time before their BD teams get their hands on

more innovative assets.

Executive Summary (Page 5/12): Gene Therapy Company Acquisitions

Source: Goswami R et al. Front Oncol. 2019;24(9):297. Kaemmerer WF. Bioeng Transl Med. 2018;3(2):66–177. Piper Jaffray Research.

EXHIBIT 3

Acquisitions of Gene Therapy Companies Over The Past Five Years

0

1

2

3

4

5

6

7

8

2014 2015 2016 2017 2018 2019 (to date)

Num

ber

of A

cquis

itio

ns o

f G

ene T

hera

py C

om

panie

s

Year


Manufacturing – more than just a black box. Just as important as the vector design, the ability to manufacture high-quality GMP-grade, scalable, and cost-efficient gene

therapy product remains a challenge and a vast majority of companies rely on contract manufacturing organizations to fill this role. However, with the recent explosion of

gene therapy programs, a shortage of contract manufacturing capabilities and human capital has resulted, driving many companies to bring manufacturing in-house. While

this appears to be a hefty upfront investment, it allows companies to have more control over product quality, production schedules, capacity, and costs, while keeping

proprietary knowledge that contributes to the unique capabilities of each company’s platform close to the vest. But we note CMOs are trying to keep up with demand, and

we have seen these organizations beef up their gene therapy manufacturing capabilities through acquisitions with Thermo Fisher’s $1.7B acquisition of Brammer Bio in

March and Catalent’s $1.2B acquisition of Paragon Bioservices in April.

Executive Summary (Page 6/12): As a Therapeutic Class, Gene Therapy has Already Delivered a Great Deal

of Value, But in Terms of its Potential, it’s Still Just an Adolescent

Source: Pettitt D et al. Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies. BioProcess International. April 2016. Piper Jaffray Research.

EXHIBIT 4

Typical Viral Vector Manufacturing Process Overview

Vector

Amplification

Vector

ExpansionPurification Polishing Fill-Finish

Thaw from master or

working cell bank

(eg, CHO)

Shake flask or spinner

Bioreactor

(5–15 L)

Bioreactor

(50–1000 L)

Transduction:

CHO + Vector

Cell lysis,

broth clarification

Filtration

Chromatography

(immunoaffinity,

ion exchange)

DNA removal

(eg, endonuclease)

Ultrafiltration

Sterile filtration

Transfer to

storage vessel

Cryopreservation

Labeling,

sterilization, storage

Se

ed

Tra

in


We’ve only scratched the surface. As we highlight in this report, a deeper understanding of, and the ability to manipulate and design viral vectors (specifically

adeno-associated viral vectors), advances in promotor technology and viral genome design, as well as improved manufacturing and process design, have all converged in

the past five plus years, creating an explosion of programs targeting an increasing array of tissues and disease targets. This includes diverse areas such as dermatology,

hematology, metabolic diseases, musculoskeletal, neurology, ophthalmology, and otology, to name a few.

In this report, we make mention of more than 100 gene therapy companies and profile 23 companies of particular interest – names which we think are best positioned to

capitalize on recent innovations in the field. While we don’t pretend to highlight every company or program, we think investors will do well to pay particular attention to these

names as the field advances further. Generally speaking, we look for future refinement of treatment options, including more diversified mechanisms for gene manipulation

(eg, virally delivered ASOs, CRISPR/Cas9), improved tissue targeting, and answers to the all-important question around re-dosing patients.

Executive Summary (Page 7/12): As a Therapeutic Class, Gene Therapy has Already Delivered a Great Deal

of Value, But in Terms of its Potential, it’s Still Just an Adolescent

Source: Goswami R et al. Front Oncol. 2019;24(9):297. Kaemmerer WF. Bioeng Transl Med. 2018;3(2): 66–177. Piper Jaffray Research.

EXHIBIT 5

Indications Being Targeted by Gene Therapies Covered in This Report


Executive Summary (Page 8/12): Key Public and Private Gene Therapy Players Profiled in This Report

Market Cap <$10BMarket Cap >$10B Private



Novel gene therapies have the potential to transform treatment landscapes for which huge unmet need remains. On the following four slides, we summarize the

available approaches and clinical trials of select companies profiled within this report. Further detail on these and additional companies is provided later in the report.

Executive Summary (Page 9/12): The Expanding Gene Therapy Landscape

Source: Piper Jaffray Research.

ADVM (Van Buren, OW). Adverum Biotechnologies’ lead candidate ADVM-022, is

an intravitreal gene therapy that produces Eylea. The ongoing ADVM-022 Phase I

OPTIC trial has already dosed 6 patients with a single intravitreal injection of 6E11

vg/eye of 022 and has also dosed the second cohort at a 2E12 vg/eye dose level

(n=6). Based on existing observations from the study, the company plans to

present initial 24-week data from the first cohort of 6 patients at the Retinal Society

meeting in September, 2019.

Akouos (Private). Akouos is a precision gene therapy company developing

treatments to restore and prevent monogenic hearing loss disorders. As the

company prepares for an IND submission in 2H20 for their lead Anc80 candidate,

management is engaging with multiple institutions to begin genetic screening in

newborns with confirmed deafness. Looking ahead, Akouos expects clinical

endpoints to include measurements of signal or noise detection, speech

perception, and QoL outcomes.

Amicus Therapeutics (FOLD, not covered). Amicus is a fully integrated, global

rare disease gene therapy company with one of the largest portfolios of gene

therapies to treat rare diseases in the field. Twelve children with Batten disease

have been dosed with lead candidate AAV-CLN6 to date, and remarkably, the

Hamburg motor and language score indicate no disease progression in children

30 months old at the time of treatment with AAV-CLN6. Data in 7 additional

patients at 2 years will be reported in 3Q19. In addition, the company plans to dose

3 additional Batten disease pediatric patients with AAV-CLN3 and is continuing to

develop AAV-GAA for the treatment of Pompe disease.

Asklepios BioPharmaceutical (Private). AskBio, a privately held AAV gene

therapy company founded in 2001, is engaged in the development, manufacture,

and delivery of novel gene therapies to treat a number of devastating diseases.

The company harnesses the scientific expertise of Dr Jude Samulski, the former

Director of the Gene Therapy Center at the University of North Carolina, and a

co-founder and current CSO of AskBio, to drive continued innovation in gene

therapy development with unique viral cassettes (i.e., self-complementary vectors,

synthetic promoters), next-generation chimeric capsids, and scaled up

manufacturing capabilities.

AVRO (not covered). AVROBIO is utilizing its proprietary commercial plato

platform which combines their lentiviral vector system with an automated, closed

cell manufacturing system for CD34+ gene therapy. AVRO’s lead asset,

AVR-RD-01, comprises autologous CD34+ HSCs transduced to express the

human α-galactosidase A (AGA) gene, and is in Phase I/II development for Fabry

Disease. Early efficacy data indicate durable AGA expression and an associated

reduction in lyso-Gb3 levels of 30%–40%. One patient treated in Phase II achieved

an 87% reduction from baseline in the average number of Gb3 inclusions per

kidney peritubular capillary (PTC) 1 year posttreatment. No treatment-related AEs

have been reported to date.




AXGT (not covered). Axovant Gene Therapies has three clinical stage gene

therapy programs. Their most advanced program, AXO-LENTI-PD, is a lentivirus-

based gene therapy for Parkinson’s Disease (PD). Employing a lentiviral vector

allows for packaging of the 3 key enzymes involved in endogenous dopamine

synthesis and delivery in a co-localized fashion to neurons. Six-month follow-up

data from the dose-ranging portion of the ongoing Phase II trial showed improved

motor symptoms, lower oral levodopa dose requirements, and reduced

dyskinesias. Axovant is also developing AAV-based gene therapies for GM1 and

GM2 gangliosidosis and both programs are now in the clinic. We expect initial

3-month data from the ongoing GM1 trial with AAV-AXO-GM1and 3-month data

from the second dose cohort of the ongoing PD gene therapy trial (AXO-LENTI-

PD) in 4Q19. Data from two dosed patients in the ongoing GM2 trial with

AAV-AXO-GM2 is expected at a medical congress in 2H19.

BMRN (Raymond, OW). BioMarin has developed and commercialized a number of

biopharmaceuticals for rare diseases, and currently has two gene therapy

programs in development – valoctocogene roxaparvovec, or valrox (AAV5-F8) for

the treatment of hemophilia A, and BMN 307 (AAV5-PAH) for the treatment of

PKU. Phase I/II updates for valrox have been impressive, with the latest Year 3

update indicating a plateauing of FVIII activity (as measured by the chromogenic

assay) and demonstrating durable and clinically meaningful reductions in

annualized bleed rates (ABRs) and FVIII usage. These data, in combination with

recently disclosed interim data from a Phase III valrox study, will support FDA and

EMA regulatory filings in 4Q19.

BOLD (Raymond, OW). Audentes is an AAV-based genetic medicines company

focused on developing and commercializing innovative therapies for serious rare

neuromuscular diseases. The company focuses on developing AAV-based genetic

medicines for monogenic diseases where the underlying biology is well understood

and amenable to treatment using BOLD’s proprietary AAV gene therapy technology

platform. The company currently has six gene therapy programs in development,

with BLA filing for lead candidate AT132 for treatment of X-linked myotubular

myopathy (XLMTM) expected mid-2020.

BLUE (Van Buren, N). bluebird is developing a pipeline of gene therapies for

severe genetic diseases. Since its inception, the company has optimized an

industry-leading HSC platform which is being leveraged across the gene therapy

portfolio. The company’s lead candidates include Zynteglo for transfusion-

dependent β-thalassemia (TDT), Lentiglobin for severe sickle cell disease (SCD),

and Lenti-D for cerebral adrenoleukodystrophy (CALD). Zynteglo recently received

approval from the EMA for the treatment of non-β0/β0 TDT and European launch

preparation is currently ongoing with initial sales expected to be recorded in 1H20.

Lentiglobin efficacy in SCD has been positive and we expect the Phase III trial to

be initiated by the end of 2019.




BBIO (Van Buren, OW). BridgeBio’s gene therapy pipeline includes two corporate

subsidiaries, Adrenas and Aspa, whose drugs target congenital adrenal

hyperplasia (CAH) and Canavan disease, respectively. The company plans to file

an IND for BBP-631 for the treatment of CAH in 1H20, following positive data in

non-human primates that demonstrated potential restoration of the natural

hormonal and steroidal cycle, which is disrupted in CAH patients. The company

also plans to complete route of administration and dose finding studies, as well as

IND-enabling toxicology studies in 2019 to support the submission of an IND for

BBP-812 for the treatment of Canavan disease in 2020.

MeiraGTx (MGTX, Van Buren, OW). MeiraGTx’s diverse pipeline spans several

ocular disorders, neurodegenerative disease, and salivary gland disease, and

incorporates a proprietary Riboswitch technology, which precisely controls target

gene protein production. The company plans to discuss registrational criteria with

the FDA for AAV-GAD in Parkinson’s disease, as well as AAV-RPE65 in RPE65

deficiency by YE19. In addition, the company expects data from ongoing Phase I/II

trials in achromatopsia (AAV-CNGB3 and AAV-CNGA3), X-linked retinitis

pigmentosa (XLRP, AAV-RPGR), and radiation-induced xerostomia (RIX,

AAV-AQP1) in the next couple of years.

Passage Bio (not covered). Passage Bio is partnering with UPenn’s Gene

Therapy Program and Orphan Disease Center to develop novel therapies for GM1

gangliosidosis, frontotemporal dementia (FTD) and Krabbe disease, which are

primed to enter the clinic throughout 2020. Preclinical biomarker data in AAV-GLB1

for GM1 and AAV-PGRN for FTD are early indicators of efficacy. Non-human

primate studies demonstrated improved HEX activity with AAV-GLB1, and

5–10-fold greater PGRN levels in the CSF following AAV-PGRN administration.

RARE (Raymond, OW). Once a wild card, Ultragenyx’s gene therapy platform has

continued to deliver on expectations with initial proof-of-concept data reported for

Phase I/II clinical programs DTX301 (OTC deficiency) and DTX401 (GSDIa), with

additional updates for patients treated at higher doses of both products expected in

3Q19. RARE has established non-GMP internal manufacturing platforms for both

HEK293 transient transfections and HeLa producer cell lines to develop these

processes to full scale before transferring them to CMOs for clinical and/or

commercial development, but plans to build out their own in-house GMP

manufacturing facility in the future.

RCKT (not covered). Rocket’s robust pipeline includes AAV- and LV-based gene

therapy programs with potential to be first-in-class for rare and devastating

pediatric disease indications. The company intends to enter registrational studies in

2020 for RP-A501 for the treatment of Danon disease (DD) and if successful,

approval may occur by the mid 2020s. Phase I RP-L102 data are expected by

YE19 in Fanconi Anemia and a registrational Phase II FA trial is expected to begin

by YE19. Finally, two Phase I studies in PKD and LAD are also expected to initiate

in the 2H19.




SRPT (Brill, OW). Sarepta is currently the market leader in developing treatments

for Duchenne Muscular Dystrophy (DMD). In addition to their commercial product,

Exondys51, Sarepta has the most advanced microdystrophin (MD) gene therapy

program, which is currently enrolling DMD patients in a Phase III study.

The company also has a deep pipeline of gene therapy candidates for various

musculoskeletal and neurological disorders including Limb-Girdle Muscular

Dystrophy (LGMD). Sarepta’s LGMD-2E gene therapy is being evaluated in a

Phase I/II trial. Given overlap in disease manifestations across LGMD subtypes,

successful development for 2E should have positive read-through across the

LGMD gene therapy platform. Sarepta’s early stage gene therapies targeting

LGMD subtypes 2A, B, C, D, and L have overlapping constructs with 2E—all utilize

the same vector, and similar promotors. Pivotal data from the MD gene program is

anticipated by YE20 and an update from the LGMD-2E study is expected at World

Muscle Society in October 2019.

QURE (Brill, OW). uniQure’s gene therapies employ the AAV5 vector.

The company’s lead-candidate AMT-061 is the most advanced, and potentially best

in-class, Hemophilia B gene therapy (AMT-061) program in the clinic. AMT-061’s

pivotal Phase III trial is currently underway and topline data are expected by YE20.

QURE plans to introduce AMT-130, their gene therapy for Huntington’s Disease

(HD), into the clinic in 2019. We expect initial patient biomarker and safety data

around YE19 or early 2020. The company also has an in-house manufacturing

facility. All clinical trials are run with commercial-grade supply to expedite

CMC scale-up.


Introduction to Gene Therapy

02.


The concept of gene therapy originated ~60 years ago and has more recently

been driven by groundbreaking insights into our DNA discovered by the

human genome project. The human genome comprises ~25,000 genes, with

mutations, disruptions, or deletions in genes encoding altered and dysfunctional

proteins underlying a plethora of rare diseases. In fact, genetic dysfunctions are

reported to cause more than 5,700 rare diseases, and the global burden of genetic

diseases is immense, afflicting almost 30 million people in the US and

300 million globally.

The basic premise of gene therapy is to correct (repair), replace, or regulate

the dysfunctional gene that is responsible for causing disease. Ultimately,

durable expression of the functional gene and stable production of the therapeutic

protein are desired, to ideally achieve a one-time curative treatment.

Several gene therapy delivery approaches are under development:

• Ex vivo: genetic modification of isolated patient (autologous) or donor

(allogeneic) cells followed by re-introduction to the patient (eg, CAR-T cells)

• In situ: direct administration of genetic material to target cells or tissues to treat

localized conditions (eg, plasmid vector gene delivery directly to target tissues)

• In vivo: viral or non-viral vectors are employed to deliver therapeutic genes or

materials to defective cells or tissues (Exhibit 7)

This report focuses on in vivo viral vector-mediated gene therapies.

Ex vivo cellular therapies, including CAR-Ts, and gene-editing technology

landscapes have been covered in previous BioInsights reports, linked herein.

The Premise and Promise of Gene Therapy

Source: Goswami R et al. Front Oncol. 2019;24(9):297. Wikimedia Commons. Piper Jaffray Research.

EXHIBIT 6

Snapshot of Genetic Diseases Caused by Single Gene Mutations

EXHIBIT 7

In Vivo Gene Therapy Delivery Methods


https://piper2.bluematrix.com/docs/pdf/d8aafe61-4734-46c9-bcf3-6d8ec5d66643.pdf

https://piper2.bluematrix.com/sellside/DocViewer?encrypt=2ae79de9-6491-4bcd-9a3f-ac7dca02aaa2&mime=PDF

Genomic medicine is by no means a new concept. The ‘birth’ of gene therapy is

attributed to Professor William Szybalski, who performed the first virus-mediated

gene transfer to mammalian cells to correct a genetic defect in 1962. The first

patient was dosed with gene therapy in 1990 for the treatment of adenosine

deaminase severe combined immune deficiency (ADA-SCID), which resulted in

durable partial control of the disease. However, subsequent trial failures ensued,

with severe and fatal immune reactions and the emergence of leukemias due to

insertional mutagenesis. Around the same time as these safety concerns arose,

Gendicine (Shenzhen SiBiono GeneTech) became the first gene therapy to be

approved worldwide, when China approved its use for the treatment of head and

neck squamous cell carcinoma in 2003. The progression of gene therapy halted

over the next decade as research efforts shifted to focus on increasing the safety of

viral vectors used to deliver genes to patients, while maintaining transduction

efficiencies necessary for efficacy. FDA and EMA guidance was established to

govern gene therapy program development. The next gene therapy approval was

obtained in 2012, when Glybera (uniQure, no longer marketed) received approval

in Europe for the treatment of an ultra-rare blood disorder, hereditary lipoprotein

lipase deficiency.

The first in vivo muscle-specific gene therapy was approved by the FDA in

December 2017 – Spark Therapeutics’ Luxturna, for the treatment of vision loss

In patients with inherited retinal dystrophy caused by biallelic mutations in the

RPE65 gene. The AAV2 vector is administered via a single subretinal injection and

delivers a functional copy of the RPE65 gene to retinal pigment epithelial (RPE)

cells, regenerating RPE65 protein production and restoring the visual cycle.

Following this in May 2019, Novartis’ Zolgensma was the first systemic gene

therapy to receive FDA approval for pediatric patients <2 years of age with

infantile-onset spinal muscular atrophy (SMA). Zolgensma also employs an

AAV vector to deliver a functional copy of the human SMN1 gene, which encodes

survival motor neuron (SMN) protein production by target motor neuron cells,

improving muscle movement and function. It is administered via a one-time

IV infusion, currently priced at $2.1 million – a source of much debate.

In January 2019, the FDA described a “surge of cell and gene therapy

products entering early development”. More than 800 active gene therapy INDs

are currently on file, and the FDA anticipates approval of 10–20 gene therapies a

year beginning in 2025. The agency likens this innovative period for

gene therapies to that of the development and mainstreaming of monoclonal

antibody therapies.

A Brief History of Gene Therapy


EXHIBIT 8

Key Events In Vivo Gene Therapy Development

1990 1995 2000 2005 2010 2015 2020 2025

1990: First patient

treated with gene

therapy for ADA-SCID

1999: Jesse Gelsinger

dies following

gene therapy

2002: Leukemia

cases in children

treated for SCID

2003: China

approves Gendicine

for H&N cancer

2012: Europe approves

Glybera for ultra-rare

blood disorder (LPLD)

2017:

FDA approves

Luxterna

FDA anticipates

surge in gene

therapy approvals

2019:

FDA approves

Zolgensma


The scope of gene therapy clinical trials that are currently underway is vast.

ClinicalTrials.gov lists 4,032 gene therapy studies, nearly 1,700 of which are

active (planned, recruiting, or ongoing). A recently published analysis illustrated

the breadth of indications being targeted in gene therapy trials, which ranged from

communicable, dermatologic, immunologic, gastrointestinal, hematologic,

metabolic, and neurologic diseases, cancer, and other syndromes (Exhibit 9).

Viral vectors remain the most dominant gene delivery method, with adenovirus

(AV), adeno-associated virus (AAV), retrovirus (RV), and herpes simplex virus

(HSV) representing the most frequently used viruses in clinical trials (Exhibit 10).

Various types of therapeutic transgenes are being evaluated, ranging

from anti-angiogenic genes, cytokines, receptors, replication inhibitors,

tumor suppressors, vaccine antigens, and other therapeutic proteins of interest.

The recovery of the gene therapy field from the initial period of enthusiasm

followed by disillusionment, to the surge in trials and anticipation of future

gene therapy drug products, has been termed the “hype cycle”. As the hype

for gene therapies continues to escalate, we dive deep into the unique product

development considerations and the key companies shaping the space.

Critical gene therapy product design considerations, spanning vector, capsid,

and promoter selection and design, tissue tropism and targeting, transgene

delivery, transduction efficiency (TE), immunogenicity, and manufacturing will be

discussed in the next section of this report.

The Resurgence of Gene Therapy Today

EXHIBIT 9

Gene Therapy Clinical Trials by Disease Type

EXHIBIT 11

The Gene Therapy Hype Cycle


EXHIBIT 10

Use of Recombinant Viral Vectors in Gene Therapy Clinical Trials

14%

15%

8%

14%13%

8%

8%

10%

10%

Immune System

Cancer

Communicable

Gastrointestinal

Genetic

Hematologic

Metabolic

Dermatologic

Total Gene Therapy Syndromes

34%

32%

24%

10% Retrovirus

Adenovirus

Adeno-associated Virus

Herpes Simplex Virus


In the process of compiling this report, we have spoken with dozens of KOLs

and industry experts in the field of gene therapy. Along the way, we’ve learned

a few things. As such, we offer herein our view of where the field might be headed

in the near-to-intermediate term.

Increasing versatility & efficiency in terms of treatment options & modalities:

• Beyond gene replacement. Companies are already developing vectorized

ASOs (eg, BOLD, NVS/AXVS), and of course delivery of gene editing

machinery (CRISPR/Cas9) is a topic worthy of its own deep dive (which we

previously published).

• Cell/tissue targeting should continue to improve. Chimeric capsids should

see increased clinical use (many companies already possess libraries with

hundreds of thousands of potential capsids). We suspect these will only

improve over time with respect to specific cell/tissue targeting

• Better expression. We anticipate increased use of synthetic and inducible

promotors will allow for more regulated gene expression

• Ablation strategies. With parallels to oncolytic viruses, controlled and targeted

cell ablation technologies could be employed, delivering inducible “cell death”

receptors, which when exposed to specific drugs could drive a highly specific,

targeted cell death

• Redosing. While this concept appears to be anathema to the traditional notion

of “one and done” that generally accompanies gene therapy, it seems most

every gene therapy company is working on such approaches, but so far largely

demur when asked to discuss these programs in detail. Given pragmatic

challenges to durability of expression, we think this work makes sense, and

foresee a generation of novel capsids developed that can evade the immune

system to allow for efficient redosing

Manufacturing – we expect a Moore’s Law (of sorts) to apply here. More

companies are bringing gene therapy manufacturing in house, and refining

proprietary processes at an ever-increasing pace. While we liken this to Moore’s

Law (doubling of components per integrated circuit, and increasing computing

speed every 2 years), we believe that, directionally, manufacturing capabilities will

continue to advance at this rapid pace for the foreseeable future, with time from

vector development to full-scale production continuing to shrink, as well as

decreasing manufacturing costs.

• Speed and Cost (AskBio). As an example, we highlight work being conducted

by private company, AskBio, who recently partnered with Toughlight Genetics to

replace plasmids with closed-linear, double stranded DNA constructs known as

doggybone DNA (dbDNA), eliminating large plasmid backbones and antibiotic

resistant genes as selection vehicles, as well as large plasmid reactor volumes

• Scalability (RARE and BOLD). Many players use HeLa producer cell lines at

2,000 L scale today, but one company, RARE, indicates their “HeLa 2.0” cell

line can be easily scaled to 10,000L. BOLD utilizes a transient transfection

suspension system at a 500 L scale today, but management notes there is no

biological limitation to going beyond that capacity

A Look Forward – Where We Think the Field is Headed

Source: Max Roser. https://ourworldindata.org/uploads/2019/05/Transistor-Count-over-time-to-2018.png. May 2019. Piper Jaffray Research.

EXHIBIT 12

Moore’s Law: Transistor Count on Integrated Circuit Chips (1971–2018)



Gene Therapy

Product Design Considerations

03.


The premise of gene therapy is to correct (repair), replace, or regulate a

dysfunctional gene that is responsible for causing disease. The basic

mechanisms by which these goals can be achieved include A) gene replacement,

B) gene addition, C) gene silencing, and D) gene editing (A–C are illustrated in

Exhibit 13, below).

Gene replacement is the mechanism currently being tested in the majority of

advanced clinical trials, and provides a straightforward mechanism by which to

treat monogenic diseases caused by a single gene defect. Gene addition is more

appropriate for complex genetic disorders and infectious diseases. Finally, gene

silencing is used to treat diseases caused by gain-of-function or gain-of-toxicity

mutations, often using gene knockdown by RNA interference or reprogramming of

mRNA splicing by antisense oligonucleotides (AONs).

In order to express or silence the gene of interest, the genetic material must

be packaged into expression cassettes for delivery to the target cells.

Expression cassettes consist of the transgene (cDNA or genomic DNA), a

promoter to drive expression of the transgene, and a transcription stop codon.

Posttranscriptional response elements (PRE) may also be incorporated to enhance

gene expression. The cassettes are typically packaged into a vector (viral or

nonviral) for delivery to the target cells.

The core steps in the gene therapy development process are summarized in

Exhibit 15, below. Key product design considerations, spanning vector, capsid, and

promoter selection and design, transduction efficiency and payload, administration,

tissue tropism and targeting, transgene delivery, and immunogenicity will be

discussed in detail on the following pages.

Introduction: Process and Components

EXHIBIT 13

Gene Therapy Strategies

Source: Wang D and Gao G. Discov Med. 2014;18(98):151–161. Johnston J et al. InTech Open. 2011. ISBN: 978-953-307-617-1. Piper Jaffray Research.

Identification of

affected gene

Develop

expression

cassette with

therapeutic

transgene

Load

vector with

expression

cassette

Vector

administration

Integration of

genetic material

into DNA and

protein

production

Vector delivery of

gene into

nucleus of cells

EXHIBIT 15

Core Steps of Gene Therapy Development

EXHIBIT 14

Components of an Expression Cassette


Viral and non-viral vectors are employed to deliver therapeutic genes or materials to defective cells or tissues, mediating in vivo treatment of systemic genetic

diseases. While numerous physical and chemical methods of gene delivery are being explored in clinical trials, viral vectors remain the predominant method of gene

delivery, having shown the most efficient delivery of genetic material to target cells and tissues. Key features of the four major viral vectors that are currently under

evaluation in clinical trials are summarized below.

An ideal vector should deliver the therapeutic gene to a specific cell type (both dividing and non-dividing), accommodate foreign genes of sufficient size, transfer a precise

amount of genetic material into each target cell, and achieve the level and duration of transgenic expression sufficient to correct the defect. The vector should be safe and

tolerable – it should not be immunogenic, pathogenic, or inflammatory, or induce insertional mutagenesis. Greater than 70% of the viral vectors being used globally in

ongoing clinical trials are non-pathogenic and replication-defective. Large scale production capability is also desired. Vector options are reviewed in more detail on the

following slides.

Vector Selection and Design

EXHIBIT 16

Key Features of Commonly Used Viral Vectors

Source: Goswami R et al. Front Oncol. 2019;24(9):297. Piper Jaffray Research.

Vector Genome

Max Size of

Exogenous

DNA Insertion

Target Cells Integration Advantages Limitations

Adenovirus

(Ad)dsDNA >8 kb

Broad tissue

tropism

Dividing and

non-dividing

cells

Episomal

• High transduction efficiency

• Demonstrated clinical efficacy

• Short-term effect (1–2 weeks)

• High immunogenicity

• Complexity of engineering

Adeno-

Associated Virus

(AAV)

ssDNA 5 kb

Episomal

(0.1%

genomic)

• Low toxicity: non-inflammatory/pathogenic

• Efficient transduction

• Long-term, durable gene expression

(months – life long)

• Cost-efficient commercial scale

production

• Low packaging capacity (max 5 kb)

• Potential triggering of existing innate and

adaptive immune responses

• Preexisting host neutralizing antibodies

• Purification may be challenging

Lentivirus

(LV)RNA 8–12 kb Genomic

• Low immune response

• Efficient transduction

• Life-long transgene expression

• Large-scale clinical production

• Insertional mutagenesis

• Limited cassette size

Herpes Simplex

Virus (HSV)dsDNA

>30 kb

<50 kb

CNS, muscle,

heart, liverEpisomal

• Efficiently infect multiple cell types

• Large packaging capacity

• Transient gene expression

• Limited clinical experience

• Immune response


Adenoviruses are non-enveloped, double-stranded DNA viruses with the

capacity to carry large genes, up to 7.5 kb in size. Over 50 serotypes of

adenovirus have been isolated.

Adenoviruses rapidly infect a broad range of human cells, both dividing

and non-dividing. The virus binds the coxsackie-adenovirus receptor (CAR)

on the host cell surface with high-affinity and enters the cell by receptor-

mediated endocytosis (RME). The endosome is uncoated, releasing the viral

DNA, which is transported into the nucleus. Within the nucleus, the viral DNA is

transcribed to produce mRNA, which is translated into the therapeutic protein

(Exhibit 18, right). Lack of integration into the host genome results in transient

gene expression, lasting ~1–2 weeks.

The major concern regarding use of adenoviral vectors is the strong

immunogenicity exhibited by the pathogenic virus. Pre-existing host

immunity may also exist. Attempts to circumvent immunogenicity include

modification of viral capsids and “sero-switch” gene transfer, a strategy that

involves the repeated administration of alternating adenovirus vectors that are

derived from different serotypes in order to avoid anti-adenovirus humoral

immune responses.

Adenoviral vectors are currently being evaluated only in very select

indications, including oncology and heart failure. The field has more broadly

shifted towards AAV and lentiviral vectors, which are discussed in more detail

on the following slides.

Focus on AV Vectors

EXHIBIT 17

Adenovirus Structure

EXHIBIT 18

Mechanism of Adenovirus-mediated Delivery of Therapeutic DNA

Source: Ip WWY & Qasim W. Adv Hematol. 2013;2013:176418. Goswami R et al. Front Oncol. 2019;24(9):297. Piper Jaffray Research.


AAVs are small, single stranded non-pathogenic DNA viruses that contain

two genes (rep and cap), and only reproduce in the presence of a helper virus

(eg, Ad, HSV, or baculovirus). This requirement for a helper virus to proliferate,

along with the nonpathogenic nature and minimal immunogenicity of AAV,

renders it one of the safest vectors to use. It is therefore not surprising that

AAV is currently the most frequently used viral vector for gene therapy.

Thirteen serotypes of AAV have been isolated. Their diverse capsids

confer distinct tissue tropism, making the AAV system attractive for

selective and highly efficient gene transduction of a wide range of cell types.

Recombinant AAV (rAAV) vector production involves a 3-plasmid

co-transfection method performed in packaging cell line. The key

components and steps involved in this process are illustrated below.

1. Transgene-containing rAAV vector: the majority of AAV’s viral genome

is replaced with the therapeutic transgene (viral packing genes remain)

2. AAV rep (replication) and cap (capsid) genes: Contains the code for

regulatory proteins involved in AAV genome replication and capsid proteins

that determine tissue tropism, respectively

3. Helper virus genes: enable rAAV replication only during the

manufacturing process

A limitation of AAV vectors is their relatively limited packaging capacity.

Up to a 5 kb therapeutic expression cassette can be incorporated in an AAV

vector, beyond which the packaging efficiency drops significantly. Several

Dual-AAV vector approaches (overlapping, trans-splicing, and hybrid) that

involve “splitting” the therapeutic expression cassette between two independent

AAV vectors are being developed to increase the size of the transgene that

AAV vector can deliver.

Focus On Adeno-Associated Virus (AAV) Vectors (Page 1 of 2)

EXHIBIT 20

rAAV2 Vector Production

Source: Schultz BR and Chamberlain JS. Mol Ther. 2008;16(7):1189–1199. Trapani I. Genes (Basel). 2019;10(4):287. Piper Jaffray Research.

EXHIBIT 19

AAV Serotypes and Tissue Tropism

Serotype Tissue Tropism

AAV1 Muscle; Adipose; CNS; Heart

AAV2 CNS (particularly ocular); Kidney; Muscle; Testes

AAV3 Liver

AAV4 Brain; Retinal pigmented epithelium (RPE); Lung

AAV5 Liver; CNS; Ocular; Pancreas

AAV6 Striated muscle (heart); Respiratory epithelium (lung)

AAV7 Brain; Photoreceptors; RPE; Striated muscle

AAV8 Hepatocyte; Pancreas; RPE; Photoreceptors; Brain; Skeletal muscle

AAV9 Heart; Skeletal muscle; Lung; Brain; CNS

AAVrh10 Pleura; CNS

Purification

TransgeneITR ITR

Promoter

rep

cap

Encapsulated

rAAV vectors

1. 2. 3.


AAV vectors are able to infect both non-dividing and dividing cell types,

entering cells via RME. Following entry, virions traffic to the host cell nucleus,

where vector uncoating likely occurs. The vector genome is released, forming

episomes, or more rarely integrating into the host

genome (as has been observed with AAV2 integrating into chromosome 19),

resulting in durable long-term gene expression.

While the immunogenicity of AAV vectors is low compared with other

viral vectors, AAVs occasionally trigger innate and adaptive immune

responses. Although administration of AAVs to immune privileged sites

alleviates this concern, mitigation of AAV immunogenicity is an ongoing area of

research. Short-term immune suppression, coadministered during the initial

AAV treatment, may minimize activation of memory T and B cells, and

contribute to gene therapy persistence. Additional strategies include genetically

modifying AAV vectors to alter their capsid structure and to restrict transgene

expression to target tissues (using tissue-specific promoters).

An additional consideration for AAV vectors is the challenge commercial

scale production and purification has faced due to the requirement for

co-infecting helper virus for productive infection.

Both FDA-approved in vivo gene therapies (Luxterna and Zolgensma)

utilize AAV vectors. Additional clinical and preclinical success has been

observed in several diseases, including hemophilia B, neurological, and

heart disease.

Focus On Adeno-Associated Virus (AAV) Vectors (Page 2 of 2)

Source: Schultz BR and Chamberlain JS. Mol Ther. 2008;16(7):1189–1199. Trapani I. Genes (Basel). 2019;10(4):287. Piper Jaffray Research.


Lentiviruses are spherical enveloped RNA viruses that belong to the

retrovirus family. With a larger genome than AAV, lentiviral vectors (LVVs) have

the capacity to incorporate therapeutic genes as large as 12 kb. They exhibit broad

cell tropism, infecting a wide range of somatic cells, including hematopoietic stem

cells (HSCs).

Unlike AAV, lentivirus incorporates its DNA directly into a cell‘s chromosome

upon infection. After the LV enters the host via fusion or RME, the RNA genome

is released into the cytoplasm of host cells and reverse transcriptase occurs,

creating viral DNA from the RNA. Viral DNA traffics to the nucleus and is

incorporated into the host genome via the viral enzyme integrase. Integrase

catalyzes both the cleavage of viral DNA and the joining of the cleaved viral DNA to

host cell DNA. After viral DNA is joined to the host DNA, post-integration repair is

conducted by the cell‘s own DNA repair proteins. Viral gene and therapeutic protein

expression subsequently occur outside the nucleus. The ability of lentivirus to

integrate into the host genome allows this vector to provide a sustained therapeutic

effect to dividing cells, such as HSCs, and effectively treat those diseases not

adequately addressed by AAV-based gene therapy.

As an integrating virus, lentivirus poses different safety risks than AAV.

Extensive research has been conducted over the last several decades to

characterize these risks, and has made great strides in improving the safety profile

of this class of viruses. The ability to integrate offers the benefit of sustained

transgene expression and these viruses can handle longer transgene cassettes.

Traditional retroviral vectors (gammaretroviruses) presented significant safety

concerns resulting from insertional mutagenesis and ensuing oncogenesis, as well

as the emergence of replication-competent virus. Lentiviruses exhibit more targeted

integration preferences, avoiding integration near promoters and genes that

regulate the cell’s growth, and favoring the bodies of transcription units, reducing

the risk for insertional mutagenesis. They have also been engineered to employ

self-inactivating (SIN) technology to prevent the formation of replication-competent

virus. In these ways, lentivirus provides significant improvements over traditional

retroviral vectors.

Focus On Lentiviral (LV) Vectors (Page 2 of 2)

Source: Applied Biological Materials, Inc. Dufait I et al. Lentiviral Vectors in Immunotherapy. InTech Open. 2013. DOI: 10.5772/50717. Piper Jaffray Research.

EXHIBIT 21

Lentiviral Structure

EXHIBIT 22

The Lentivirus Replication Cycle

Envelope

Envelope protein

RNA genome

Reverse

transcriptase

Proteinas

estruturais


The key components of the lentiviral genome are illustrated in Exhibit 23 below.

• LTRs, or long terminal repeats, act as a promoter, or “control center”, for the

expression of viral genes

• Gag, pro, pol, and env genes encode for the structural proteins of the capsid,

protease, reverse transcriptase, and envelope proteins, respectively

• The remaining genes perform regulatory functions (tat and rev) as well as alter

cellular function

To form a lentiviral vector, ~1/3 of the viral genome (encoding the virulence

factors) is deleted and the vector system is divided into several plasmids

(Exhibit 24). Plasmids are small, double-stranded DNA molecules that are used as

tools for transferring and manipulating genes. Separation of the various

components of the LV into these distinct plasmids is an important safety step

designed to prevent the resulting LV vector from replicating and causing infection.

1. Vector plasmid: contains the therapeutic transgene. One LTR is deleted,

which renders the other LTR transcriptionally inactive, resulting in a vector

which cannot replicate

2. Packaging plasmid: contains the gag, pro, pol, rev, and tat genes

3. Envelope plasmid: encodes the envelope protein and determines what

receptor the virus binds to when entering a cell

Lentiviruses can be pseudotyped with heterologous viral envelopes to direct

their tissue tropism. One popular example of this is the envelope glycoprotein

derived from vesicular stomatitis virus (VSV), which confers broad tropism and

facilitates transduction of many cell types.

Focus on Lentiviral Vectors (Page 2 of 2)

EXHIBIT 23

Key Component of the Lentivirus Genome

EXHIBIT 24

Lentiviral Vector Plasmids and Components

Source: Dufait I et al. Lentiviral Vectors in Immunotherapy. InTech Open. 2013. DOI: 10.5772/50717. Piper Jaffray Research.


The viral capsid forms the protein shell that contains the viral genome and

differs in structure between serotypes. The viral proteins that make up the

capsid determine tissue tropism by their specificity for host cell surface receptors,

and further influence intracellular trafficking. The capsid also contributes to the

potential immunogenicity of a viral vector.

As reviewed in Exhibit 19 on slide 26, AAV serotype selection for gene therapy is

determined by these differences in tissue tropism. AAV2, 8, and 9 are the most

frequently used serotypes of AAV due to their abilities to infect a diverse array of

target tissues.

While AAV-based therapies have shown success with gene delivery, opportunities

exist to refine vector functionality, by improving transduction efficiency, specificity,

and immunogenicity. Capsid optimization can be achieved by implementing the cap

gene modification strategies illustrated in Exhibit 25, below.

• Amino acid point mutations can be employed to:

• Prevent posttranslational modifications that potentially lead to capsid

degradation, thereby enhancing transduction efficiency

• Increase gene delivery specificity

• Minimize immune recognition by preexisting neutralizing antibodies to AAV

in the host, enhancing transduction efficiency

• Peptide motif insertions:

• Transference or grafting of peptide domains (eg, receptor binding domains)

between serotypes to impart specific functions on a serotype of interest

• DNA shuffling to create capsid chimeras that possess functional domains

with specific properties of interest (eg, a ‘blood brain barrier traversing

footprint‘ that affords greater specificity and transduction efficiency)

• Insertion of nonviral motifs can be performed to selectively transduce target

cells and minimize off-target transgene expression; “peptide locks” can be

inserted to regulate transduction in response to endogenous or chemical

stimuli; mosaic capsids can be created for activateable peptide displays

• Chemical biology approaches:

• Precise capsid modifications such as insertions of tags, amino acids, or

motifs to specific subunits of the viral capsid facilitates site-specific addition

of moieties, vector retargeting, and improves transduction efficiency

Analogous to this is the process of pseuodtyping of lentiviral particles to

alter cellular tropism and intracellular trafficking. Envelope proteins (rather

than capsid proteins) determine viral entry into specific types of host cells and

the transduction efficiencies in quiescent vs differentiated cells. LVs can be

pseudotyped with heterologous viral envelopes or artificially engineered

envelope proteins that trigger transient activation of host cells, increasing TE.

Tissue Tropism and Targeting: Capsid Selection and Optimization

EXHIBIT 25

Rational Design Strategies for AAV Capsid Engineering

Source: Lee EJ et al. Curr Opin Biomed Eng. 2018;7:58-63. Durand S & Cimarelli A. Viruses. 2011;3(2):132–159. Piper Jaffray Research.

Amino Acid Mutation Motif Insertion Chemical Biology


Promoters are regulatory units located upstream of the transgene that initiate

transcription of the transgene, driving both the level and durability of gene

expression. The regulatory unit encompasses the promoter itself (the RNA

polymerase binding site) and associated operators, or response elements.

Promoters are activated by transcription factors.

The promoter to be used in a when building a vector is chosen based on the

following criteria:

• Compatibility with the type of RNA to be produced (i.e., RNAP II promoter for

mRNA expression, RNAP III for small RNA)

• Host organism suitability: bacterial promoters for prokaryotic cells, eukaryotic

(endogenous), viral (exogenous), hybrid, or synthetic promoters

• Desired promoter activity: constitutive, inducible, regulated

Promoters may be native or composite in nature. Native, or minimal, promoters,

are single 5’ gene fragments that comprise a core promoter and its natural 5’UTR

(generally a weaker promoter). Composite, or hybrid, promoters may comprise

promoter elements from distinct origins or combine a distal enhancer with a

minimal promoter of the same origin. Hybrid promoters that comprise viral

enhancer/endogenous fusions may enhance the level, durations, and specificity of

the transgene expression.

Tissue-specific promoters are commercially available for a broad range of cells

and tissues, including bone, endothelial, hematopoietic, liver, lung, muscle, and

neuronal, to name a few. Tumor-specific promoters have also been identified and

are employed to drive targeted gene expression in tumor vs normal cells.

Synthetic promoters, novel DNA sequences, are also being developed to

optimize the size, selectivity, and activity of the promoter, specific for a given tissue

or cell type, or mode of delivery. Promoters can be designed to be constitutively

active, drug regulatable, or inducible, or active under specific conditions (i.e., in a

disease state, or in response to an infection or treatment). Companies are

developing proprietary platforms, such as Synpromics' (acquired by AskBio in

August 2019) PromPT "a unique, and multi-dimensional bioinformatics engine", to

create libraries of promoters that can be adapted per the above criteria.

Synthetic promoters may also play a role in bioprocessing and gene therapy

manufacturing by facilitating the development of stable producer cell lines with

greater productivity, which may remove the requirement for multiple transfections

per manufacturing run. Inducible promoters may be regulated with small molecules

to provide tight control over the manufacturing process.

The promoters most commonly used in viral vectors are summarized below:

• Chicken beta actin (CAG): universal promoter that drives constitutive

expression of mRNA; may be combined with a CMV enhancer

• Cytomegalovirus (CMV): strong mammalian promoter that constitutively

expresses mRNA. Initially drives high levels of transcription that may later

decline due to promoter inactivation

• The inducible H1 and constitutive U6 promoters may be used to drive

transcription of miRNAs by lentiviral vectors

Promoter Selection

Source: Zheng C & Baum BJ. Methods Mol Biol. 2008;434:205-19. Synpromics Company Website. Piper Jaffray Research.


The transfer of a gene via a viral vector is termed transduction.

The delivery of the viral vector, or vehicle, may be performed by directly injecting

the virus into the body (in vivo) or by exposing a patient’s cells to the virus outside

the body, then re-introducing these cells to the body (ex vivo). The delivery method

selected is disease-specific and determined by the vector used and target cells.

Transduction efficiency (TE) is a measure of the percentage of target cells

transduced by the viral vector and expressing the gene of interest. The TE of

in vivo gene therapies can be influenced by several factors, including the number of

vectors reaching the target cell, vector affinity for target cells, target cell expression

of surface receptors for viral entry, target cell division activity, antiviral host immune

responses (nAbs), and ultimately, delivery of the genetic payload (transgene) and

expression of the therapeutic protein.

As such, the serotype of the viral vector, viral load, vector-specificity for target

tissues, and the promotor used can all affect TE and transgene expression.

Recombinant AAV (rAAV) are able to infect both dividing and non-dividing host

cells. Following host cell infection, the AAV genome is transformed into episomes,

circular double-stranded genetic elements that are stably maintained

extrachromosomally, and can replicate independently of the host, providing long-

term gene expression in non-dividing cells. However, episomes undergo enzymatic

degradation over time, and the gene becomes diluted as cell proliferation

continues, attenuating gene expression. The presence of pre-existing host nAb to

AAV is one of the biggest barriers to efficient transduction with rAAV vectors;

Capsid engineering of AAV vectors is an effective approach to evading the immune

response and augmenting transduction potential.

Lentiviral vectors exhibit enhanced TE compared with traditional retroviral-based

vectors due to their ability to also infect quiescent host cells. Upon host cell

infection, integration of lentiviral genetic information into the host’s genome occurs.

As the transgene replicates along with the host cell and is transferred to daughter

cells, more durable gene expression is theoretically achieved. The specific site of

the host’s genome at which the LVV integrates can affect the level of transgene

expression.

Efficient transduction is essential to optimize therapeutic outcomes.

Vectors with greater TEs can be administered at lower doses to achieve a

therapeutic benefit, minimizing risk for inflammatory host reactions and associated

safety concerns.

A number of processes may contribute to the potential decline or loss of transgene

expression over time, including gene silencing and deletion.

Transgene Delivery: Vector Administration, Transduction Efficiency, and Payload

EXHIBIT 26

Direct (In Vivo) vs Cell-based (Ex Vivo) Gene Therapy

Source: Collins M & Thrasher A. Proc Biol Sci. 2015;282(1821):20143003. Fischer L et al. Exp Clin Cardiol. 2002; 7(2-3): 106–112. Piper Jaffray Research.


Manufacturing high-quality, scalable, cost-efficient gene therapy products is

challenging due to the complex multi-step processes involved in production

(Exhibit 27). While the exact steps of which differ according to the specific vector

used, the core goal of each process remains the same – to consistently produce

safe, pure, potent, and durable gene therapy products.

The recent explosion of gene therapy programs has resulted in shortage of

contract capabilities, with 12–18 month manufacturing wait times. As such,

pharmaceutical companies are increasingly developing their own gene therapy

manufacturing systems, leveraging their knowledge base of quality systems from

biologics manufacturing to create commercial-scale fully-integrated gene therapy

manufacturing facilities.

In-house manufacturing capabilities provide control over product quality,

production schedules, capacity, and cost, along with flexibility and business

continuity, while keeping proprietary knowledge in-house. Establishment of

such capabilities, and the production of commercial-grade gene therapy products,

prior to initiating Phase III trials de-risks clinical trial programs, reducing regulatory

concerns regarding changes in manufacturing processes or facilities between

Phase III and commercial production.

The quality and efficiency of the manufacturing process may become a

dividing factor among competitive programs. Investment in manufacturing at an

early stage is key for gene therapy’s commercial success. When evaluating gene

therapy companies - especially those developing their own manufacturing systems

- to fully understand the company’s logic behind:

• Cell line selection: The industry is split between two approaches to production,

insect (baculovirus) vs human cell lines. Insect lines are generally easier to

grow, achieving ~40-fold greater productivity in suspension, with a volumetric

benefit (2000 L vs 200–400 L scale), similar conditions of cell infection at low

and high volumes (supporting ease of scalability), and are less likely

contaminated with human pathogens. Human cell lines may be transiently

transfected with the transgene, an approach that uses a tremendous amount of

capsid and may be challenging to scale up

• Plasmid complexity: Human producer cell lines may generated by

incorporating rep, cap, and the transgene to the genome, to be banked and

used repeatedly – providing consistency and realizing cost reductions

• Purification validation: Techniques to isolate and remove empty capsids from

the end product are important for product purity and potency. Removal of

deamidated capsids is also crucial to ensure liberation of the transgene

following vector administration

Efforts to increase yields and improve purity and consistency should all help

maximize margins and minimize development/regulatory delays. As an increasing

number of gene therapy products enter the market and gene therapy manufacturing

processes become better validated and more established, regulatory comfort

around the quality and safety of manufacturing processes is likely to increase.

Gene Therapy Manufacturing (Page 1 of 3)

Source: Pettitt D et al. Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies. BioProcess International. April 2016. Piper Jaffray Research.

EXHIBIT 27

Typical Viral Vector Manufacturing Process Overview


Gene Therapy Manufacturing – Diving into AAV Manufacturing Platforms (Page 2 of 3)


General Overview of AAV Gene Therapy Manufacturing. Innovation and refinement of AAV gene therapy manufacturing approaches has rapidly progressed within the

last five years. Below, we highlight major differences between the commonly used manufacturing platforms. While challenges exist with each system, many companies

have made improvements to these platforms to reduce costs, increase scalability and production timelines, and improve quality control and safety. In our view, there is

no best platform, but instead believe there are certain considerations, which we highlight on the following slide, as guiding to the most appropriate system to utilize.

Transient Transfection Platform Producer Cell Line Platform

REP/CAP Plasmid Plasmid Integrated in cell line Integrated in cell line

ITR-transgene Plasmid Plasmid BEV* Integrated in cell line

Helper genes Plasmid Plasmid BEV WT adenovirus

Cell line HEK293 (adherent) HEK293 (suspension) Sf9 insect cells HeLa S3 (suspension)

Production system

examplesCellFactory, CellCube, iCELLis WAVE Bioreactor Stirred tank reactor Stirred tank reactor

Efficiency of DNA delivery ++ + +++ +++

Scalability -++

(500 L scale-up common)

+++

(2,000 L scale-up common)

+++

(2,000 L scale-up common)

Safety concerns None None NoneContaminating

helper virus

AdvantagesQuick to produce virus in small scale

Helper virus-free AAV

Added safety of insect cells/virus

Efficient large-scale production

Same helper virus for all

production runs

Efficient large-scale production

Challenges

Low scalability of triple transfection

Low % of full capsids

High plasmid costs

Potentially low BEV stabilityStable producer cell line to

produce for each project

Examples of companies

using the platformSarepta, Passage Bio

Audentes, Ultragenyx, Spark,

AveXis/Novartis, AskBio

BioMarin, MeiraGTx

uniQure, VoyagerBayer, Ultragenyx

EXHIBIT 28

Key Features of Commonly Used Viral Vectors

BEV=baculovirus expression vector.


Gene Therapy Manufacturing (Page 3 of 3)


Everybody wants to rule the (manufacturing) world. But with respect to platform selection, beauty remains in the eye of the beholder. Manufacturing is a

key aspect for emerging gene therapies, not just in terms of COGS and margins, but for clinical development and commercialization, where reproducibility and safety

remain top concerns for regulators. With a number of companies bringing gene therapy manufacturing capabilities in-house, and confusion as to which AAV platform may

be king, we break down some important considerations for investors when thinking about the most appropriate platform for a company to develop and/or utilize.

• For ongoing programs, what’s the indication size? For many rare disease companies treating small numbers of patients a year with a certain gene therapy, there

may be no need to scale up to 2,000L+ capacity with a producer cell line. Rather, transient transfection systems may be the most efficient for producing sufficient

quantities of product

• What diseases is the company looking to treat in the future? Is the company planning to move into a larger indication that may require scale-up beyond the

capabilities of a transient transfection system? If so, how do they plan to do this, especially if they’ve already established a system in-house?

• For in-house manufacturing, what scale-up capacity can the current facility accommodate? Can the company add additional bioreactors into the facility, or

are there physical limitations?

• How quickly does the product need to be made? For companies competing to be first to market (but depending on the indication), it may be most appropriate to

produce a gene therapy product in a transient transfection system and bridge to product made by a producer cell line platform post-approval

• What are the timelines for scale up? For CMOs and companies producing product in-house, with ongoing enhancements to the capabilities of the platforms,

including speed and scalability of production, how quickly can these players establish a fully scaled-up GMP manufacturing process?

• Is the company using commercial material in preclinical and clinical studies? The FDA’s draft guidance on gene therapy development highlights the importance of

using “to be” commercial gene therapy product as soon as possible in preclinical and/or clinical development. It’s important to consider what process the company is

currently using to manufacture product and whether this will be the process used during commercialization. For companies that plan to switch platforms (eg, transient

transfection to producer cell line), bridging studies in preclinical and or small clinical studies may be needed and could be a source of delay or complication


Targeting Indications of Interest With

Gene Therapy

04.


Indications of Interest Covered Within This Report

Source: Company Reports. Myotonic Dystrophy Foundation, NORD. Piper Jaffray Research.

Hematology

Inborn errors of

metabolism

Musculoskeletal

Ophthalmology

Otology

Dermatology

Neurology

Lysosomal storage disorders

• Becker Muscular Dystrophy (BMD)

• Myotonic Dystrophy Type 1 (DM1)

• Duchenne’s Muscular Dystrophy (DMD)

• Limb-Girdle Muscular Dystrophy (LGMD)

• Oculopharyngeal muscular dystrophy (OPMD)

• X-linked myotubular myopathy (XLMTM)

• Achromatopsia

• Choroideremia

• Retinitis pigmentosa

• Wet Age-Related Macular

Degeneration (AMD)

• X-Linked Rentinoschisis

(XLRS)

• Hearing loss

• Epidermolysis

bullosa

• ALS - C9ORF72

• Huntington's Disease

• Friedreich's Ataxia

• Frontotemporal dementia

• Parkinson's disease

• SCA-Type 3

• Alpha-1 Antitrypsin (A1AT) Deficiency

• Congenital Adrenal Hyperplasia

• Ornithine Transcarbamylase (OTC) Deficiency

• Phenylketonuria (PKU)

• Wilson disease

Neurological disorders

Other

• Danon Disease

• Fabry’s disease

• GM1

• GM2

• MPS IIIA

• MPS IIIB

• Pompe disease

• Batten Disease (CLN1)

• Batten Disease (CLN3)

• Cerebral

adrenoleukodystrophy

(CALD)

• β-Thalassemia

• Hemophilia A

• Hemophilia B

• Hereditary Angioedema

• Sickle Cell Disease


Dermatology

04.1


Epidermolysis bullosa (EB) encompasses a family of rare inherited diseases

that are characterized by skin fragility and blistering in response to

mechanical trauma. The prevalence is estimated to be ~1 in 30,000–50,000

people, or 1,100–2,500 patients in the US. More than 30 clinical subtypes of EB

have been described to date, which can be distinguished based on patterns of

structural basement membrane alterations and underlying genetic mutations, 20 of

which are known. The four predominant forms of EB are summarized in Exhibit 29,

below. Clinical phenotypes are heterogeneous and range from mild to severe and

life threatening.

No cure exists for any subtype of EB. Current SOC focuses on skin protection,

constant wound care, and management of secondary comorbidities.

Elucidation of the pathogenetic mechanisms underlying each subtype has

facilitated the design of novel protein and gene therapies that aim to correct the

functional deficiencies that lead to this devastating collection of diseases.

For the purpose of this report, we will focus on novel gene therapies that are

currently in development for the treatment of recessive DEB (RDEB).

RDEB is caused by mutations in the COL7A1 gene that lead to a deficiency in

collagen VII gene and subsequent separation of the sublamina densa. This results

in painful blistering and epidermal erosion of the skin and mucous membranes.

Gene therapy approaches aim to deliver wildtype COL7A1 cDNA to the skin

to restore functional collage VII (C7) production and skin integrity. On the

following page we summarize gene therapies in Phase I/II clinical trials and beyond

for RDEB, some of which are described in more detail later in the report. A number

of additional companies are in preclinical stages of RDEB gene therapy

development, and are not covered by this report.

Gene Therapy for Epidermolysis Bullosa

Genetic Mutations and Splitting Sites Underlying EB

Source: Kiritsi D & Nyström A. F1000Res. 2018 Jul 17;7. pii: F1000 Faculty Rev-1097. Bhattacharjee O et al. Front Cell Dev Biol. 2019; 7: 68. Piper Jaffray Research.

EXHIBIT 30

Subtype Structural

Change

Gene

MutationProtein Deficiency

EB Simplex

(EBS)

Intraepidermal

split

KRT5

KRT14

Keratin 5 and keratin 14

Abnormal intermediate filaments

Junctional EB

(JEB)

Separation within

lamina lucida LAMB3

Laminen-332

Abnormal anchoring filaments

Dystrophic EB

(DEB)

Sublamina densa

separationCOL7A1

Collagen VII

Anchoring fibril deficiency

Kindler

Syndrome

Various split

levelsFERMT1

Kindlin-1

Focal adhesion/growth

deficiency

EXHIBIT 29

Main Subtypes of EB


All current clinical-stage therapies aim to deliver wildtype COL7A1 gene to patient keratinocytes in order to drive expression of normal Type VII collagen and

restore anchoring fibrils and skin function. The therapies differ in terms of vector employed (adenoviral, lentiviral, retroviral), target cell (keratinocytes, epidermal stem

cells, dermal fibroblasts) and mode of administration (skin graft vs intradermal injection). Key features of clinical stage RDEB assets are outlined below. Available clinical

data for select companies are described in Section 5 of the report.

Gene Therapies Landscape: Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Source: Company Reports. Piper Jaffray Research.

EXHIBIT 31

Clinical Stage Companies Developing Gene Therapies for Recessive Dystrophic EB

Company Ticker Drug Vector (Gene) Mode of AdministrationDevelopment

StageNotes

Abeona

TherapeuticsABEO

EB-101Retrovirus

(COL7A1)

• Skin graft: autologous keratinocytes

• LZRSE-Col7A1 Engineered Autologous

Epidermal Sheets (LEAES)

Phase I/II• Initiating Phase III

mid-2019

EB-201AAV

(COL7A1)

• Skin graft: autologous keratinocytes

• AAV-mediated gene editing and delivery

approach

Preclinical• No data presented at

this time

Fibrocell Science FCSC FCX-007Lentivirus

(COL7A1)

• Intradermal injection: autologous

fibroblastsPhase I/II

• Phase III trial initiation

expected 2Q19

• If successful, BLA filing

expected 2021

Holostem Terapie

AvanzatePrivate Hologene 7

Retrovirus

(COL7A1)

• Skin graft: autologous cultured

epidermal grafts containing epidermal

stem cells

Phase I/II • Clinical trial recruiting

Krystal Biotech KRYS

KB103

(Bercolagene

Telserpavec)

HSV1

STAR-D platform

(COL7A1)

• Topical formulation: Off-the-shelf, non-

invasive modified HSV-1 therapyPhase II

• Pivotal Phase III trial to

initiate 2H19

• BLA filing expected

1H20


Several lessons have been learned from initial clinical trials in both

RDEB and JEB.

The large size of the COL7A1 cDNA (8,833 nucleotide open reading frame) has

presented several challenges in terms of limiting transduction efficiency, virus

packaging, and viral titer.

Vector selection: Both lentiviral and retroviral vectors are being explored in

clinical-stage gene therapy trials for RDEB.

• Retroviral vectors still carry safety concerns relating to the risk for oncogenesis

due to random integration, especially given the tumor susceptible

microenvironment of DEB skin. However, this risk is somewhat alleviated by the

ease of monitoring the skin for, and excising, any carcinogenic effects.

Advantages include stable gene expression and low immunogenicity

• Replication-defective non-integrating HSV-1 vectors have a high payload

capacity to accommodate the large COL7A1 cDNA, efficiently penetrate skin

cells following topical application, and exhibit low immunogenicity

• Lentiviral vectors facilitate direct delivery of COL7A1 to skin cells via intradermal

injection of C7-expressing keratinocytes, which, unlike genetically-corrected

epidermal graft therapy, does not require anesthesia or hospitalization

Mode of administration. Three main modes of gene therapy delivery are currently

employed by assets in clinical trials, epidermal sheet graft, local intradermal

injection, and topical application to wounds. Transplantation of epidermal sheet

grafts requires immobilization of grafts for several days following placement, which

can be challenging depending on the wound location. Local intraepidermal injection

offers targeted delivery of gene therapy, but may be more likely to initiate

immunogenic reactions at the injection site. Topical application may be the simplest

approach, facilitating treatment by dermatologists vs specialists.

Durability: Preliminary data from small clinical trials of keratinocyte grafts suggest

that the durability of gene therapy responses in EB may be influenced by the

following factors:

• Transduction efficiency and successful delivery of stem cells to the skin

• Whether gene-corrected cells confer a selective advantage over nontransduced

resident skin cells

• Age-related decline in the regenerative potential of patient keratinocytes

• Pre-existing immunogenicity and alloreactivity to the therapeutic gene product

While initial data with keratinocyte grafts certainly suggest a clinical

advantage over the current SoC for RDEB, the relatively short half life of C7

points to an anticipated need for repeated grafts or other local treatments, a

far cry from a desired single-dose gene therapy. The need for repeated

treatments raises several concerns, such as a) repeated biopsying of patients to

collect autologous keratinocytes/skin cells for transduction, b) potentially increased

immunogenicity/development of neutralizing antibodies, c) repeated costs. Local

administration vs systemic correction of C7 also clearly lacks the potential to ‘cure’

DEB, as the approach is limited to treating existing wounds rather than preventing

their occurrence in the first place.

The factors described above provide a number of considerations for gene therapy

product design, mode of delivery, and potential patient inclusion criteria for

clinical trials. Specific trial information and data from select companies will be

discussed in the following section of this report.

Specific Considerations for RDEB Gene Therapy

Source: Marinkovich MP & Tang JY. J Invest Dermatol. 2019;139:1221e1226. Company Reports. Piper Jaffray Research.


Hematology

04.2


Gene therapy for the correction of inherited blood disorders. Similar to other

indications, inherited hematologic disorders or those blood disorders caused by a

single gene variant are the best candidates for treatment. Inherited genetic

alterations are responsible for a range of devastating hematological diseases

including β-thalassemia, sickle cell disease, and other hemoglobinopathies, as well

as bleeding disorders such as hemophilia. Correction of the causal single gene

defect could potentially provide a one-time, curative treatment approach rather than

the current lifelong, multidisciplinary disease management and treatment SOC.

Hemophilia is a group of inherited, genetic disorders that impairs the body’s

ability to clot blood. There are two forms of hemophilia that are caused by

mutations in genes that encode Factor VIII (F8, Hem A) and Factor IX (F9, Hem B),

with different mutations variably affecting levels of factor activity, blood clotting

ability, and severity of disease. While injuries/lacerations may cause potentially

life-threatening bleeding, patients may also experience spontaneous bleeds into

joints and other tissues, causing significant tissue damage. There is no cure for

hemophilia, but current treatment significantly improves patient outcomes, quality of

life (QoL), and life expectancy.

Hemoglobinopathies are a group of blood disorders that impair production of

hemoglobin by red blood cells (RBCs). These disorders fall into two main

categories – thalassemia syndromes and structural hemoglobin variants. Clinical

manifestations of hemoglobinopathies are highly variable and range from mild

hypochromic anemia to moderate hematological disease to severe, lifelong,

transfusion-dependent anemia with multiorgan involvement. In this section, we

highlight two hemoglobinopathies, β-thalassemia and sickle cell disease, for which

gene therapy development is currently ongoing.

Briefly, β-thalassemias are autosomal recessive diseases caused by the

insufficient production of β-globin chains, a key protein subunit of

hemoglobin. Generally, mutations are grouped as those that cause zero functional

β-globin production (β0) or reduced functional β-globin (β+). For severely affected

patients, the disease state requires chronic blood transfusions with healthy RBCs

every 3–5 weeks to maintain hemoglobin levels and control disease. However,

chronic use has the potential to induce iron overload, and results in significantly

increased mortality risk due to heart and liver toxicity.

Sickle cell disease is a life-threatening inherited hematological disorder

characterized by abnormally shaped RBCs which disrupt blood flow in small

blood vessels. A single point mutation in the beta-chain of hemoglobin causes

abnormal sickle hemoglobin (HbS) formation, leading to lower affinity for oxygen.

Over time repeated RBC sickling and ongoing hemolytic anemia result in organ

damage and substantial morbidity and mortality. Treatment is primarily geared

towards reducing symptoms and is not universally effective.

Thus, for both β-thalassemia and sickle cell disease, single gene replacement of

the non-functional or dysfunctional β-globin gene presents a compelling option to

life-long treatment.

Gene Therapy for Hematologic Disorders

Source: QURE R&D Day 2018. Company Reports. Piper Jaffray Research.

EXHIBIT 32

The Coagulation Cascade


Selected Gene Therapy-amenable Hematologic Disorders

Source: Company Reports. NORD. Piper Jaffray Research.

EXHIBIT 33

Rationale for Targeting Select Hematological Disorders With Gene Therapy: Blood Clotting Disorders

Disease US Prevalence Disease Background Unmet Need Gene Therapy Rationale & Approach

Hemophilia A ~15,000

• Bleeding disorder caused by

insufficient levels of the blood clotting

protein, factor VIII (F8)

• ~70% of cases are inherited, X-linked

recessive; ~30% occur spontaneously

• Patients are classified as mild

(6%–30% of normal F8 levels; 30% of

patients), moderate (1%–5% of normal

F8; 20% of patients), and severe

(<1% of normal F8; 50% of patients)

• Age of diagnosis depends on disease

severity – mild: 36 months, moderate:

8 months, severe: 1 month

• Clotting factor replacement treatment

is the current SOC for patients, but

treatment must be administered for

the life of the patient

• Maintaining a level of no or very low

bleeding rates is critically important,

but recurring bleeds, including joint

bleeds, do occur which can result in

debilitating disease and chronic pain

• Gene therapy reduces treatment

burden and improves QoL with a

one-time treatment

• Consistent levels of F8 provide better

protection from bleeding episodes due

to spontaneous or traumatic events

• Though F8 gene is large with over

200 disease alleles described in

HemA, disorder can be treated by

replacing the non-functional/

dysfunctional gene with a modified

version of F8 (B-domain deleted)

Hemophilia B ~6,000

• Bleeding disorder caused by defective

or insufficient levels of the blood

clotting protein, factor IX (F9)

• 70% inherited x-linked recessive;

30% spontaneous

• Classified mild/moderate/severe

(see above)

• Age of diagnosis depends on disease

severity – mild: 36 months, moderate:

8 months, severe: 1 month

• Gene therapy reduces treatment

burden and improves QoL with a

one-time treatment

• Consistent levels of F9 provide better

protection from bleeding episodes due

to spontaneous or traumatic events

• Disorder can be treated by replacing

the non-functional/dysfunctional gene


Selected Gene Therapy-amenable Hematologic Disorders


EXHIBIT 34

Rationale for Targeting Select Hematological Disorders With Gene Therapy: Hemoglobinopathies + Others


β-Thalassemia ~5,000

• Blood disorder that reduces the

production of hemoglobin, the iron-

containing protein in RBCs that carries

oxygen to cells throughout the body

• Caused by mutations in the HBB

gene, which encodes beta-globin, a

subunit of hemoglobin

• 60%–80% of patients require

regular red-cell transfusions and

iron chelation for proper treatment of

the disease (transfusions Q3–5 wks)

• Chronic transfusions may lead to

iron overload, significantly increasing

mortality risk due to heart and

liver toxicity

• A single treatment to genetically

modify a patient’s hematopoietic stem

cells to replace the dysfunctional

HBB gene

Sickle Cell Disease ~50,000

• An inherited disease caused by

defects in the beta-globin gene (HBB)

• ~65k patients with HbSS genotype

• Mutated hemoglobin polymerizes and

causes RBCs to form a “sickle” shape

which causes RBC aggregation –

restricts blood flow to organs, causes

pain, cell death, and organ damage

• Hydroxyurea is the current SOC

(promotes expression of normally-

repressed fetal hemoglobin), but

causes severe side effects – reduced

white blood cell and platelet counts

• Bone marrow transplant also an

option, but less than 10% of patients

are eligible due to donor

matching/availability

• A single treatment to genetically

modify a patient’s hematopoietic stem

cells to replace the dysfunctional

HBB gene

Hereditary

Angioedema~7,000

• Several types of HAE - Types I and II

caused by genetic mutations in C1NH

(aka SERPING1) which encodes C1

esterase inhibitor (C1-INH), a protein

that regulates kallikrein

• Lack of kallikrein regulation puts

patients at risk of uncontrolled

swelling attacks that can be life

threatening

• Inheritance of Types I and II are

autosomal dominant

• Age of onset varies, but most people

have first attack in childhood or

adolescence; frequency of attacks

increases after puberty

• Current SOC involves frequent

infusions or injections of plasma-

derived C1-INH to prevent swelling

• Response to treatment varies patient

to patient; long-term patient outlook

varies depending on the frequency

and location of attacks

• Replacement of the C1-INH gene


Early setbacks, but the science behind gene therapy has rapidly evolved.

As we've gained greater knowledge and a better understanding of viruses and their

underlying biology, researchers have continued to unlock ways to design safer and

more effective gene therapies. It wasn't that long ago that initial challenges were

encountered for Hem B AAV gene therapies, which drove immunological

responses, resulting in the clearance of functional protein product. Ex vivo gene

therapy for hemoglobinopathies has also met with its share of setbacks, with early

challenges of transplant-related toxicities and leukemia induced by viral vector

integration into the host genome. However, the field has made giant strides

forward, even in just the past few years, as we've gained more clinical experience,

created better recombinant viruses, and improved the design of gene

therapy cassettes.

Considerations for hemophilia treatments – durability is key. Though SOC for

patients with hemophilia has its limitations, in relation to many other diseases,

hemophilia patients have access to reasonably effective treatment options. In this

regard, while gene therapy is potentially transformative for these patients, products

need to demonstrate not only efficacy and safety, but also long-term duration of

expression to help support the price tag that comes along with these treatments.

Currently, most competitors in clinical development are taking similar approaches

for the treatment of Hem A and Hem B – targeting the liver with a recombinant AAV

gene therapy (eg, AAV5), and using a modified F8 (B-domain deleted) or

F9 (gain of function Padua mutation) gene to replace the underlying dysfunctional

protein. The design and manufacturing of these vectors is important for the safety,

efficacy, and durability of treatment, and while safety and efficacy have both been

demonstrated in clinical trials thus far, durability remains an unanswered question.

In the end, the gene therapy treatment that produces durable responses –

sustained expression of clotting factor, no or very few spontaneous bleeds, and

avoidance of arthropathy – will be crowned the winner.

Considerations for the treatment of hemoglobinopathies – is ex vivo gene

replacement the best strategy? Transplantation of autologous, genetically

corrected hematopoietic stem cells (HSCs) is one approach being developed by

multiple companies for the treatment of β-thalassemia and sickle cell disease.

Thus far, the strategy has been safe and effective, but key questions remain as to

the longevity of treatment as well as the cost and complexity of both the lentiviral

vector and ex vivo manufacturing process – the latter being a key concern as

patients affected by these disorders skew towards lower socioeconomic conditions.

However, companies continue improving this approach with innovation ongoing in

HSC procurement, transduction, and transplantation efficiency.

As an offset, we note that additional treatment strategies are currently being

developed for β-thalassemia and sickle cell disease including AAV delivery of

CRISPR/Cas9 to drive endogenous fetal hemoglobin production, as well as oral

compounds with disease modifying capabilities (eg, GBT’s voxelotor) that may

prove to be more durable or convenient approaches to disease management.

That said, it’s still too early in the game to know for sure who the winner will

be here.

Gene Therapy for Hematologic Disorders: Special Considerations for Select Indications



Gene Therapies Landscape: Hematological Disorders – Hemophilia A

Source: Company Reports. GlobalData. Piper Jaffray Research.

EXHIBIT 35

Companies Developing Gene Therapies for Hemophilia A

Company Ticker Disorder Asset Vector Target Gene Stage of Development

BioMarin

PharmaceuticalBMRN Hem A

Valoctocogene

roxaparvovec

(valrox, BMN 270)

rAAV5 F8 (B-domain deleted) Phase III

Spark

TherapeuticsONCE Hem A SPK-8011 Novel rAAV F8 (B-domain deleted) Phase III

Bayer/

Ultragenyx

BAYRY/

RAREHem A DTX-201 rAAV F8 Phase II

Sangamo

TherapeuticsSGMO Hem A SB-525 rAAV6 F8 (B-domain deleted) Phase I/II

Takeda

PharmaceuticalTAK Hem A TAK-754 rAAV F8 Phase I

UniQure QURE Hem A AMT-180 rAAV5FIX-FIAV

(activates FX in absence of FVIII)Preclinical

Expression

TherapeuticsPrivate Hem A Undisclosed Lentivirus F8 Preclinical

Expression

TherapeuticsPrivate Hem A Undisclosed rAAV F8 Preclinical


Gene Therapies Landscape: Hematological Disorders – Hemophilia B


EXHIBIT 36

Companies Developing Gene Therapies for Hemophilia B


Spark

TherapeuticsONCE Hem B

Fidanacogene

elaparvovec

(SPK-9001)

AAV F9 (Padua variant) Phase III

UniQure QURE Hem B AMT-061 AAV5 F9 (Padua variant) Phase III

Freeline

TherapeuticsPrivate Hem B FLT-180a AAVS3 F9 (Padua variant) Phase I/II

Expression

TherapeuticsPrivate Hem B Undisclosed AAV F9 Preclinical

Takeda

PharmaceuticalTAK Hem B SHP648 Undisclosed F9 Preclinical

Logicbio

TherapeuticsLOGC Hem B LB-101 AAV F9 Preclinical/Discovery

Catalyst

BiosciencesCBIO Hem B CB 2679d-GT AAV8 F9 (patented sequence) Preclinical


Gene Therapies Landscape: Hematological Disorders – β-Thalassemia, Sickle Cell, Hereditary Angioedema


EXHIBIT 37

Companies Developing Gene Therapies for Hematological Disorders


bluebird bio BLUE β-thalassemia LentiGlobin LentivirusHBB

(Beta-globin, T87Q variant)Phase III

Orchard

TherapeuticsORTX β-thalassemia OTL-300 Lentivirus

HBB

(Beta-globin)Phase I/II

Aruvant

SciencesPrivate β-thalassemia ARU-1801 Lentivirus Modified fetal hemoglobin Phase I/II

Errant Gene

TherapeuticsPrivate β-thalassemia Thalagen Lentivirus

HBB

(Beta-globin)Preclinical

bluebird bio BLUE Sickle cell disease LentiGlobin LentivirusHBB

(Beta-globin)Phase II

Aruvant

SciencesPrivate Sickle cell disease ARU-1801 Lentivirus Modified fetal hemoglobin Preclinical

CSL Behring CSL:AUΒ-thalassemia,

sickle cell diseaseCAL-H Lentivirus Gamma-globin Preclinical

Adverum

BiotechnologiesADVM

Hereditary

angioedemaADVM-053 AAVrh.10 C1INH Preclinical


Inborn errors of metabolism• Lysosomal storage disorders

• Neurological disorders

• Other

04.3


Lysosomal storage disorders: A family of ~70 genetically distinct diseases

with a monogenic basis. LSDs are rare, inherited metabolic disorders primarily

characterized by dysfunction of lysosomes – membrane-enclosed organelles filled

with enzymes (>60) that function to break down different types of biological

products (eg, proteins, lipids, carbohydrates) within cells. When one of these

enzymes is dysfunctional or non-functional, progressive accumulation of biological

products occurs, driving cellular dysfunction, oxidative stress, inflammation, and

impaired organ function in tissues throughout the body, ultimately resulting in

death. While each LSD is individually rare, collectively these disorders are

common, with a frequency of ~1 in 7,000 births.

For a small number of LSDs, enzyme replacement therapy (ERT) provides a

disease modifying option, but the vast majority of disorders lack effective

therapies. ERTs are recombinant enzymes (proteins) that transiently replace the

missing or defective enzyme that causes the disease. The first ERT was approved

in 1991 for the treatment of Gaucher disease, and while additional ERTs have been

approved since that time, approved treatments have only been developed for eight

LSDs: Fabry disease, Gaucher disease, lysosomal acid lipase deficiency, MPS I,

MPS II, MPS IVA, MPS VI, and Pompe disease.

While ERTs reduce the severity of disease for many patients, recombinant

enzymes (generally) degrade rapidly and require frequent dosing (Q1W,

Q2W), which leads to fluctuations in enzyme levels over time, allowing the disease

to progress. In addition, ERTs are unable to cross the blood brain barrier (BBB),

presenting a challenge for LSDs that primarily affect the CNS, and though some

disorders can be treated by administering ERTs intra-cerebroventricularly or

intrathecally, a number of complications may arise. Since LSDs are monogenic

(single gene) disorders, and the enzymes are not subject to complex regulatory

mechanisms, these disorders are excellent candidates for treatment with

gene therapy.

There’s no one and done way to treat all LSDs; the approach to gene delivery

depends on the disorder. Though LSDs share a common feature (enzyme

dysfunction in lysosomes), the approach to delivering the functional gene of interest

depends on the underlying disease (i.e., affected tissues, need for episomal vs

integrated DNA). With >65% of LSDs having a neurological component, accounting

for the need to deliver genetic material to the CNS is one of the most important

considerations. Currently, there are three main approaches used in clinical

development for the treatment of LSDs using gene therapy: (1) systemically

delivered vectors, (2) direct delivery of vectors to the CNS, and (3) ex vivo gene

therapy. We describe these approaches in more detail on the following page.

Gene Therapy for Lysosomal Storage Disorders and Specific Considerations (Page 1 of 2)

Prevalence of Lysosomal Storage Disorders


EXHIBIT 38


Systemic administration using AAVs. This approach involves the direct delivery

of a gene into an organ so that the gene product will not only correct the locally

transduced cells, but will also be secreted at high levels and subsequently

recaptured by other cell types via the mannose-6-phosphate receptor (though we

do note that M6P receptor expression varies between tissues types, thus not all

tissues may be treated equally). The secreted enzyme cannot cross the BBB,

therefore the benefits of this approach are generally limited to the peripheral

organs. However, certain AAV serotypes (eg, AAV9) do penetrate the BBB and can

infect cells in both the CNS and in other tissues throughout the body when given

systemically. Thus, choosing the proper capsid allows for a potentially “one and

done” treatment strategy when administered via IV.

Direct CNS administration of AAVs. Alternatively, AAVs can be directly injected

into the CNS utilizing different types of delivery methods (eg, intra-parenchymal,

intrathecal). This method bypasses the viscera and generally keeps viral

transduction and enzyme expression restricted to the brain and spinal cord.

AAV serotype remains a key factor to ensure the proper transduction of cells

(i.e., neurons, oligodendrocytes, and/or astrocytes).

Additional ways to deliver functional enzyme to the CNS: Ex vivo lentiviral

treatment of hematopoietic stem cells. For LSDs affecting the CNS, modifying

hematopoietic stem cells (HSCs) also presents a viable option for gene therapy

treatment. In this approach, autologous CD34+ HSCs are isolated from a patient

and modified outside of the body (ex vivo) with a viral vector. Because these stem

cells will regraft in the bone marrow of the patient and be maintained long-term,

utilizing a virus that integrates into the host genome is the most effective approach

with this strategy. Thus, autologous CD34+ HSCs are transduced with a lentivirus,

and cells with a successfully integrated copy of the functional gene are infused

back into the patient. Following this, partially differentiated hematopoietic cells can

produce other immune cells within the body, but can also cross the BBB where

they subsequently differentiate into microglia. These resident CNS immune cells

then produce functional enzyme within in the brain.

Gene Therapy for Lysosomal Storage Disorders and Specific Considerations (Page 2 of 2)



Selected Gene Therapy-amenable Lysosomal Storage Disorders

Source: Company Reports. NORD. NIH Rare Diseases. Piper Jaffray Research.

EXHIBIT 39

Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy


Fabry Disease ~4,000-5,000

• Caused by mutations in α-

galactosidase A gene (AGA)

• Enzyme deficiency causes build up of

glycolipids in the body that particularly

affect small blood vessels, heart,

and kidneys

• X-linked dominant inheritance

• Age of onset varies by disease type

(Type 1: Classic; Type 2: Later Onset)

• Symptoms lead to renal failure,

cardiac disease, early death

• No cure or standard treatment for

patients; because disease causes

multi-organ dysfunction, patients need

individually tailored comprehensive,

multi-disciplinary treatment

• Enzyme replacement therapy (ERT) is

a cornerstone of treatment and must

be initiated early for best results

• Single gene replacement of AGA via

lentiviral or AAV gene delivery

MPS IIIA ~600

• Caused by mutation in SGSH

• Autosomal recessive inheritance

• Signs and symptoms usually begin in

early childhood (1-4 years) and

include severe neurological symptoms

such as progressive dementia,

aggressive behavior, hyperactivity,

seizures, deafness, and loss of vision

• No cure or standard treatment for

patients; medications are used to

relieve symptoms (eg, anticonvulsants

for seizures) and improve QoL

• Single gene replacement of SGSH via


MPS IIIB ~400

• Caused by mutation in NAGLU


• Signs and symptoms the same as

MPS IIIA, but symptom onset slightly

less severe

• No cure or SoCs; medications are

used to relieve symptoms

(eg, anticonvulsants for seizures)

and improve QoL

• Single gene replacement of NAGLU

via lentiviral or AAV gene delivery

Pompe Disease ~3,000

• Caused by mutations in GAA


• Glycogen accumulation affects

muscles causing weakness and

diminished muscle tone; cardiomegaly

also common

• Symptom onset: infantile (after few

months of birth), non-classic infantile

(~1 year of age), late-onset (teenage

years or adulthood)

• Enzyme replacement therapy (ERT)

common, but therapy does not

produce stable GAA levels

• Relative instability of GAA requires

frequent dosing to maintain enzyme

levels

• Patients typically develop an immune

response to ERT

• Single gene replacement of GAA via



Selected Gene Therapy-amenable Lysosomal Storage Disorders

Source: Company Reports. Mytonic Dystrophy Foundation. NORD. Piper Jaffray Research.

EXHIBIT 40



Danon Disease

(GSD IIb)

Unknown

(Est. range

from 1,000-

15,000)

• Caused by mutations in LAMP2, with

>160 different mutations identified

• X-linked dominant inheritance

• Key features are diseased heart

muscle (cardiomyopathy), weakness

of body muscles (skeletal myopathy),

and intellectual disability

• Symptoms of disease vary from

person to person and depend on

gender; boys tend to be more severely

affected than girls

• No curative treatments available

• No symptomatic SoC – treatments

need to be tailored to each individual

and their symptoms

• Current disease management requires

multi-disciplinary team of physicians

(cardiologist, neurologist,

ophthalmologist, geneticist, etc)

• In patients that progress rapidly,

heart transplantation may be need

almost immediately

• Gene replacement of LAMP2 via

AAV gene delivery

GM1

Gangliosidosis<500

• Caused by mutations in GLB1 gene

• Divided into three forms based on

disease onset: type 1 (infantile), type

2 (juvenile), type 3 (adult/chronic)


• Several tissue types are affected,

leading to developmental defects,

enlarged liver and spleen, skeletal

abnormalities, seizures, vision loss

• No curative or disease modifying

treatments available

• Symptomatic treatment for some

neurologic signs are available


• Limited success with cord-blood

HSC transplantation in

presymptomatic patients

• Gene replacement of GLB1 via

AAV gene delivery

GM2

Gangliosidosis<500

• Caused by mutations in HEXA

(Tay-Sachs) or HEXB (Sandhoff

disease) that encode subunits of

beta-hexosaminidase

• Autosomal recessive genetic disorder

• Symptoms include motor delays,

mental deterioration, motor weakness,

heart murmurs, seizures, blindness,

splenomegaly

• Divided by age of disease onset:

infantile/juvenile (3-6 months of age)

and adult

• No curative or disease modifying

treatments available – only

symptomatic therapies

• Death from respiratory infections

usually occurs by age three for the

infantile form

• Symptomatic treatment for some

neurologic signs are available


• Gene replacement of both HEXA and

HEXB via AAV gene delivery


Gene Therapies Landscape: Lysosomal Storage Disorders


EXHIBIT 41

Companies Developing Gene Therapies for Fabry Disease


AVROBIO AVRO Fabry Disease AVR-RD-01 LentivirusAGA

(alpha-galactosidase A)Phase I/II

Abeona

TherapeuticsABEO Fabry Disease Undisclosed AAV

AGA

(alpha-galactosidase A)Preclinical

Amicus

TherapeuticsFOLD Fabry Disease Undisclosed AAV

AGA


Freeline

TherapeuticsPrivate Fabry Disease FLT190 AAV

AGA


Sangamo

TherapeuticsSGMO Fabry Disease ST-920 AAV6

AGA


uniQure QURE Fabry Disease AMT-190 AAVAGA





EXHIBIT 42

Companies Developing Gene Therapies for MPS IIIA and MPS IIIB


Lysogene/

Sarepta

Therapeutics

LYS/

SRPTMPS IIIA LYS-SAF302 AAVrh10 SGSH Phase III

Esteve

PharmaceuticalsPrivate MPS IIIA EGT-101 AAV9 SGSH Phase II

Abeona

TherapeuticsABEO MPS IIIA ABO-102 AAV9 SGSH Phase I/II

Orchard

TherapeuticsORTX MPS IIIA OTL-201 Lentivirus SGSH Preclinical

Abeona

TherapeuticsABEO MPS IIIB ABO-101 AAV9 NAGLU Phase I/II

Orchard

TherapeuticsORTX MPS IIIB OTL-202 Lentivirus NAGLU Preclinical

Esteve

PharmaceuticalsPrivate MPS IIIB EGT-201 AAV9 NAGLU Preclinical




EXHIBIT 43

Companies Developing Gene Therapies for Pompe Disease


Actus

TherapeuticsPrivate Pompe Disease ACTUS-101 AAV2/8 GAA Phase II

Audentes

TherapeuticsBOLD Pompe Disease AT845 AAV8 GAA Preclinical

Spark

TherapeuticsONCE Pompe Disease

SPK-3006

(AAV-sec-GAA)AAV GAA Preclinical

AVROBIO AVRO Pompe Disease AVR-RD-03 Lentivirus GAA Preclinical

Abeona

TherapeuticsABEO Pompe Disease Undisclosed AAV GAA Preclinical

Amicus

TherapeuticsFOLD Pompe Disease Undisclosed AAV GAA Preclinical

Sarepta

TherapeuticsSRPT Pompe Disease Undisclosed AAV GAA Discovery




EXHIBIT 44

Companies Developing Gene Therapies for Danon Disease and GM1/GM2 Gangliosidosis


Rocket Pharma RCKTDanon Disease

(GSDIIIb)RP-A501 AAV9 LAMP2 Phase I

Axovant

SciencesPrivate

GM1

GangliosidosisAXO-AAV-GM1 AAV9

GLB1

(B-galactosidase 1)Phase I/II

Lysogene LYSGM1

GangliosidosisLYS-GM101 AAVrh10

GLB1

(B-galactosidase 1)Preclinical

Passage Bio PrivateGM1

GangliosidosisAXO-AAV-GM1 AAV

GLB1

(B-galactosidase 1)Preclinical

Axovant

SciencesPrivate

GM2

GangliosidosisAXO-AAV-GM2 AAVrh8

HEXA

(Β-hexosaminidase A)Phase I/II


Gene replacement tends to be the modality of choice for in-born metabolic

errors with neurological manifestations. In-born metabolic errors impact a wide

range of physiological systems, including the CNS. In many of these conditions,

neurological function is disrupted when genetic mutations in enzymes lead to

irregular processing of biological compounds. Since these mutations cause loss of

function in enzymes, gene replacement strategies are optimal for functional

restoration. However, certain conditions already have enzyme replacement

therapies that may be effective for disease treatment, so developing gene therapies

for these disorders would need to be justified in terms of efficacy and cost-savings

to be a commercially viable option.

With some exceptions, considerations for gene therapy for in-born metabolic

conditions that affect the CNS are similar to other neurological conditions.

Various factors involved in gene therapies for neurological conditions have been

discussed elsewhere in this report; metabolic conditions that affect the CNS must

also consider the same aspects as these neurological conditions, such as the site

of administration. However, a few factors are not as challenging to address, making

gene therapy development for in-born metabolic errors with neurological

manifestations less complicated. For example, many of the mutated enzymes and

proteins involved in these conditions are soluble and capable of being secreted and

taken up by cells. This characteristic lowers the viral load required from gene

therapy since fewer cells need to be transduced for a system-wide impact. Intrinsic

obstacles of gene therapies, like the risk of immune response, still exist but are not

as high due to the lower viral load.

Treatments must be designed for pediatric patients with these types of

disorders. Onset of disorders of metabolic errors typically occurs at birth or during

childhood. In metabolic disorders with neurological manifestations, this generally

leads to progressive, systemic loss of normal body function during the childhood

and adolescent years. Many of these disorders eventually lead to full dependence

on caregivers and eventual death due to respiratory or cardiac issues. With the

early age of onset and rapid progression of diseases, gene therapies within this

sector must be designed to be administered to a young population.

Many of these disease are ultra-rare, leading to limited interest but also

additional opportunities. While the ultra-rare nature of some these conditions

keeps companies from developing gene therapies for them, the high unmet need

also makes them ideal candidates to provide proof-of-concept of their potential in

treating some of the most devastating diseases. For example, bluebird bio is

developing its Lenti-D therapy for the ultra-orphan indication, cerebral

adrenoleukodystrophy (CALD), which to date has demonstrated meaningful benefit

to patients and highlights the power of their HSC technology platform (see below).

Gene Therapy for In-born Metabolic Errors (Neurological Disorders) & Related Considerations

bluebird bio’s approach to gene therapy for CALD

Source: bluebird bio Company Reports. Piper Jaffray Research.

EXHIBIT 45


Selected Gene Therapy-amenable In-born Metabolic Errors (Neurological Disorders)

Source: NINDS. GHR. Company Reports. Piper Jaffray Research.

EXHIBIT 46

Rationale for Targeting Select Musculoskeletal Disorders With Gene Therapy (1 of 2)

DiseaseUS

PrevalenceDisease Background Unmet Need

Potential Gene Therapy Rationale &

Approach

Batten Disease

(CLN1 - infantile)~3,000

• Mutation in CLN1 gene leads to build up of

lipids and proteins

• Onset by 1 year, some at 5 or 6 years

• Symptoms include loss of motor function,

seizures, blindness

• No cure, antiepileptics for seizures

• Feeding tube after 3–4 years

• Death by early-to-mid childhood

(except for juvenile form)

• Gene replacement of CLN1 gene

(PPT1 protein) via gene therapy

Batten Disease

(CLN3 - juvenile)~5,000

• Mutation in CLN3 gene leads to build up of

lipids and proteins

• Onset at 4–7 years

• Symptoms include blindness, learning and

behavioral problems, dementia, seizures,

loss of balance, and stiffness

• No cure, antiepileptics for seizures

• Caregiver-dependent by teenage

years

• Death by age 15–30 years

• Gene replacement of CLN3 gene

(batennin protein) via gene therapy

Cerebral

Adrenoleuko-

dystrophy

(CALD)

<500

(worldwide)

• X-linked recessive condition caused by

mutation in the ABCD1 gene that leads to

rapid neurological function loss and death

• Onset in early childhood

• Symptoms include hormonal deficiencies

and downstream affects like abnormal

blood pressure, heart rate, and sexual

development

• No cure, QoL treatments

• Six major functional disabilities:

communication loss, cortical

blindness, total incontinence,

wheelchair dependence, and

complete loss of voluntary movement

• Death within 1–10 years after onset

• Gene replacement of ABCD1 gene

(ABCD1 protein) via gene therapy


Selected Gene Therapy-amenable In-born Metabolic Errors (Neurological Disorders)


Source: Company Reports. Myotonic Dystrophy Foundation, NORD. Piper Jaffray Research.

Companies Developing Gene Therapies for Inborn Errors of Metabolism (Neurological)


Abeona

TherapeuticsABEO Batten Disease ABO-201 AAV9 CLN3 Phase I/II

Abeona

TherapeuticsABEO Batten Disease ABO-202 AAV9 CLN1 Phase I/II

Amicus

Therapeutics FOLD Batten Disease AAV-CLN6 AAV9 CLN6 Phase I/II

Amicus

Therapeutics FOLD Batten Disease AAV-CLN8 AAV9 CLN8 Phase I/II

Amicus

Therapeutics FOLD Batten Disease AAV-CLN3 AAV CLN3 Phase I/II

Amicus

Therapeutics FOLD Batten Disease AAV-CLN1 AAV9 CLN1 Preclinical

bluebird bio BLUE

Cerebral

Adrenoleukodystrophy

(CALD)

ALD-102

ALD-104Lenti-D ABCD1 Phase II/III

EXHIBIT 47


Other Selected Gene Therapy-Amenable Inborn Errors of Metabolism


EXHIBIT 48

Rationale for Targeting Other Select Metabolic Disorders With Gene Therapy


Alpha-1 Antitrypsin

(A1AT) Deficiency~100,000

• Autosomal codominant disorder

caused by mutations in the

SERPINA1 gene that leads to

dysfunctional alpha-1 antitrypsin

• Onset of lung disease at 20–50 years;

liver disease occurs in infants

• Symptoms: Shortness of breath,

fatigue, emphysema, jaundice,

cirrhosis

• Emphysema is managed with

bronchodilators, steroids, or oxygen,

but QoL is greatly impaired

• Treatment for liver disease is limited

due to lack of approved therapies

• A1AT patients may have normal life

expectancy. However, smoking may

exacerbate lung symptoms and result

in faster decline

• AAV delivery of functional A1AT gene

to liver cells aims to replace

dysfunctional neutrophil elastase

activity in the lungs. The goal of this

treatment is to protect the lung against

proteolytic damage and restore lung

health in A1AT patients

Congenital Adrenal

Hyperplasia (CAH)~30,000

• Autosomal recessive disorder caused

by mutations in the CYP21 gene,

encoding 21-hydroxylase (21OH)

• Onset typically during adolescence

• Symptoms: Adrenal crisis due to

cortisol deficiency, salt-wasting

disease due to aldosterone

imbalance, excess testosterone leads

to virilization, infertility

• Steroid supplementation is the SoC

to improve basal cortisol and

suppress ACTH

• Standard steroids offer a marginal

benefit to patients and carry serious

toxicities related to long-term use

• Patient mortality is three times higher

than healthy peers

• AAV delivery of the CYP21A2 gene

to adrenal cortex cells restores

homeostatic control of adrenal

hormones

• 21OH increases aldosterone and

cortisol production, while reducing

testosterone, thereby mitigatin the risk

of adrenal crisis

Ornithine

Transcarbamylase

(OTC) Deficiency

~2,500

• X-linked recessive disorder caused

by mutation in the OTC gene, which

encodes a liver enzyme responsible

for detoxification of ammonia

• Onset occurs during childhood

• Symptoms: excessive levels of

ammonia in their blood can potentially

result in neurological deficits

• Arginine-rich, protein-restricted diets

are used to manage OTC disease

• Ammonia concentrations may still

persist despite dietary changes

• Patients with <2% of normal OTC

activity die within one week;

14% activity leads to normal

development with diet restriction

• AAV delivery of the OTC gene with

the goal of reducing the occurrence

of cognitive and neurological

complications associated with

ammonia buildup due to OTC

deficiency

Phenylketonuria

(PKU)~15,000


by mutations in the PAH gene

encoding phenylalanine hydroxylase

• Onset occurs within months of life

• Symptoms: Drowsiness, listlessness,

and difficulties feeding. Severe infants

develop intellectual disability,

seizures, and psychiatric disorders

• Brain phenylalanine levels mainly

controlled by diet; may also be treated

with Kuvan or Palynziq (BioMarin,

covered by Chris Raymond)

• Treatment must be started at a very

young age (under 3 months)

• Life expectancy may be normal if diet

is maintained indefinitely

• Hematopoietic stem cell-derived AAV

delivery of a functional copy of the

PAH gene to liver cells aims to

restore the normal phenylalanine

metabolic pathway


Other Selected Gene Therapy-Amenable Inborn Errors of Metabolism


EXHIBIT 49

Rationale for Targeting Other Select Metabolic Disorders With Gene Therapy


Wilson’s Disease ~10,000

• Autosomal recessive disorder

caused by mutations in the ATP7B

gene encoding a copper-transporting

ATPase

• Onset as early as 2 years old

• Symptoms: Toxic accumulation of

copper in the liver and CNS,

resulting in chronic cirrhosis, tremors,

and migraines

• Decoppering is achieved with copper

chelators (D-penicillamine), and a low

copper diet, maintained indefinitely

• Up to 50% non-compliance to

treatment and up to 24% of patients

with neurological or liver disease

progression despite treatment

• Without treatment, life expectancy is

estimated to be 40 years

• AAV delivery of APT7B gene to the

liver to restore physiological copper

metabolism, optimize adherence to

treatment, and prevent disease

complications such as neurological

deterioration, psychiatric

manifestations and progressive

liver diseases


Gene Therapies Landscape: Other Inborn Errors of Metabolism


EXHIBIT 50

Select Companies Developing Gene Therapies for Other Inborn Errors of Metabolism


BridgeBio

(Adrenas)BBIO

Congenital Adrenal

Hyperplasia (CAH)BBP-631 AAV5 CYP21A2 (21OH) Preclinical

Ultragenyx RARE

Ornithine

Transcarbamylase

(OTC) Deficiency

DTX301 AAV8 OTC Phase I

Homology

MedicinesFIXX Phenylketonuria (PKU) HMI-102 AAVHSC PAH Phase I/II

BioMarin BMRN Phenylketonuria (PKU) BMN 307 AAV5 PAH Preclinical

Ultragenyx RARE Phenylketonuria (PKU) UX-501 AAV8 PAH Preclinical

Pfizer (Vivet) PFE Wilson’s Disease VTX-801Proprietary liver-trophic

AAVAPT7B Phase I/II

Ultragenyx RARE Wilson disease UX701 AAV APT7B Phase I/II


Musculoskeletal

04.4


Musculoskeletal diseases are uniquely suited for gene therapies. Genetic

musculoskeletal diseases are of particular interest as targets for gene therapies

due to a multitude of factors. Skeletal muscles do not divide after they are formed,

which protects against durability loss from the transient transduction of vectors.

Additionally, many of these disorders are monogenic with well-known

pathophysiologies but have a high unmet need for treatments. Since the

pathophysiologies can overlap for these disorders, this presents the possibility of

viral vectors and constructs being useful in multiple indications.

Many musculoskeletal disorders amenable to gene replacement are related to

the dystrophin-associated glycoprotein (DAG) complex. The DAG complex is

responsible for connecting the cytoskeleton to the extracellular matrix. The complex

houses key sub-complexes and proteins that maintain structural integrity of the

musculature and facilitate signaling from the external musculoskeletal junction into

the cell. Malfunctioning proteins normally involved in the DAG complex can

generate several types of muscular dystrophies (see Exhibit 51, right) by disrupting

proper formation and function of the complex. Gene therapies targeting these

disorders are ultimately aiming to restore DAG complex functionality by replacing

the effected protein within it.

Other musculoskeletal disorders require different modalities of action

through gene therapy. Certain musculoskeletal disorders result from progressive

nucleotide repeats within a gene. These repeats cause build up of protein and

RNA aggregates that cannot be broken down. Unlike DAG complex-related

dystrophies, these conditions are better suited for exon-skipping or target

knockdown gene therapies, which can reduce the amount of toxic protein, instead

of gene replacement.

Gene Therapy for Musculoskeletal Disorders

The DAG Complex & associated musculoskeletal disorders

Source: Company Reports. Sarepta R&D Day Presentation 2018. Piper Jaffray Research.

EXHIBIT 51

Sarcoglycan sub-complex contains α, β, γ, δ

subunits and is responsible for stabilizing the

sarcolemma; dysfunction in the subunits lead

to Limb-Girdle Muscular Dystrophies

Dystroglycan links the

cytoskeleton to the

extracellular matrix to

provide structural integrity to

muscles and facilitate cell

signaling; dysfunction leads

to various dystrophies like

Walker-Warburg Syndrome

and Fukuyama

Congenital Dystrophy

Dystrophin connects actin

filaments to the

cytoskeleton and creates a

scaffold for cell signaling;

malfunction results in

Duchenne Muscular

Dystrophy (DMD) or Becker

Muscular Dystrophy (BMD)


Selected Gene Therapy-amenable Musculoskeletal Disorders

Source: Company Reports. Myotonic Dystrophy Foundation. NORD. Piper Jaffray Research.

EXHIBIT 52


DiseaseUS



Approach

Becker Muscular

Dystrophy

(BMD)

10,000

• X-linked recessive disorder caused by

mutations in the DMD gene, encoding

dysfunctional dystrophin

• Symptoms: progressive weakness and

wasting of skeletal and cardiac muscles, with

onset often observed between 8–25 years old

• Exondys51 available for DMD patients

with exon 51 mutation, Translarna

available for nonsense mutations in EU

• All other treatments symptomatic

• Life expectancy to mid-to-late

adulthood; normal life expectancy if

there are no cardiac issues

• Microdystrophin (shortened, functional

dystrophin) gene therapy to replace

dysfunctional gene

• Exon-skipping gene therapy to correct

native dysfunctional dystrophin transcript

into functional form

Myotonic

Dystrophy 1

(DM1)

30,000

• Autosomal dominant disorder caused by

expansion of CTG repeats in DMPK gene that

leads to protein aggregates

• Age of onset ranges from 20 to 70 years

• Symptoms include progressive weakness and

wasting of skeletal muscles

• Severity based on age of onset

(congenital being most severe)

• Minimal impact on life expectancy

• No cure available; treatment is

symptomatic

• Potential of utilizing gene knockdown

methods to reduce mutated DMPK levels

• Possibility of delivering exon-skipping

technology via gene therapy to produce

functional DMPK variants

Duchenne’s

Muscular

Dystrophy

(DMD)

10,000


mutations in the DMD gene, encoding

dysfunctional dystrophin

• Symptoms include progressive muscle

weakness with onset at age 6–7 years,

leading to loss of ambulation by 12–15 years

• Exondys51 available for DMD patients

with exon 51 mutation (low efficacy)

• No other treatments available

• Life expectancy ~24–27 years

• Microdystrophin (shortened, functional

dystrophin) gene therapy to replace

dysfunctional gene


native dysfunctional dystrophin transcript


OPMD~3,000 –

4,000

• Autosomal dominant disorder caused by

mutation in the PABPN1 gene that leads to

PABPN1 aggregates

• Onset typically around 40 years of age

• Symptoms include muscle weakness, ptosis,

dysphagia

• No cure available

• Treatment centers around addressing

symptoms (plastic surgery, orthopedic

devices, cricopharyngeal myotomy)

• Replacement of PABPN1 by gene

therapy

• Potential of utilizing gene knockdown

methods to reduce mutated PABPN1

• Possibility of delivering exon-skipping

technology via gene therapy to produce

functional PABPN1 variants

XLMTM~2,700 –

3,000


mutation in the MTM1 gene

• Onset evident at birth

• Symptoms include myopathy, hypotonia, and

fragile bones

• No cure available

• Most severe-form is most common

• Symptomatic treatment

• Average life expectancy is 29 months

• Replacement of MTM1 via gene therapy


native dysfunctional myotubularin

transcript into functional form



Source: Chu et al. J Exp NeuroThera. 2018. NORD.

EXHIBIT 53


DiseaseUS

PrevalenceDisease Background Unmet Need Potential Gene Therapy Rationale & Approach

LGMD-2A NR

• Autosomal recessive disease caused by mutations

in Calpain 3 gene

• Age of onset 2–53 years

• Symptoms defined by phenotype (Leyden-Mobius,

Erb LGMD, HyperCKermia)

• No cure exists

• Cardiac and respiratory issues

are rare

• Gene therapy to replace dysfunctional gene

with full-length calpain 3


native dysfunctional calpain 3 transcript into

functional form

LGMD-2B 2,600


in dysferlin protein that disrupts sarcolemma

resealing

• Age of onset between 15–30 years

• Symptoms characterized by muscle wasting in the

proximal limbs; progression is slow

• No cure exists


• Patient remain ambulatory

• No respiratory or cardiac issues


with full-length or shortened (micro) dysferlin


native dysfunctional dysferlin transcript into

functional form

LGMD-2C 640


in γ‐sarcoglycan, part of the sarcoglycan

subcomplex of DAG


proximal limbs

• No cure exists


• Patients wheel-chair bound

by teenage years

• Cardiomyopathy is common


with full-length γ‐sarcoglycan


native dysfunctional γ‐sarcoglycan transcript


LGMD-2D 1,100


in α‐sarcoglycan, part of the sarcoglycan

subcomplex of DAG


proximal limbs

• No cure exists



by teenage years

• Rare to see cardiomyopathy


with full-length α‐sarcoglycan


native dysfunctional α‐sarcoglycan transcript




Source: Chu et al. J Exp NeuroThera. 2018. NORD.

EXHIBIT 54


DiseaseUS

PrevalenceDisease Background Unmet Need Potential Gene Therapy Rationale & Approach

LGMD-2E 1,100


in β‐sarcoglycan, part of the sarcoglycan

subcomplex of DAG


proximal limbs

• No cure exists



by teenage years

• Cardiomyopathy is common


with full-length β‐sarcoglycan

• Exon-skipping gene therapy to correct native

dysfunctional β‐sarcoglycan transcript into

functional form

LGMD-2G NR


in TCAP protein


• Symptoms characterized by muscle wasting in

the proximal limbs with significant variation

in phenotype

• No cure exists


• Males more severely affected

• ~50% of cases have cardiac

issues


with full-length or shortened telethonin gene


dysfunctional telethonin transcript into

functional form

LGMD-2L 1,800


in anoctamin 5


• Symptoms include distal leg phenotype,

asymmetric thigh atrophy

• No cure exists


• Males more severely affected

• No respiratory or cardiac issues


with full-length anoctamin 5


dysfunctional anoctamin-5 transcript into

functional form


The biology of the musculoskeletal disorder may dictate which modality of

gene therapy is best. As previously discussed, certain musculoskeletal diseases

may be able to be addressed by simply replacing the dysfunctional gene with a

functional copy via gene therapy. However, certain genes are too large to fit into

viral capsids and other genetic approaches may need to be taken. One such

method would be to deliver an engineered abridged variant of the gene that still

retains its functionality. Another method would be to utilize exon-skipping

technology via gene therapy to deliver oligonucleotides can help “skip” mutated

exons to generate a functional, slightly shortened version of the protein product

from the original, native DNA transcript.

Vector and promoter selection is usually based on indication and goals of the

gene therapy. Special considerations are given to the selection and design of a

vector for gene therapy in musculoskeletal disorders based on the specific

indication. Certain indications, like Duchenne Muscular Dystrophy, are known to be

fatal due to cardiac failure and improvements in cardiac function are highly sought-

after – thus, promoters with high cardiac muscle activity are typically selected for

such indications. Transduction efficiency of viral capsids can differ between tissue

types and so viral capsids must be selected based on whether they have suitable

transduction (eg, AAV9 is known to be able to cross the blood-brain barrier and is

frequently selected for musculoskeletal diseases with a CNS component).

Immunogenicity is a major concern for any vector but is heightened for

musculoskeletal gene therapy. Given the high doses of vector that a patient may

receive in musculoskeletal gene therapy, the possibility of an immune response is

always a major risk. This risk is increased in the presence of neutralizing antibodies

and so gene therapy clinical trials traditionally screen patients for preexisting host

antibodies against the vector. In order to maximize the patient pool and lower

safety risk, vectors chosen for gene therapy tend to have relatively lower

prevalence of neutralizing antibodies within the patient population. Musculoskeletal

disorders typically have a higher gene therapy vector burden that further

exacerbates the risk of immune responses, so proper safety management is

paramount for development of gene therapies in this sector.

Considerations for Gene Therapy in Musculoskeletal Disorders

Tissue Tropism And Neutralizing Antibody Prevalence In AAV Serotypes


EXHIBIT 55

AAV

SerotypeTissue Tropism

Prevalence of

Pre-existing nAbs

AAV1 Muscle; Adipose; CNS; Heart 67%

AAV2CNS (particularly ocular); Kidney;

Muscle; Testes72%

AAV3 Liver

AAV4Brain; Lung;

Retinal pigmented epithelium (RPE)40%

AAV5 Liver; CNS; Ocular; Pancreas 46%

AAV6Striated muscle (heart);

Respiratory epithelium (lung)

AAV7Brain; Photoreceptors; RPE;

Striated muscle38%

AAV8Hepatocyte; Pancreas; RPE;

Photoreceptors; Brain; Skeletal muscle47%


Gene Therapies Landscape: Musculoskeletal Disorders


EXHIBIT 56

Companies Developing Gene Therapies for Musculoskeletal Disorders


Audentes BOLD DM1 AT466 AAV8 (potentially)DMPK (knockdown)

DMPK (exon-skipping)Preclinical

Audentes BOLD DMD

• AT702 (exon 2)

• AT751 (exon 51)

• AT753 (exon 53)

AAV8 (potentially) DMD (exon-skipping) Preclinical

Sarepta SRPT DMDSRP-9001

microdystrophinAAVrh74

Microdystrophin

(replacing dystrophin)Phase II

Solid Bio SLDB DMD SGT-001 AAV9Microdystrophin

(replacing dystrophin)Phase I/II

Pfizer PFE DMD PF-06939926 AAV9Minidystrophin

(replacing dystrophin)Phase Ib

AskBio Private Limb Girdle 2i Unnamed AAV FKRP (replacement) Preclinical

Sarepta SRPT LGMD-2A LGMD2A or Calpain 3 AAVrh74 (potentially) Calpain 3 Preclinical

Sarepta SRPT LGMD-2B MYO-201 AAVrh74 Dysferlin Clinical

Sarepta SRPT LGMD-2C SRP-9005 AAVrh74 (potentially) Gamma-sarcoglycan Preclinical

Sarepta SRPT LGMD-2D SRP-9004 AAVrh74 Alpha-sarcoglycan Clinical

Sarepta SRPT LGMD-2E SRP-9003 AAVrh74 Beta-sarcoglycan Clinical

Sarepta SRPT LGMD-2L SRP-9006 AAVrh74 (potentially) Anoctamin 5 Preclinical

Audentes BOLD XLMTM AT132 AAV8 MTM1 (replacement) Phase I/II


Neurology

04.5


Neurological diseases present distinctive challenges for gene therapy.

Many neurological diseases have multiple causes, involve the malfunction of

multiple proteins within biochemical pathways, or their pathophysiologies have not

been fully elucidated. Additional complexity in developing neurological disease

gene therapies lies within determining the optimal route of administration

(eg, intrathecal vs intracranial). As will be discussed later, selecting the route and

site of administration may have significant impact on the efficacy of gene therapy

since neurological conditions can be localized to certain areas of the brain or be

systemic. There are, of course, exceptions to these limitations, such as spinal

muscular atrophy 1 (SMA1). Zolgensma became the first gene therapy to be

approved for SMA1, which is monogenic in nature and affects the motor neurons in

the spinal cord.

Unique strategies are sometimes required to address unique neurological

conditions. In developing gene therapies for neurological disorders, companies

often have to develop novel workarounds to overcome the diverse etiologies found

in these disorders and the specific hurdles described above. However, the high

unmet need in many of these conditions makes them prime candidates for novel

solutions that can address even a few aspects of the disease, if not cure it outright.

One salient example of this is Parkinson’s disease (PD), which is known to have

multiple etiologies and no known cure. Levodopa is used in PD for symptomatic

treatment but has a well-known side effect of dyskinesia at peak-dose, which can

drastically lower QoL. To address this, Axovant Gene Therapies (AXGT, not

covered) has taken a novel approach for PD in which three different genes are

delivered using a lentiviral vector (Exhibit 57). The goal of this therapy is to produce

tonic levels of dopamine, which may reduce the dyskinesia brought on by variability

in levodopa and dopamine levels.

Another difficult-to-treat neurological condition is Huntington’s Disease (HD),

caused by the mutated HTT protein (mHTT). mHTT is known to aggregate and

induce progressive neurodegeneration. Since the toxicity is being driven by

aggregation, gene replacement therapy is not a viable option. Instead, companies

are developing a gene therapy to supplement a downregulated gene in HD,

CYP46A1. The gene encodes an enzyme that plays a neuroprotective role in the

brain. The goal of this approach is to slow the progression of HD by replenishing

down-regulated levels of the protein.

Gene Therapy for Neurological Disorders

Axovant’s Gene Therapies Strategy for Parkinson’s Disease


EXHIBIT 57

Tyrosine

hydroxylase (TH)

& cyclohydrolase

(CH1)

Aromatic

L-amino acid

decarboxylase

(AADC)

All 3 genes in

one lentiviral

capsid

TH and CH1

fused together to

promote

co-localizaton


Selected Gene Therapy-amenable Neurological Disorders

Source: Company Reports. Young et al. Ther Adv Psych Pharm. 2017. NIH. Curts et al Gene Reviews. 2015.

EXHIBIT 58

Rationale for Targeting Select Neurological Disorders With Gene Therapy

DiseaseUS



Approach

ALS

(ΔC9ORF72)

15,000(Total)

600(C90RF72)

• Condition with deterioration of neurons

resulting gradual neurodegeneration

• 10% inherited (~4% C90RF72 mutation)

• Age of onset typically between 55–75 years

• No cure

• Death within 2–5 years

• Riluzole & Radicava approved to slow

progression to paralysis

• Gene silencing of C90RF72 to slow

aggregation of protein

• Gene silencing of SOD1 to slow the

aggregation of mutant protein

Huntington’s

Disease30,000

• Autosomal dominant condition in the HTT

gene that results in CAG repeats and leads

to progressive degeneration due to

aggregation

• Onset typically between 30–50 years of age

• Symptoms include chorea, depression, and

cognitive impairment

• No cure to-date

• Death usually 20 years after

diagnosis

• Severity and speed of disease

progression correlated with number of

CAG repeats

• Gene silencing of mHTT to slow


• Gene replacement of CYP46A1 to

enhance neuroprotective features

Friedrich’s Ataxia 8,000

• Autosomal recessive condition in the FXN

gene that cause triplet repeats.

• Age of onset: 5–15 years

• Symptoms include ataxia, spasticity, and

loss of strength & sensation

• No cure; symptom management &

physical therapy

• Wheel-chair bound in 10–20 years

• Cardiac issues common; some live to

60+ years

• Gene replacement of FXN to restore

frataxin functionality

Frontotemporal

Dementia

20,000 –

30,000

• Disease of unknown cause that results in

gradual loss of cognitive function

• Age of on-set between 40–60 years

• Mutated progranulin has been shown to be

associated as a biomarker

• No cure; treatment involves lifestyle

changes

• Death typically ~10 years after onset

• Gene replacement of PGRN to

enhance progranulin functionality

Parkinson’s

Disease60,000

• Disease with multiple causes (recessive &

dominant mutations); not fully understood

• Age of onset: ~60 years

• Symptoms include trembling, stiffness, slow

movement with gradual decline

• No cure, levodopa & dopamine

receptor agonists used to treat

symptoms

• Levodopa treatment causes L-DOPA-

induced dyskinesia

• Gene replacement of CH1, TH, AADC

genes to enhance dopamine

biosynthesis from tyrosine/levodopa

SCA-Type 3 10,000

• Autosomal dominant condition that causes

CAG repeat expansion in ATXN3 gene,

leading to neurodegeneration in the

cerebellum & brain stem

• Onset typically in mid-adulthood

• Symptoms: ataxia, dystonia, spasticity

• No cure

• 10–20 years of survival after

diagnosis

• Gene silencing of ATXN3 to slow



Identifying the appropriate target genes to treat neurological conditions can

be challenging. Neurological conditions are prone to having multiple causes –

genetic and non-genetic, which makes them especially difficult to treat. Companies

developing gene therapies for these conditions are faced with the challenge of

identifying which sub-group of patients with the disorder they would be treating to

generate the most impact from their gene therapy. For example, in a condition like

ALS, only a small subset of patients have mutations in specific genes such as

SOD1 or C90RF72 that may be amenable for gene therapy; a company

developing a gene therapy in ALS would have to consider commercial and

clinical development viability aspects in selecting which target gene to use.

Gene therapies for neurological disorders can be difficult to administer, with

many requiring transduction directly into brain cells. There are several routes of

administration that can be used to achieve this, with various benefits/drawbacks.

Intrathecal administration may be implemented for a relatively safe delivery;

however, this mode of administration is best suited for diseases that affect the

spine and cortical neurons, since vector penetration to internal regions of the brain

may be limited. Multiple diseases, including HD and PD, originate in the internal

portions of the brain and spread towards the external cortices as the disease

progresses to later stages (Exhibit 59). In order to deliver genes to these internal

regions, an intracranial procedure targeting specific regions of the brain, may result

in high transduction rates than IV or intrathecal (Exhibit 60). There are obvious

risks related to the surgical procedure, such as intracranial hemorrhaging, and

considerations must be made about the site of delivery to ensure optimal

transduction. For example, uniQure (QURE, covered by Danielle Brill) is delivering

their gene therapy for HD directly to the striatum, where the putamen resides and is

known to be most significantly affect portion of the brain in early-stage HD patients.

Considerations for Gene Therapy in Neurological Disorders

Huntington’s Disease Progression from Early Stage to Late Stage

Source: Company Reports. uniQure R&D Day Presentation 2018. Piper Jaffray Research.

EXHIBIT 59

Neurodegenerative effects of

Huntington’s Disease are most

visible in the putamen and

caudate of the striatum, where

mHTT aggregation is most

prevalent. As aggregates build

up, the degenerative effects

progress to the cortical

portions of the brain in

later-stages of the disease.

Speed of progression depends

on number of repeats within

the mHTT gene.

Neurological Gene Therapy: Various Routes of Administration

EXHIBIT 60

Gene therapies can be

delivered via 4 major routes of

administration depending on

target region, safety profile of

gene therapy and target effect.

IV administration may also be

possible for neurological

conditions but would need to

overcome lower transduction

efficiency issues that result

from lack of blood-brain barrier

penetration.


Gene Therapies Landscape: Neurological Disorders


EXHIBIT 61

Companies Developing Gene Therapies for Neurological Disorders


Voyager

TherapeuticsVYGR Monogenic ALS VY-SOD102 AAV2 SOD1 RNAi Preclinical

AskBio Private Epilepsy Unnamed AAV Undisclosed Preclinical

Voyager

TherapeuticsVYGR Friedreich’s Ataxia VY-FXN01 AAV2 FXN Preclinical

Passage Bio Private Frontotemporal dementia Unnamed AAV9 PGRN Preclinical

uniQure QURE Huntington’s Disease AMT-130 AAV5mHTT exon1 targeting

miRNAClinical (2H19)

AskBio Private Huntington’s Disease Unnamed AAV Undisclosed Preclinical

Voyager

TherapeuticsVYGR Huntington’s Disease VY-HTT01 AAV2 mHTT RNAi Preclinical

Voyager

TherapeuticsVYGR Parkinson’s Disease VY-AADC AAV2 AADC Phase II

Axovant Gene

TherapiesAXGT Parkinson’s Disease AXO-LENTI-PD Lentiviral AADC/TH/CH1 Phase I/II

MeiraGTx MGTX Parkinson’s Disease NLX-P101 AAV GAD Phase I/II

AskBio Private Parkinson’s Disease Unnamed AAV Undisclosed Clinical

Gene Therapy

Research

Institute

Private Parkinson’s DiseaseAAV2-AADC

AAV2-TH-GCHAAV.GTX AADC/TH/CH1 Preclinical

Gene Therapy

Research

Institute

Private Sporadic ALS AAV.GTX-AADR2 AAV.GTX AADR2 Preclinical


Ophthalmology

04.6


The eye presents advantages for gene therapy: accessibility and ease of

evaluation. Ophthalmic disorders, particularly retinal disorders, result from genetic

mutations in genes that are essential for retinal health, such as CHM or RS1, and

genes that lead to inherited degeneration of the retina. However, they can also be

caused by non-genetic factors including age in the case of wet age-related macular

degeneration (wet AMD). Ocular diseases are of particular interest as targets for

gene therapies due to their often monogenic nature, as well as the isolated, fluid-

filled and privileged space of the eye, which is easily accessible by injection.

Gene therapy for ocular disease is clinically validated. Luxturna (Spark

Therapeutics, which was acquired by Roche, uncovered) is a serotype 2 adeno-

associated virus (AAV2)-based vector encoding the RPE65 gene. The goal of this

therapy is to replace dysfunctional RPE65 in patients with Leber congenital

amaurosis type 2 (LCA2), an inherited retinal disease caused by mutations in this

gene. Luxturna is administered in the subretinal space following vitrectomy

(removal of the vitreous humor gel that fills the eye). Preclinical and clinical studies

have shown that the AAV2-RPE65 vector is safe and effective, as patients

demonstrated improvements in light sensitivity and in navigating dim lighting

conditions. Importantly, these effects were sustained over a 3-year follow-up period

in most of the studies. This initial success with gene therapy for an ocular disease

has provided proof of concept and given hope to the thousands of patients with the

various retinal diseases for which there are no approved therapies. It also paved

the way for several companies to develop other AAV vectors targeting different

retinal gene mutations. In fact, there are currently >30 ocular clinical trials studying

gene replacement in ocular/retinal disease using AAV vectors, including studies in

choroideremia, age-related macular degeneration (AMD), X-linked retinitis

pigmentosa (XLRP), and X-Linked Rentinoschisis (XLRS). With established

evidence now in place that the delivery of a gene to the retina can safely restore

visual acuity and retinal health in LCA2, additional genes may be delivered

accordingly in various disease settings.

Ocular gene therapies may potentially treat non-inherited retinal disorders.

As previously mentioned, diseases such as wet AMD are not caused by inherited

mutations in retinal genes, and are instead caused by age, or behavioral and

environmental factors. Anti-VEGF therapy is used in treating AMD, as the disease

is characterized by vascular overgrowth in the retina. Several therapies are in use,

including EYLEA (Regeneron Pharmaceuticals, covered by Chris Raymond),

Lucentis (Roche/Genentech, uncovered), Macugen (Pfizer, uncovered), and

Avastin (Roche/Genentech). Anti-VEGF is effective initially after injection;

however, “real-world” data from long-term clinical trials showed a surprising lack of

durability in the response to therapy. After one year of treatment, patients no longer

had meaningful improvement in visual acuity like that seen in pivotal trials for these

drugs. This may be due to the number of injections that are required (1 injection

per month) leading to non-compliance, among several other reasons associated

with injection of this protein. Therefore, gene therapy may be a favorable

alternative to repeated Intravitreal injection of recombinant anti-VEGF or other

recombinant proteins with the potential to (1) avoid peak and trough levels

associated with protein injection, (2) avoid potential safety issues with repeated

injections, and (3) to lower the burden on patients. We see from previous

experience with Luxturna and the myriad trials currently ongoing that gene therapy

is capable of achieving high levels of protein and long-term expression.

Gene Therapy for Ophthalmic Disorders



Selected Gene Therapy-Amenable Ophthalmic Disorders


EXHIBIT 62



Choroideremia ~5,000


mutations in the CHM gene, encoding

dysfunctional Rab-escort protein-1

(REP1), which leads to the death of

the retinal epithelium, photoreceptors,

and the choroid

• Symptoms: progressive loss of vision

• No approved treatments

• Symptom management includes

visual aids

• Significantly impaired QoL due to

vision loss

• AAV delivery of functional CHM gene

to retinal cells aims to replace REP1,

reducing the accumulation of waste

products to reduce cell death. The

ultimate goal of gene therapy in this

disease is to slow or halt vision loss

that result from CHM mutations

Wet Age-Related

Macular Degeneration

(Wet AMD)

1.2M

• Non-genetic retinal disease brought

on by age, inflammation,

hypertension, or by smoking

• Symptoms: abnormal vascular growth

on the retina that results in severe

vision loss, which may be rapidly

progressive

• EYLEA, Lucentis, Macugen, and

Avastin are all anti-VEGF therapies

designed to stop the growth of new

blood vessels by blocking the effects

of VEGF growth signals

• Anti-VEGF treatment requires monthly

injections, which is burdensome

• AAV delivery of aflibercept (anti-VEGF

antibody) aims to minimize the

treatment burden of repeated anti-

VEGF injection. This therapy restores

physiological angiogenic balance in

the retina, thereby halting or slowing

the progression of retinal damage

Retinitis Pigmentosa

(RP)~10,000

• Autosomal or X-linked disorder

caused by various mutations across

several chromosomes, and may even

be polygenic in some cases

• Symptoms: progressive vision loss,

dim light sensitivity, night blindness


• Dietary vitamin A supplements have

been shown to restore partial vision;

however, vitamin E leads to rapid

progression of disease, therefore

multivitamins may be dangerous

• AAV delivery of the functional RPGR

gene, which encodes the retinitis

pigmentosa GTPase regulator that is

responsible for protein transport in

photoreceptors. The aim of gene

therapy in XLRP is to restore vision

X-Linked

Rentinoschisis (XLRS)~15,000


mutations in the rentinal-specific RS1

gene which encodes dysfunctional

retinoschisin protein

• Symptoms: reduced visual acuity,

retinal detachment, retinal bleeding


• Retinal detachment may be treated

surgically, but splitting or schisis of the

retina cannot be corrected

• Low vision aids are often provided

• AAV delivery via Intravitreal injection

of the functional RS1 gene targets the

therapy to retinal cells in XLRS

patients. The goal of this therapy is to

achieve a functional cure and prevent

further retinal damage

Achromatopsia ~10,000


by mutations in CNGB3 and CNGA3

encoding a subunit of the cone

photoreceptor cyclic nucleotide-gated

(CNG) channel

• Symptoms: day blindness, reduced

visual acuity and color discrimination


• Tools are available for symptom

management, including deep red

tinted glasses or contact lenses, and

magnifying lens to deal with poor

visual acuity

• AAV delivery of the functional CNGB3

or CNGA3 gene targets the cone

receptors at the back of the eye where

they are most focused via subretinal

injection in achromatopsia patients.

The goal of this therapy is to restore

cone function


Vector selection is dependent upon disease etiology and gene size.

Viral vectors are the most common gene delivery systems for ocular diseases.

However, viral specificity is a challenge due to tissue tropism. Moreover, AAV

vectors have limited capacity. Some genes, such as TIMP3, which causes

Stargardt’s hereditary maculopathy (an inherited macular disease), are too large

(6.2 kb) to be carried to the retina by the AAV virus, as they only have a <5 kb

capacity. Lentiviral vectors may be used to carry larger genes. Alternatively, non-

viral gene therapy approaches offer the benefit of the same sustained, fine-tuned

expression of desired proteins and can address more common non-genetic retinal

diseases, such as age-related macular degeneration (AMD). In general, non-viral

vectors have better safety profiles, as they are less immunogenic, and can

therefore be administered repeatedly, if needed. They also have a lower risk of

insertional mutagenesis than viral vectors.

Surgical considerations remain an important issue to focus on for ocular

gene therapy. Subretinal dosing of a gene therapy requires an invasive surgical

procedure that can only be performed following vitrectomy by a trained surgeon.

During this procedure, a subretinal “bleb” is formed, resulting in transient

detachment of retinal pigment epithelium from the photoreceptors, which could

aggravate the already ongoing degenerative process that several patients are

already experiencing. Complications from the surgical process can arise, including

the creation of macular holes, unresolved retinal detachment (this will require an

additional surgery), choroidal effusions (accumulation of fluid in the suprachoroidal

space), and retinal tears. Importantly, it is also crucial to understand that cellular

transduction using subretinal injection is restricted only to the bleb location, which

limits the treatment area. It is for these reasons that companies like Adverum are

developing intravitreal injection (IVI) administered gene therapy. This process is

less invasive and is considered by some physicians to be safer due to reduced risk

of retinal damage. However, KOLs have noted that subretinal injection can be

100–1000x more efficient at targeting retinal cells than IVI. In fact, there are data

supporting the notion that IV only transduces cells in the fovea due to the presence

of the internal limiting membrane (ILM), which acts as a barrier between the retina

and the vitreous space. Moreover, IVI administration of gene therapy can lead to

high neutralizing antibody titers (which would increase the immune-mediated

elimination of drug), whereas almost no antibody response is seen following

subretinal injection. Therefore, it is clear that both IVI and subretinal injection have

their drawbacks. However, as 88% of retinal specialists believe that a surgical

procedure is warranted if a therapy offers a durable benefit of 6–12 months, we

note that it is extremely important to consider on a disease basis which route of

administration is required for effective delivery of gene therapy to the eye.

Long-term expression and efficacy in patients are still open questions.

There is a chance, as with any gene therapy, that it may not be possible to turn off

therapeutic gene expression once it is delivered to the eye. It is therefore

imperative to study the long-term safety of these gene therapies once injected into

the eye. Fortunately, the first gene therapy trials for Luxturna in LCA2 have not

shown any long-term safety issues. We believe this is de-risking for the field.

AAV gene therapies are expensive. Costs of production of AAV gene therapies

are exorbitant. Manufacturing of these low-yield vectors will have to drastically

improve to make economic sense for developers. Moreover, the prices of these

therapies are a significant burden. For example, Luxturna is marketed in the US at

$425,000 per eye. Questions regarding reimbursement and patient access remain.

Specific Considerations for Gene Therapy in Ophthalmic Disorders



Gene Therapies Landscape: Ophthalmic Disorders


EXHIBIT 63

Companies Developing Gene Therapies for Neurology Disorders


agtc AGTCAchromatopsia

(ACHM-A3)AAV-CNGA3 AAV CNGA3 Phase I/II

agtc AGTCAchromatopsia

(ACHM-B3)AAV-CNGB3 AAV CNGB3 Phase I/II

MeiraGTx MGTX Achromatopsia AAV-CNGA3 AAV CNGA3 Phase I/II

MeiraGTx MGTX Achromatopsia AAV-CNGB3 AAV CNGB3 Phase I/II

Biogen BIIB Choroideremia BIIB111 AAV2 Choroideremia (CHM) Phase III

MeiraGTx MGTX Retinitis Pigmentosa (RP) AAV-RPE65 AAV RPE65 Phase I/II

REGENXBIO REGX Wet AMD RGX-314 AAV8

Gene encoding

anti-VEGF monoclonal

antibody fragment

Phase I/IIa

Adverum

Biotech ADVM Wet AMD ADVM-022 AAV.7m8 Aflibercept (anti-VEGF) Phase I

agtc AGTCX-Linked Retinitis

Pigmentosa (XLRP)AAV-RPGR AAV RPGR Phase I/II

Biogen BIIBX-Linked Retinitis

Pigmentosa (XLRP)BIIB112 AAV8 RPGR Phase II/III

MeiraGTx MGTXX-Linked Retinitis

Pigmentosa (XLRP)AAV-RPGR AAV RPGR-ORF15 Phase I/II

agtc AGTCX-linked retinoschisis

(XLRS)AAV-RS1 AAV RS1 Phase I/II


Otology

04.7


Source: Company Reports. Mytonic Dystrophy Foundation. NORD. Piper Jaffray Research.

EXHIBIT 64

Rationale for Targeting Hearing Loss With Gene Therapy


Hearing Loss ~300,000

• Roughly 50% of congenital hearing

loss has a genetic etiology, and more

than 300 different gene mutations

have been implicated

• The same genes responsible for

monogenic deafness may also

contribute to environmental hearing

loss due to drug exposure, noise,

and aging

• There are currently no FDA-approved

therapies to address hearing loss

• SoC includes hearing aids that offer

sound amplification and cochlear

implanted electrodes that stimulate

the auditory nerve

• These treatments only offer partial

recovery of function, only work in a

limited patient population, and do not

fully restore natural hearing

• Daily activities are significantly

impacted by hearing loss

• AAV or Adenoviral vectors are used to

deliver functional versions of genes

responsible for the loss of hearing,

including ATOH1, which encodes the

atonal transcription factor. This gene

is essential in the development of

inner ear hair cells. The aim is to

replace dysfunctional genes that

impair hearing and restore

dysfunctional or absent hearing ability

in individuals with a genetic basis

of disease

EXHIBIT 65

Companies Developing Gene Therapies for Hearing Loss


Akouos PrivateSensorineural

hearing lossAnc80AAV AAV Undisclosed Preclinical

Novartis NVSSevere to profound

hearing lossCGF166 Ad5

Atonal transcription factor

(Hath1)Phase I/II

Genetic hearing loss is caused by mutations affecting over 300 different loci

in many different ear cell types. Hair cells of the inner ear are the most common

target of gene therapy studies, most likely due to the fact they express that more

than 50% of the mutations leading to deafness. However, hair cells are postmitotic

and therefore do not divide, and are also organized within the inner ear hair bundle

in a compact arrangement – making them slightly more difficult targets for even

localized gene therapy. Other ear cells with known mutations causing hearing loss

that may be viable targets include the spiral ganglion neurons and support cells.

The inner ear is an attractive target for gene therapy. Similar to the eye, the

inner ear is an enclosed, fluid-filled space, offering several advantages and

disadvantages in the development of gene therapies. For example, the blood-

labyrinthine barrier within the inner ear provides a significant physical and diffusion

barrier which may make it difficult to treat inner ear hair cells systemically.

Conversely, this barrier allows therapeutic agents injected directly into the cochlea

to remain isolated there at elevated concentrations, which would reduce systemic

toxicity due to off-target effects.

Gene Therapy for Otological Disorders


Emerging Approaches in

Gene Therapy

05.


We believe that following our below checklist for valuating gene therapy companies mitigates some of the risk of investing in gene therapy, thereby creating compelling

investment opportunities with a more favorable risk/ reward ratio.

Our Checklist for Valuing Gene Therapy Companies


Despite much recent progress in the field there are still more questions than answers when it comes to gene therapy. And in our view,

how gene therapies will pan out once they reach the clinic is highly unpredictable. For that reason, we prefer companies that have

generated compelling clinical efficacy and safety data, or at least clinical POC.01 CLINICAL DATA

02 UNMET NEED

03 COMPETITION

04 MARKET

OPPORTUNITY

05 PIPELINE

We look for companies developing gene therapies where existing therapies are limited and there is a high degree of unmet need.

We think physicians and patients will generally prefer other available treatment modalities (if efficacy/safety are comparable) over

gene therapy, because no one wants to be a guinea pig. However, for diseases with no alternatives, or suboptimal treatments with a

high morbidity/mortality, we expect broad utilization of gene therapies.

Many companies are developing gene therapy products for the same indications. We have two different approaches to picking stocks

in this situation. 1. Attempt to pick the winner and assign them majority of market share (most compelling data, most advanced,

cleaner safety profile, less invasive administration). 2. Assume they divide the market. If competing programs are too early to identify

areas of differentiation, we assume they share the market.

In our view, a deep pipeline is especially important when considering companies developing products targeting ultra-rare indications.

With that said, we are cautious about ultra-orphan indications. We worry about products in development targeting worldwide

population numbers in the hundreds. We think there is a cap on pricing, even if overall impact to health systems would be small.

As such, we worry about sustainability.


Companies Covered

4D Molecular Therapeutics (Private)

Abeona Therapeutics (ABEO)

Adverum Biotech (ADVM; OW)

Akouos Therapeutics (Private)

Amicus Therapeutics (FOLD)

AskBio (Private)

Audentes Therapeutics (BOLD; OW)

AVROBIO (AVRO)

Companies Covered Within This Report


In this section of the report, we dive into 22 companies that are developing novel gene therapies for the treatment of the conditions described previously. The companies

range from small private companies to large cap pharmaceutical companies, with assets that are currently being evaluated in preclinical and clinical stages

of development.

Please refer to the hyperlinked list below to jump to a company of interest.

Axovant Sciences Ltd (AXGT)

Biogen (BIIB; N)

Biomarin (BMRN; OW)

bluebird bio (BLUE; N)

BridgeBio (BBIO; OW)

Gemini Therapeutics (Private)

Gene Therapy Research Inst Co (Private)

Krystal Biotech (KRYS)

MeiraGTx (MGTX; OW)

Orchard Therapeutics (ORTX)

Passage Bio (Private)

Rocket Pharma (RCKT)

Sarepta Therapeutics (SRPT; OW)

Ultragenyx (RARE; OW)

UniQure (QURE; OW)


Company overview. 4D Molecular is a next-generation gene therapy platform

company that uses therapeutic vector evolution to create optimized and proprietary

AAV vectors specifically tailored to the treatment of specific rare diseases.

The current pipeline spans four therapeutic areas including ophthalmology, heart,

muscle, and lung disorders.

Therapeutic vector evolution. To design next-gen AAV vectors, 4DMT works

with physicians/scientists to design optimized vector profiles for a given disease,

and then creates a highly complex and unique vector capsid library for

high-throughput screening. Using the power of natural selection in primates,

vectors with desirable profiles are enriched and isolated, and then further

engineered to carry specific therapeutic transgenes of interest. These optimized

vectors allow for highly efficient gene uptake and delivery, have increased tissue

specificity, and are less immunogenic than first generation AAV vectors.

Enhanced transduction efficiency of next-gen AAV vector, 4D-C102 vs AAV1

and AAV9 vectors. Relevant to Fabry disease, which affects heart tissue,

human pluripotent stem cell-derived cardiomyocytes were transduced with 4D-

C102, a next-gen AAV optimized to transduce the heart, or first-generation

AAV1 or AAV9 vectors encoding CAG-EGFP at multiple MOIs. Six days post-

infection, cardiomyocytes were analyzed for GFP fluorescence, with 4D-C102

transduced cells showing a statistically significant dose-dependent increase in

transduction efficiency compared to first-generation vectors. 4DMT will use 4D-

C102 as the novel vector for its Fabry product candidate, 4D-310, which is

expected to enter the clinic in 2020. The company presented these findings at

the 6th International Update on Fabry Disease held in May 2019.

4D Molecular Therapeutics (Private)

Source: 4D Molecular Therapeutics. Piper Jaffray Research

EXHIBIT 66

4DMT’s Gene Therapy Pipeline

EXHIBIT 67

Upcoming Catalysts

Indication Drug Catalyst

Choroideremia 4D-110 Initiation of P1 study expected in 2019

Choroideremia 4D-110 Natural History study (ongoing, n=50)

Fabry disease 4D-310 Anticipated FIH clinical trial initiation in 2020

Stage of Development

Indication Program DiscoveryPre-IND

Candidate

IND

Candidate

Choroideremia 4D-110

Retinal

Rare Disease4D-125

Fabry Disease 4D-310

Muscle

Rare Disease4D-510

Cystic Fibrosis 4D-710


Upcoming Catalysts

A fully-integrated gene and cell therapy company rapidly advancing genetic

medicines. Abeona Therapeutics (ABEO) is a biopharmaceutical company

focused on developing gene therapy products to treat severe, life-threatening rare

diseases. The company has three ongoing clinical programs with additional gene

therapies in preclinical development (Exhibit 68). ABEO is currently preparing to

initiate a pivotal Phase III trial for lead product candidate, EB-101 (ex vivo

autologous gene therapy of patient keratinocytes), for the treatment of Recessive

Dystrophic Epidermolysis Bullosa (RDEB) in 4Q19. In addition, the company has

two AAV gene therapy candidates in Phase I/II clinical development for the

treatment of Sanfilippo Syndrome (MPS III), a lysosomal storage disorder primarily

affecting the CNS, including ABO-102 (rAAV9-SGSH) for the treatment of MPS

IIIA, and ABO-101 (rAAV9-NAGLU) for the treatment of MPS IIIB.

Abeona Therapeutics (ABEO): Not Covered

Source: ABEO. Piper Jaffray Research

EXHIBIT 68

ABEO’s Gene Therapy Pipeline

EXHIBIT 70

Indication Drug Upcoming Catalyst

RDEB EB-101 Initiation of pivotal multi-center P3 trial in 4Q19

MPS IIIA ABO-102Pursuing an RMAT meeting with FDA in 2H19 to

determine development path forward

MPS IIIB ABO-101 Interim data update expected 2H19

Infantile

BattenABO-202

Guidance on timing of first clinical study

expected in 2019

EXHIBIT 69

Cognitive Benefits in Young Children with MPS IIIA Treated with ABO-102


Indication Program Preclinical Phase I/II Phase III

RDEB EB-101

MPS IIIA ABO-102

MPS IIIB ABO-101

Infantile Batten

DiseaseABO-202

Juvenile Batten

DiseaseABO-201

Cystic Fibrosis ABO-401

Retinal Diseases ABO-50X

(Above) While all patients in the ongoing Phase I/II study for ABO-102 have shown

reductions in CSF and urine heparan sulfate levels and also shown reductions in

liver volume, the three youngest patients treated with ABO-102 have maintained

normal neurocognitive development within the range of unaffected children.

These data support the need and potential approach to treating MPS III children as

early as possible in the course of disease, prior to symptom onset when significant

neuronal loss has occurred.


Adverum Biotechnologies, is a clinical stage gene therapy company targeting

ocular and rare disease. The company’s lead candidate is ADVM-02, a

proprietary AAV.7m8 vector driving the expression of aflibercept (anti-VEGF

antibody) for the treatment of wet AMD, for which we expect initial data from the

first cohort of patients treated in the OPTIC Phase I study on September 12, 2019.

ADVM-022 is Adverum’s lead AAV-based candidate for the treatment of

wet AMD. There are several approved anti-VEGF therapies for the treatment of

wet AMD including Avastin (Genentech, uncovered), Lucentis (Genentech), and

Eylea/aflibercept (Regeneron, covered by Chris Raymond). We know these drugs

work well and the anti-VEGF approach is well-validated. However, these therapies

lack meaningful durability after one year of treatment because of non-compliance

due to the frequency of injections required for efficacy (1 per month).

ADVM-022 does not require sub-retinal surgery and has demonstrated robust and

stable intraocular expression of aflibercept well beyond a year, which resulted in

reductions of CNV lesions and complexes comparable to the standard bolus

administration of aflibercept. The ongoing ADVM-022 Phase I OPTIC trial has

already dosed 6 patients with a single intravitreal injection of 6E11 vg/eye of 022

and a preliminary review of safety data from this cohort by the independent data

monitoring committee (DMC) revealed no serious adverse events (SAEs) or

dose-limiting toxicities (DLTs) associated with treatment for up to 5 months.

Adverum has also dosed the second cohort at a 2E11 vg/eye dose level (n=6).

Based on existing observations from the study, the company plans to present initial

24-week data from the first cohort of 6 patients at the Retinal Society Meeting in

London on September 12, 2019. Importantly, in addition to primary safety data, we

now expect to see secondary efficacy data, including an analysis of rescue

injections. We believe this suggests there may be early signs of efficacy at the

initial 6E11 dose level, which would be encouraging. Recall that with the final

dataset at optimal dose levels, we hope to see: (1) at least a 50% reduction in the

need for rescue injections; (2) maintenance of best corrected visual acuity (BCVA);

and (3) maintenance of central retinal thickness (CRT) by OCT. The initial 6E11

dose appears clinically relevant (and higher than ADVM's direct competitor), and if

data are positive, the company will meet with the FDA to discuss a development

path moving forward, which may potentially be expedited given 022’s Fast

Track status.

The company’s AAV vector manufacturing process is based on the

Baculovirus Expression Vector System (BEVS), which is a well-validated

approach that can accommodate large, high-yielding batches of AAVs due to the

use of insect cells grown in suspension cultures. This is differentiated from typical

mammalian cell-based approaches, which produce lower yields and are less

cost-effective. We anticipate Adverum’s manufacturing protocol to be highly

scalable for commercial use.

Adverum (ADVM): Van Buren, OW


Upcoming Catalysts

EXHIBIT 72


Wet AMD ADVM-022Initial Phase I data from

first 6 patients expected 3Q19

Adverum Pipeline

EXHIBIT 71


Akouos is a precision gene therapy company developing treatments to

restore and prevent hearing loss. 360 million people worldwide experience

hearing loss and there are currently no approved therapies to treat it. The company

is developing AAV-based gene therapies for sensorineural hearing loss that is

characterized by dysfunctional sensory cells and nerve fibers in the inner ear. It is

the leading cause of newborn deafness, and ~25% of adults over the age of 65

develop this condition, making it the most common of sensory disorders in general.

Sensorineural hearing loss is a great candidate for gene therapy as most cases are

monogenic in nature. Monogenic sensorineural hearing loss affects ~300,000

individuals in the US alone, and millions worldwide.

The company is developing a novel AAV-based platform technology to target

the gene therapy to the sensory cells of the inner ear. This platform is an

Ancestral AAV (Anc-AAV) technology that was originally developed by one of the

company’s co-founders at Massachusetts Eye and Ear. The lead vector for use in

gene therapy for hearing loss is Anc80, which was chosen out of over 40,000

ancestral vectors. The process behind the development of Anc80 and the broader

AncAAV portfolio involved predicting ancestors of AAV9. To achieve this, the

company used the sequence of AAV1-9 to phylogenetically predict where ancestral

nodes would be, synthesize them, and apply selective pressures to the ancestors.

It was serendipitous that one of these novel, created ancestors—the Anc80

library—transduced cochlear cells more potently than other AAV capsids. Akouos

plans to announce the identity of the target gene for the lead therapy later this

month at the American Neurotology Society annual meeting on September 14,,

2019. To prepare for target selection, Akouos has performed a systematic analysis

of 150 genes implicated in hearing loss, including STRC and GLB2.

The Anc80 gene therapy is delivered via minimally-invasive surgery to the

inner ear. Sensory cells sit upon an epithelial membrane that is suspended

between two fluid-filled spaces that are encapsulated in bone (Exhibit 73). Similar

to the eye, this portion of the ear is a prime target for gene therapy as local delivery

can achieve a high local concentration of gene of interest, which can overcome

efficiency challenges experienced with systemically delivered gene therapies.

Local injection also limits the possibility of systemic or off-target toxicities. Another

added benefit of targeting sensory cells is that they are post-mitotic, which means

there is a higher probability of achieving transduction of the gene of interest.

Akouos has a well-established, experienced team of leading experts in inner ear

drug delivery and pharmacokinetics. This team has significant experience

developing novel gene therapy technology for delivery to the inner ear.

Akouos (Private, Page 1 of 2)

Source: Akouos Company Reports. Piper Jaffray Research.

Inner Ear Delivery of Anc80 Gene Therapy

EXHIBIT 73


Non-human primate data provided confidence to select Anc80 as the lead

program vector. Akouos presented data in 3 different NHPs at ASGCT in May of

this year, showing that treatment with the Anc80 vector expressing GFP for

visualization purposes achieves up to 100% transduction of its target hair cells in a

dose-dependent fashion (Exhibit 74). Moreover, the pattern of transduction within

the inner ear was consistent across a large part of the cochlea in several cell types,

including fibrocytes and support cells. This level of transduction is important, as the

company notes that 30%–40% restoration of WT levels of protein will likely be

sufficient to achieve clinically meaningful responses. Although we have not seen

data expressing protein quantity for a target gene of interest, management believes

the Anc80 vector can achieve a therapeutic level of protein expression based on its

ability to transduce inner ear cells to this extent. Also of note is the remarkable level

of hair cell survival following treatment with Anc80-GFP and the low levels of

neutralizing antibodies that the macaques developed against the vector up to

21 days following treatment. Together, these data suggest that high levels of

transduction are achieved with Anc80 in inner ear cells, without inducing cell death

or triggering a CNS immune response.

As the company prepares for an IND submission in 2H20 for their lead Anc80

candidate, management is engaging with multiple institutions to begin genetic

screening in newborns with confirmed deafness. The company estimates initial

studies in infants younger than 1 year old will initially take place outside of US

since there is higher potential for benefit and less risk for long, slow degeneration

over time in infants due to the health of hair cells being greater with younger age.

Moreover, the company notes that language plasticity is reduced after 3 years of

age, so they expect some children may be able to develop language skills following

treatment with the Anc80 gene therapy. Looking ahead, Akouos expects clinical

endpoints to include measurements of signal or noise detection, speech

perception, and QoL outcomes. Management has also scheduled a pre-IND

meeting with the FDA in September, and will have more clarity on the exact timing

of the IND submission thereafter (currently estimated for 2H20).

In addition, the company stated that it potentially has 3 programs that may enter

the clinic over the next 5 years, which includes work across 15 different types of

hearing loss. Management is setting up an internal research network as well as

strategic collaborators to establish proof of concept in mouse models to accelerate

lead programs that show early viability. Importantly, the company has an ongoing

manufacturing collaboration with Lonza that should provide supply for preclinical

and clinical needs in the near-term.

Akouos (Private, Page 2 of 2)

Source: Akouos Company Reports. Piper Jaffray Research.

Upcoming Catalysts

EXHIBIT 75


Sensorineural Hearing Loss UndisclosedAnnounce target gene selection in

September 2019

Sensorineural Hearing Loss Undisclosed IND submission in 2H20

Dose-dependent Transduction with Anc80 Vector and Cochlear Frequency

EXHIBIT 74


Amicus is a fully integrated, global rare disease gene therapy company

that has the largest portfolio of gene therapies for rare diseases in the field.

Amicus’ lead gene therapy candidates include:

• AAV-CNL6: an AAV-based viral vector expressing the CLN6 gene that

encodes the linclin protein for the treatment of Batten disease

• AAV-CLN3: AAV-based viral vector expressing the CLN3 gene that encodes

the battenin protein for the treatment of Batten disease

• AAV-GAA: AAV-based viral vector expressing the GAA gene that encodes the

alpha glucosidase enzyme for the treatment of Pompe disease

Amicus’ main Batten disease asset in AAV-CLN6. Batten disease with the

CLN6 variant is characterized by late-infantile onset of disease and symptoms

including developmental delay, seizures, and eventual loss of mobility before

death. 12 children have been dosed with AAV-CLN6 to date, and to date, there is

no disease progression in children 30 months old at the time of treatment with

AAV-CLN6. Data in 7 additional patients at 2 years will be reported in 3Q19.

Amicus is also developing AAV-CLN3, an AAV-based gene therapy that

replaces the protein battenin. Batten disease caused by CLN3 mutations is also

rapidly progressive and leads to vision impairment, movement problems, and

seizures before death. Amicus has completed dosing of AAV-CLN3 in three

children in the low dose cohort and expects to dose three more in a higher dose

cohort in H2:2019. Preclinical data showed AAV-CLN3 improved motor function,

cognitive behavior, and survival in a Batten disease mouse model.

The company also has a preclinical gene therapy candidate for Pompe

disease. Amicus is developing hAAV-GAA to treat Pompe patients, who

experience symptoms including weak muscles, enlarged livers, failure to gain

weight, and respiratory issues. Preclinical data showed that hAAV-GAA reduced

glycogen levels in the central nervous system, as shown by glycogen Luxol/PAS

staining, in GAA knockout mouse spinal cord tissue.

Amicus Therapeutics (FOLD): Not Covered


Upcoming Catalysts

EXHIBIT 77


Batten Disease AAV-CLN62-year data from 7 patients

in 3Q19

Batten Disease AAV-CLN3Dosing of 3 additional children

in 2H19

Pompe Disease AAV-GAA Continued preclinical development

Amicus’ Pipeline

EXHIBIT 76


Indication Program Preclinical Phase I/II

Fabry Disease AAV-GLA

Batten Disease AAV-CLN6




Pompe Disease AAV-GAA

CDKL5 Deficiency AAV-CDD

Niemann-Pick Type C AAV-NPC

MPS IIIB Undisclosed

MPS IIIA Undisclosed


AskBio: Advancing the therapeutic boundaries of clinical gene therapies.

Asklepios BioPharmaceutical (AskBio) is a privately held AAV gene therapy

company founded in 2001, engaged in the development, manufacture, and delivery

of novel gene therapies to treat a number of devastating diseases. The company

harnesses the scientific expertise Dr Jude Samulski, the former Director of the

Gene Therapy Center at the University of North Carolina, and a co-founder and

current CSO of AskBio, to drive continued innovation in gene therapy development

with unique viral cassettes (i.e., self-complementary vectors, synthetic promoters)

and next-generation chimeric capsids with enhanced properties including improved

tissue selectivity and immune system evasion.

A differentiated business model. AskBio acts as a project incubator by internally

developing drug candidates and after a certain successful point, establishes a new

therapeutically-focused subsidiary special purpose entity (SPE) to continue

development. This model has a proven track record of success, with AskBio

successfully spinning out two SPE’s – Chatham Therapeutics (acquired by Baxter

in 2014) and Bamboo Therapeutics (purchased by PFE in 2016).

Scaled-up manufacturing. AskBio is a pioneer in vector manufacturing, and has

developed a proprietary gene therapy manufacturing system with the Pro10 cell

line, a suspension-adapted, HEK293 cell-based platform. The system requires no

up-front development (transient transfection system), and produces some of the

highest viral yields in the field. The system has been optimized to produce fewer

empty capsids and is universal so that it can produce all serotypes and chimeric

forms of AAV, and is currently scalable to 2000 L.

Asklepios BioPharmaceutical (Private)

Source: AskBio. Piper Jaffray Research.

EXHIBIT 78

AskBio’s Gene Therapy Pipeline


Indication Program Discovery Preclinical Phase I/II

Pompe disease AAV2/8-GAA

Limb Girdle 2i AAV

Huntington’s AAV

Epilepsy AAV

Parkinson’s

DiseaseAAV

Congestive Heart

FailureAAV

Clinical programs ongoing. Though we don’t have much clarity on future clinical

updates, AskBio currently has Phase I/II programs ongoing for Pompe disease

(ACTUS-101; first patient dosed January 22, 2019) and Parkinson’s disease, with

additional programs potentially moving into the clinic in 2019 and 2020.


Developing AAV-based therapies to treat rare neuromuscular disorders.

Audentes (BOLD) is an AAV-based genetic medicines company focused on

developing and commercializing innovative therapies for serious rare

neuromuscular diseases. The company focuses on developing AAV-based genetic

medicines for monogenic diseases using BOLD’s proprietary AAV gene therapy

technology platform. The company currently has six gene therapy programs in

development, with BLA filing for lead candidate AT132 expected mid-2020.

A robust pipeline with a number of candidates brimming to enter the clinic

soon. Lead candidate AT132 has continued to show impressive results in children

with X-linked myotubular myopathy (highlighted in more detail on the following

page), and after recent discussions with FDA and EMA, BOLD is enrolling

8 additional patient in a pivotal expansion cohort to generate final data requested

by regulators to support regulatory filings next year. Beyond AT132, BOLD expects

two additional programs to enter the clinic this year – AT845 (AAV8-GAA) in

Pompe disease and AT702 (AAV9-ASO) a vectorized approach to drive exon

skipping of the mutant dystrophin gene in Duchenne muscular dystrophy.

In-house gene therapy manufacturing has its perks. BOLD invested early on in

internal large scale cGMP manufacturing, with a state-of-the art facility located in

San Francisco, and is currently manufacturing at 1,000 L scale (2 x 500 L

bioreactors) with capacity to increase to 8,000 L if needed. The company uses a

transient transfection platform with a mammalian (HEK293) serum-free suspension

culture system for gene therapy product production, and recently brought internal

plasmid manufacturing in-house to improve supply chain control, reduce costs, and

accelerate production timelines for key starting material.

Audentes Therapeutics (BOLD): Raymond, OW (Page 1 of 2)


EXHIBIT 79

BOLD’s Gene Therapy Pipeline

EXHIBIT 80

Upcoming Catalysts


Pompe AT845 Expected IND submission 3Q19

XLMTM AT132 Phase I/II ASPIRO update at WMS Oct. 1–5, 2019

XLMTM AT132Complete dosing in pivotal expansion cohort by

Fall 2019

DMD AT702 P1/2 trial initiation 4Q19

DMD AT702 Submit IND-amendment for new AT702 product 1Q20

XLMTM AT132 Expected BLA filing mid-2020


Indication Program Discovery Preclinical Phase I/II

XLMTM AT132

Pompe AT845

DMD

(Exon 2, 1-5)AT702

DMD

(Exon 51)AT751

DMD

(Exon 53)AT753

Myotonic

DystrophyAT466


Spotlight on AT132 for the treatment of XLMTM. XLMTM is a rare genetic

disorder that primarily affects boys, and is characterized by severe muscle

weakness resulting in feeding difficulties and breathing complications, with only

~50% of affected children surviving to their 2nd birthday. AT132 is an AAV-based

gene therapy designed to deliver a functional copy of the myotubularin gene

(MTM1) to patients. In May, BOLD presented updated results for Cohorts 1

(1E14 vg/kg) and 2 (3E14 vg/kg) in the ongoing Phase I/II ASPIRO trial for AT132,

with continued clinical benefits observed in all patients in Cohort 1, and initial

(~6 month) positive data for Cohort 2, with accelerated muscle recovery

demonstrated.

• Impressive muscle recovery in Cohort 2 patients. As highlighted by a study

histologist, the muscle in XLMTM recovers in a two-step process. First, the

cellular machinery must return to its proper position in a cell, which is measured

through organelle localization. Following this, muscle fibers can begin to grow

and recover. In Cohort 1 (Exhibit 81), patients had improved organelle

localization at 6 months, and fiber growth was observed in the 1-year muscle

biopsy samples. Cohort 2 had a more rapid time to recovery, with more normal

organelle localization and fiber growth observed at 6 months in these patients.

• Cohort 2 hit expectations; Cohort 1 patients continued to improve.

For Cohort 2 (n=3), functional benefits were observed across the board, with an

average increase in CHOP-INTEND (measure of neuromuscular function) of

~56%. For patients in Cohort 1, patients tended to improve the longer they’re

monitored after AT132 treatment, and the trend continued with improvements in

CHOP-INTEND scores and reductions in ventilator use noted (Exhibit 82).

Audentes Therapeutics (BOLD): Raymond, OW (Page 2 of 2)


EXHIBIT 82

Rapid Reductions in Ventilator Use in All Treated Patients

EXHIBIT 81

Improvements in Histopathological Hallmarks of XLMTM

Cohort 1 (1E14 vg/kg) Cohort 2 (3E14 vg/kg)


AVROBIO is a clinical stage company developing ex vivo lentiviral-based

gene therapies to potentially cure rare genetic diseases with a single dose of

gene therapy. The technology underpinning these therapies is the company’s

proprietary commercial plato platform, which combines their lentiviral vector system

with an automated, closed cell manufacturing system for CD34+ gene therapy.

The system is designed to consistently produce potent cells with enhanced gene

activity and long-term durability.

Each drug product comprises autologous CD34+ cell-enriched fractions of

HSCs transduced with a lentiviral vector containing a transgene encoding for

the following protein of interest:

• AVR-RD-01: human α-galactosidase A (AGA) for Fabry disease

• AVR-RD-02: glucocerebrosidase (GCase) for Type 1 Gaucher Disease

• AVR-RD-03: acid alpha-glucosidase (GAA) for Pompe disease

• AVR-RD-04: CTNS gene encoding cystinosin, for patients with cystinosis

AVRO’s gene therapy treatment protocol involves mobilization of a patients

CD34+ hematopoietic stem cells (HSC) from their peripheral blood stem cells

(PBMC). CD34+ cells are then transduced with the relevant lentiviral vector.

Patients undergo myeloablative preconditioning with busulfan prior to the infusion

of the drug product to enhance engraftment.

In July 2019, AVRO provided a data update on its lead asset, AVR-RD-01, with

8 patients dosed across Phase I and II trials. In the Phase I trial, a

30%–40% reduction in plasma lyso-Gb3 levels compared with baseline ERT was

observed in four patients. The reduction in leukocyte and plasma AGA enzyme

activity has been sustained >2 years in Patient 1, coincident with stable VCN

(~5%–10% of all nucleated cells average 1–2 copies of the transgene). AEs were

generally consistent with myeloablative conditioning, underlying disease, or

pre-existing conditions. No SAEs related to the drug product were reported. A mild

increase in anti-AGA antibody titer was observed in one patient.

AVROBIO (AVRO): Not Covered (Page 1 of 2)

Source: AVROBIO Investor Presentations. Piper Jaffray Research.

EXHIBIT 83

AVROBIO’s Pipeline

EXHIBIT 84

AGA Enzyme Activity in Phase I Trial of AVR-RD-01 for Fabry Disease

Note: Enzyme measurements are taken at ERT troughs; Dotted line illustrative onlyPatient #5’s Day 12 data point was utilized since the one month data was not obtained


The ongoing Phase II FAB-201 trial of AVR-RD-01 for Fabry Disease has

reported promising early data. The first patient dosed achieved an

87% reduction from baseline in the average number of Gb3 inclusions per

kidney peritubular capillary (PTC) 1 year post treatment (the primary efficacy

endpoint). Reductions in substrate inclusions were also recorded in skin endothelial

cells. These clinical improvements coincided with sustained leukocyte and plasma

AGA enzyme activity at 1 year, and VCN stability.

Kidney and cardiac function remained stable in this patient at 1 year, and no

unexpected safety events have been identified among the 3 patients dosed in the

Phase II trial to date. Secondary efficacy endpoints will evaluate kidney and cardiac

function, GI distress, pain, QoL, and various biomarkers. The study continues to

enroll (N=8) and is estimated to complete in December 2020.

AVROBIO’s beginning-to-end manufacturing platform, plato, provides the

foundation for worldwide commercialization. In 2019, plato obtained regulatory

clearance for Fabry disease in the US, Canada, and Australia. It is also cleared for

use in Gaucher disease in Canada. The proprietary vector toolbox has driven

improvements in VCN, transduction efficiency, and enzyme activity, with transgene

distribution shown in the kidney, brain, bone, muscle, and heart. Therapeutic drug

monitoring informs optimal balancing of engraftment with potential toxicity.

AVROBIO (AVRO): Not Covered (Page 2 of 2)

Source: AVROBIO Investor Presentations. Piper Jaffray Research.

EXHIBIT 85

FAB-201: Substrate Reduction in Kidney Biopsy 1 Year Post Treatment

EXHIBIT 87

Upcoming Catalysts

Indication Drug Upcoming Catalysts

Fabry AVR-RD-01FAB-201 Phase II trial recruitment continues;

plato to be incorporated

Gaucher AVR-RD-02

Initiate GAU-201 Phase I/II clinical trial in patients

with Type 1 Gaucher Disease in 2H19,

incorporating plato from the outset

Cystinosis AVR-RD-04Initiate Phase I/II investigator-sponsored clinical

trial and dose first patient in 2H19

Pompe AVR-RD-03 Initiate preclinical IND-enabling study 2H19

Unpaired t test for

difference between n=55

PTCs at baseline vs n=101

PTCs at 1 year; p < 0.0001

Error bar represents the

standard deviation

EXHIBIT 86

Scalability of the plato Platform for Commercial Supply


Company Overview. Axovant is a clinical stage company that focuses on

developing gene therapies for serious neurological conditions. The company has

three gene therapy candidates in their pipeline for the treatment of Parkinson’s

Disease, GM1 gangliosidosis, and GM2 gangliosidosis. All three programs are in

the clinic and data for the PD and GM1 programs are expected later in 2019.

Lead candidate AXO-LENTI-PD is in Phase II development for Parkinson’s

Disease. AXO-LENTI-PD is a lentivirus-based therapy that delivers all three genes

required for endogenous dopamine synthesis – tyrosine hydroxylase (TH),

cyclohydrolasae (CH1), and aromatic L-amino acid decarboxylase (AADC).

The therapy is administered directly into the brain (putamen) by MRI-guided

stereotactic delivery. The goal of therapy is to reduce variability and restore steady

dopamine levels in the brain, which should translate to motor function improvement

with less dyskinesia. AXO-LENTI-PD was acquired from Oxford Biomedica in

June 2018. The construct was modified to enhance co-localization of the TH and

CH1 proteins (with the goal of tonic generation of dopamine). The company is

currently running a Phase II trial of the gene therapy (“SUNRISE-PD”). The 2-part

trial includes a dose-escalation and dose-expansion phase. Part A (or dose-

escalation) is open-label, and includes 3 dose levels. Once the optimal dose is

selected, it will be moved into Part B, where patients will be randomized 1:1 to

treatment vs sham control for primary endpoint evaluation.

Initial clinical data with AXO-LENTI-PD show signals of efficacy. In June 2019,

Axovant announced 6-month data from SUNRISE-PD’s first dose cohort

(4.2 x 106 TU). The results showed increases in “ON” times (when levodopa

treatment is working) without any dyskinesia – a common side effect of levodopa

treatment. There was a reduction of ~21% in average levodopa dose requirements

(Exhibit 89). Patients also showed a 17-point improvement from baseline in the

UPRDS III Motor score (FDA-recognized scale measuring motor function in PD).

Positioning of gene therapy in PD treatment paradigm. Axovant will initially

target the ~10,000 PD patients who currently undergo deep brain stimulation

(DBS). These patients are generally in the later stages of the disease, and DBS is

an equally invasive procedure as that required for gene therapy delivery. Data from

their 2nd dose cohort (4Q19E), is expected to guide future program directions.

Axovant Gene Therapies (AXGT): Not Covered (Page 1 of 2)

Source: Axovant Gene Therapies. Piper Jaffray Research.

EXHIBIT 88

Axovant’s Clinical Pipeline

EXHIBIT 89

Phase II SUNRISE-PD Dose Cohort I Data


Axovant is also developing gene therapies for GM1 and GM2 gangliosidosis.

Both GM1 and GM2 are fatal pediatric lysosomal storage disorders.

GM1 gangliosidosis is caused by deficiency in beta-galactosidase (lactase) while

GM2 gangliosidosis (Tay-Sachs/Sandhoff) is caused by deficiency in

beta-hexosaminidase (HexA). There are no approved disease modifying therapies

available for either indication.

Axovant dosed a 30 month-old baby with Tay-Sachs disease with AXO-AAV-GM2

via intrathecal and intrathalamic injections (Exhibit 90, top right). Natural history

data suggest HexA enzyme activity correlates with severity of disease and

restoration of HexA activity to 0.5% of normal could produce a clinically meaningful

effect. This therapeutic threshold appears achievable, as CSF HexA activity in the

first treated patient increased by ~3-fold vs baseline (see top right).

Axovant is also dosing patients with GM1 gangliosidosis with AAV-AXO-GM1 in a

registrational study. Part A of the two-part adaptive design trial is evaluating safety

and efficacy of 1.5 x1013 vg/kg of the vector in 4 GM1 patients. Efficacy will be

assessed by monitoring developmental changes using the VINELAND-3 scale and

physiological changes via MRI visualization. AAV-AXO-GM1 is administered by

IV infusion in order to address both systemic manifestations (osteoporosis and

blindness) and CNS-specific aspects of the disease. Initial clinical data are

expected in 4Q19 and will include safety/tolerability, CSF and serum biomarkers,

clinical and development changes, and MRI visualizations.

Manufacturing partnership in place. The company recently announced a

partnership with Yposkesi (a spinout from Genethon) to manufacture cGMP grade

viral vector for their gene therapy programs. The arrangement provides preferred

access and reserved capacity for vector production to Axovant that is sufficient to

meet the expected demand for the gene therapy. Under the agreement, Yposkesi

will provide process development expertise, technology transfer, manufacturing

scale-up, quality control, and quality assurance services.

Axovant Gene Therapies (AXGT): Not Covered (Page 2 of 2)

Source: Axovant Gene Therapies. Piper Jaffray Research.

EXHIBIT 91

Upcoming Catalysts

Indication Gene Upcoming Catalyst

PD TH-CH1-AADC 3-month update on Cohort 2 in 4Q19

GM1Beta-

galactosidase3-month data from patients in 4Q19

GM2 HexA Interim data expected in 2H19

EXHIBIT 90

AAV-AXO-GM2 Appears Safe and Shows Signals of Efficacy in First GM2

(Tay-Sachs) Patient Dosed


Growing the ophthalmology portfolio with recent acquisition of Nightstar

Therapeutics. Biogen, a biopharmaceutical company focused on developing

therapies for serious neurological and neurodegenerative diseases, recently

accelerated their ophthalmology efforts with the acquisition of Nightstar

Therapeutics in mid-2019, bringing in up to seven new programs to the pipeline –

clinical candidates NSR-REP1 (now BIIB111), an AAV2 for choroideremia (CHM),

and NSR-RPGR (now BIIB112), an AAV8 for X-linked retinitis pigmentosa, as well

as five additional preclinical candidates including NSR-ABCA4 for Stargardt

disease, and NSR-BEST1 for Best disease.

Biogen (BIIB): Raymond, N

Source: BIIB. Piper Jaffray Research.

EXHIBIT 92

BIIB’s Gene Therapy Pipeline

EXHIBIT 93

Upcoming Catalysts


CHM BIIB111 Phase III data expected in 2H20

XLRP BIIB112 Phase II/III data expected in 2H20

EXHIBIT 94

Evidence of Maintained Visual Acuity in Phase I/II Studies


Indication Program Preclinical Phase I Phase II Phase III

Choroideremia BIIB111

XLRP BIIB112

Stargardt

diseaseNSR-ABCA4

Best disease NSR-BEST1

Additional

programsUndisclosed

Compelling Phase I/II proof-of-concept data in CHM. Based on measurements

of visual acuity, initial studies of NSR-REP1 (BIIB111) demonstrated a higher rate

of maintained vision (loss of <5 letters) with only 8% of patients receiving high dose

gene therapy treatment losing ≥5 letters on the ETDRS chart compared to 13% of

patients in the NIGHT natural history study over a one year period. At 20 months,

22% of patients in NIGHT had lost five or more letters compared to a consistent

8% of patients treated with gene therapy at 24 months.

In addition, 21% of patients treated with NSR-REP1 demonstrated a meaningful

improvement in visual acuity (gain of ≥15 letters on ETDRS chart) at one year post-

treatment compared with only 1% of patients in the NIGHT study.

NSR-REP1 is currently in a randomized, open-label Phase III study (n=111)

assessing two doses of gene therapy (low vs high dose) in patients with

choroideremia, with data expected in 2H 2020.


A diversified rare-disease growth story with a soon-to-be validated gene

therapy platform. BMRN has developed and commercialized a number of

biopharmaceuticals for rare diseases, and currently has two gene therapy programs

in development – valoctocogene roxaparvovec, or valrox (AAV5-F8) for the

treatment of hemophilia A, and BMN 307 (AAV5-PAH) for the treatment of PKU.

Phase I/II updates for valrox have been impressive, with the latest year 3 update

(Exhibit 96) indicating a plateauing of FVIII activity (as measured by the

chromogenic assay) and demonstrating durable and clinically meaningful reductions

in annualized bleed rates (ABRs) and exogenous FVIII usage. These data, in

combination with recently disclosed interim data from the Phase III (additional

details on next page) will support FDA and EMA regulatory filings through an

accelerated approval pathway, with submissions expected in 4Q19.

Valrox launch will be supported by in-house gene therapy manufacturing.

BMRN utilizes an insect producer cell line platform to manufacture product with the

current setup supporting multiple 2000 L bioreactors and treatment of 4000+

patients per year. BMRN has conducted Phase III studies with material

manufactured at scale in the “to be” commercial facility, which simplifies process

validation efforts, avoids the need for conducting large, time consuming

bioequivalence bridging studies, and reduces potential regulatory concerns.

The platform has been optimized to increase viral titers (~30x more productive than

human cell lines in their hands), reduce the number of empty capsids produced,

and drive transduction efficiency that is on par with, if not better than, mammalian

cell platforms.

BioMarin Pharmaceutical (BMRN): Raymond, OW (Page 1 of 2)

Source: BMRN. Piper Jaffray Research.

EXHIBIT 95

BMRN’s Gene Therapy Pipeline


Indication Program Preclinical Phase I/II Phase III Registration

Hem A Valrox

PKU BMN 307

UndisclosedSeveral

undisclosed

EXHIBIT 96

Phase I/II Update: Durable Efficacy Benefits Continue to Year 3

FV

III A

cti

vit

y (

IU/d

L)

Annualized Bleed Rate Control Reductions in FVIII Usage


Recap of Phase III valrox data. Prior discussions with FDA indicated valrox

would be eligible for regulatory review using an accelerated approval pathway if

initial data from a subset of patients in the ongoing Phase III study met a

pre-specified number of patients achieving FVIII levels above 40 IU/dL by

23 weeks. The company hit the pre-specified interim analysis endpoint, and plans

to submit regulatory filings for valrox to FDA and EMA in 4Q19.

• Phase III hits on pre-specified FDA expectations. As of the April 30, 2019

cut-off, 16 subjects had reached the 26 week post-treatment timepoint, and

seven had mean FVIII levels above 40 IU/dL. It was noted that an eighth

subject met this pre-specified criteria after the data-cut off and three more

subjects are expected to be evaluated. Though three patients were

unevaluable, we anticipate seeing data from these subjects during the next

tranche of updates expected in 2020.

• Efficacy demonstrated on other measures, too. In regard to annualized

bleed rates (ABRs, episodes/year) and FVIII usage (infusions/year), patients in

the interim analysis cohort demonstrated dramatic reductions in ABRs from

~10/year on SoC to ~1.5/year within 6 months of treatment, and mean FVIII

usage meaningfully decreased by ~95%. These data, in combination with

longer-term follow up in patients from the Phase I/II study will be used to

support regulatory filings to FDA and EMA in 4Q19.

BioMarin Pharmaceutical (BMRN): Raymond, OW (Page 2 of 2)

Source: BMRN. Piper Jaffray Research.

EXHIBIT 97

Phase III Update: FVIII Activity Hits on Pre-Specified FDA Expectations

EXHIBIT 98

Upcoming Catalysts


Hem A Valrox FDA and EMA regulatory filings expected 4Q19

Hem A Valrox Potential FDA and EMA approvals in 2020

PKU BMN 307 Potential IND filing expected by YE19

Annualized Bleed Rate Control Reductions in FVIII Usage


bluebird bio is developing a pipeline of gene therapies for severe genetic

diseases. bluebird’s pipeline includes several drug candidates that have the

potential to transform the way clinicians treat patients.

Lenti-D, one of bluebird’s first products to reach the clinic, is an autologous

HSC therapy for patients with cerebral adrenoleukodystrophy (CALD), a rare

hereditary neurological disorder. This therapy provides functional

adrenoleukodystrophy protein (ALDP) to the brain to prevent life-threatening

disease progression, which includes severe myelination degradation and

cerebral inflammation.

The next most-advanced candidate is Zynteglo/LentiGlobin, which is being

developed as a therapy for transfusion-dependent β-thalassemia (TDT) and

severe sickle cell disease (SCD). This product corrects the defective globin gene

by the patient’s HSCs, which when reintroduced to the patient, can produce red

blood cells (RBCs) with functional and anti-sickling hemoglobin. The company

currently has five clinical studies to evaluate the efficacy and safety of LentiGlobin

in these indications.

Recently, bluebird made significant improvements to the HSC protocol which

have increased HSC quality and, importantly, improves the patient

experience by eliminating the need for bone marrow harvest. These changes

have led to better drug product characteristics which should increase clinical

efficacy – not only for this product – but for future candidates as well. The improved

protocol has been implemented in ongoing LentiGlobin clinical studies and the

learnings can be applied across the HSC platform.

smIR approach offers another way to edit HSCs. As an alternative strategy to

the company’s gene therapy approaches, we note that gene editing has the

potential to offer effective treatment options in the future. This product utilizes

bluebird’s lentiviral vector delivery technology to introduce a microRNA- (miRNA)

embedded short hairpin RNA (shRNA), referred to as shRNAmiR, to knock down

the enhancer of BCL11a. Suppression of this target is intended to upregulate fetal

hemoglobin and provide potential relief to patients with severe SCD.

bluebird bio (BLUE): Van Buren, N (Page 1 of 3)


Upcoming Catalysts

EXHIBIT 100


β-thalassemia (TDT) Zynteglo Ongoing

LentiGlobin LentiGlobin Phase III Initiation By YE:2019

CALD Lenti-D BLA/MAA Submission By YE:2019

bluebird bio Severe Genetic Disease Pipeline

EXHIBIT 99


Zynteglo is bluebird’s most-advanced gene therapy product for

hemoglobinopathies. bluebird is developing a potential one-time curative gene

therapy, Zynteglo, for patients with transfusion-dependent thalassemias (TDTs).

This approach uses a self-inactivating lentiviral vector to introduce a single codon

variant (T87Q) of the normal β-globin gene into the patient’s HSCs to induce the

production T87Q-globin and incorporation of it into normal functioning hemoglobin

A in the RBCs. Thus, the final drug product is the patient’s own genetically-

modified HSCs, and the T87Q mark can serve as a biomarker for in vivo production

of functional hemoglobin in patients. Zynteglo has been granted Orphan Drug

status by the FDA and EMA for β-thalassemia. Additionally, the FDA has granted

Breakthrough Therapy designation and the EMA has granted Priority Medicines

(PRIME) eligibility for the treatment of TDT patients.

Latest data overview in TDT. The company has initiated companion international

Phase I/II clinical studies to evaluate the safety and efficacy of Zynteglo using the

BB305 vector – an improved but similar vector similar to HPV569. The goal of the

studies is to observe increases in hemoglobin production that eliminate or reduce

dependency on chronic transfusions after treatment. bluebird believes that an

increase in hemoglobin levels could reduce or eliminate the need for chronic

transfusions in TDT patients. In the Phase I/II Northstar study (HGB-204), one of

the company’s longest running trials, patients have achieved up to 3.8 years of

transfusion independence. In the Phase III Northstar-2 study (HGB-207), which

utilizes a refined manufacturing process, the median total hemoglobin level at

6 months post-infusion was 11.9 g/dL with 9.5 g/dL being that from T87Q (n=11).

Patients who achieved transfusion-independence (TI, n=4) achieved an average

total hemoglobin level of 12.4 g/dL. In both of these studies, all patients who

achieved TI have maintained TI. Based on these results, bluebird believes that

once TI has been achieved, it is possible that the effects of Zynteglo will be lifelong.

The ongoing Northstar-3 (HGB-212) study is evaluating Zynteglo in patients with

the β0/β0 genotype (n=15). Currently, for the 5 patients who are 3 or more months

post-infusion, hemoglobin levels are between 10.2–13.6 g/dL. All studies described

above are intended to serve the basis of regulatory filings in both the US and EU.



EXHIBIT 101

HGB-204: 8/10 Patients With Non-β0/β0 Have Achieved TI

EXHIBIT 102

HGB-212: Gene Therapy-Derived T87Q Significantly Contributes To Hb Levels


HGB-206: Median HbS ≤50% of Total Hb in Patients With ≥6 Months Follow-Up

bluebird is seeking to provide relief to SCD patients through their LentiGlobin

product. As described previously, the self-inactivating lentiviral vector encodes the

T87Q variant, which in addition to providing the formation of functional hemoglobin,

also inhibits hemoglobin polymerization, which is critical to reducing the symptoms

in SCD patients. Therefore, this product has the potential to provide a long-term

and potentially curative treatment for SCD. Similar to LentiGlobin for use in

β-thalassemia, it has also been granted Orphan Drug status by the FDA and EMA

for SCD, and Fast-Track designation by the FDA for the treatment of severe SCD.

The FDA has also granted Regenerative Medicine Advanced Therapy (RMAT)

designation for the treatment of severe SCD. Bluebird is actively engaged with

these regulatory agencies in regards to their proposed development plans for

LentiGlobin in severe SCD.

Latest data overview. The benefits of LentiGlobin in SCD patients are indisputable

and potentially offer a cure for patients who are suffering from severe SCD.

In Group A patients with 30–36 months follow-up (ASH 2018), patients achieved

T87Q levels of 0.7–2.8 g/dL, total Hb of 7.6–11.8 g/dL, 6/7 patients achieved RBC

TI (n=6/7), and VOEs declined by 71.5%. In Group B patients with 15–18 months

follow-up (ASH 2018), 2 patients achieved T87Q levels of 3.4 and 6.5 g/dL, total Hb

of 11.0 and 12.3 g/dL, and experienced 84% and 100% reductions in VOEs.

In Group C patients (EHA 2019) the refined manufacturing procedure yielded drug

product that at ≥6 months provides robust HbA-T87Q production between 4.5 and

8.8 g/dL, total Hb of 10.2–15.0 g/dL, decreased reduction in hemolysis, and

pan-cellular distribution of T87Q. Median HbS for these patients was ≤50% of total

Hb in patients with ≥6 months follow-up. No serious ACS or VOCs occurred in any

Group C patient post-LentiGlobin treatment to date (n=6).

Based on the increases in the Hb/HbS ratios, total Hb levels, and reduction in

VOEs observed in patients thus far, we believe the HGB-206 trial is likely to meet

both primary and secondary endpoints, especially given the fact that these

endpoint criteria have been met in patients who received a less-optimal drug

product. The HGB-210 Phase III study is expected to launch this year and with the

primary endpoint being T87Q and total hemoglobin levels.



EXHIBIT 103

Hypothesis For LentiGlobin In Severe Sickle Cell Disease

EXHIBIT 104


Adrenas is a corporate subsidiary of BridgeBio (BBIO; Tyler Van Buren, OW)

and is one of the four key value drivers of the company. Adrenas is developing

BBP-631, a gene therapy for congenital adrenal hyperplasia (CAH), which is

expected to be IND-ready by early 2020.

CAH is a rare, inherited, autosomal recessive disorder that is debilitating and

life-threatening. Over 90% of CAH cases are caused by inactivating mutations in

CYP21, the gene which accounts for the production of 21-hydroxylase enzyme

deficiency (21OH). 21OH deficiency sends cortisol/ACTH homeostasis into

disarray, where uninhibited ACTH primarily directs androgen production through

17OHP. This renders the patient unable to produce cortisol and aldosterone, while

producing an excess of testosterone, which can lead to fatal adrenal crises.

BBP-631 is an adeno-associated virus-5, or AAV5, gene therapy with a codon-

optimized CYP21A2 transgene and a constitutively active CAG promoter designed

to allow patients to achieve homeostatic control of adrenal hormones by treating

the root cause of the disease, 21OH deficiency. By expressing the CYP21

transgene, it replaces the 21OH defective gene in transduced adrenal cortex cells,

which then produce and replace the essential enzyme. 21OH, once restored, will

activate the natural hormonal and steroidal cycle by increasing aldosterone and

cortisol production, while reducing testosterone levels, and therefore minimizing the

risk of adrenal crisis.

BBP-631 has demonstrated the ability to transduce adrenal cortex cells and

produce 21OH in nonhuman primates (NHPs), which suggests that it can

potentially restore the natural hormonal and steroidal cycle that is disrupted in CAH

patients. RNA levels increased dramatically (>10x) in BBP-631-treated NHPs from

4 to 12 weeks at all three doses used (5E12, 1.5E13, and 4.5E13). Unsurprisingly,

the highest RNA expression was seen with the highest dose at 12 weeks. Overall,

data provided thus far suggest that there is significant transduction in the adrenals

with sufficient vector genome counts and mRNA expression three months following

a single dose of BBP-631. 24-week data will be key to assessing durability moving

forward, and should be reported soon. While we haven’t seen the data, the

company noted that durability is still being observed at this time point.

BridgeBio (Aspa) is also developing BBP-812, a self-complementary adeno-

associated viral vector 9 (scAAV9) gene therapy, to restore functional ASPA gene

expression in the brain. This is a potentially curative treatment for Canavan

Disease as it directly addresses the underlying genetic cause of disease. BBP-812

will deliver a functional copy of the ASPA gene using a brain-penetrant AAV9

delivery vector, which will be GMP manufactured in partnership with

Paragon Biosciences.

BridgeBio (BBIO): Van Buren, OW

Upcoming Catalysts


BridgeBio Gene Therapy Pipeline

EXHIBIT 105

EXHIBIT 106


Congenital Adrenal

Hyperplasia (CAH)BBP-631 IND filing by 1H20


Company Overview. Gemini Therapeutics is a biotechnology company focused

on developing treatments for genetically-defined dry age-related macular

degeneration (AMD) and associated ocular diseases. The company deems itself a

product engine that can utilize three different modalities (recombinant proteins,

monoclonal antibodies, and/or gene therapies) to treat diseases by finding the best

therapeutic solution for patients. Their main asset, GEM103, is a recombinant CFH

protein replacement currently in preclinical development for dry AMD, with

development ongoing for GEM104 (preclinical, rCFI protein replacement) and up to

three gene therapies (CFH, CFI, and one undisclosed target).

Precision medicine for dry AMD. AMD is the leading cause of irreversible

blindness in the US and EU, with currently no approved therapies. Genetic variants

identified within CFH, the gene that encodes Complement Factor H, have been

shown to increase the risk of developing dry AMD (some variants by 20x or more)

and also play a role in the severity of clinical phenotypes. Thus, restoring functional

CFH in certain patient subsets could be therapeutically meaningful, and the

company believes developing a recombinant protein and gene therapy could

provide an integrated solution to patient treatment.

Gemini Therapeutics (Private)

Source: Gemini Therapeutics. Piper Jaffray Research.

EXHIBIT 107

Gemini’s Gene Therapy Pipeline

EXHIBIT 109

Upcoming Catalysts


Dry AMD GEM103 CFH protein replacement; IND expected Q419

Dry AMD GEM103 Clinical data including pharmacological POC, 2020

EXHIBIT 108

Preclinical Data Limited, but Initial Recombinant Protein Data Interesting


Indication Program Discovery Preclinical Phase I/II Phase III

AMD CFH

AMD CFI

Other

ocular

Not

Disclosed

(Above) CFH is a complement control protein that functions by regulating both the

decay of C3 convertase and complement Factor I mediated C3b cleavage. In the

first panel, reduced CFH activity as a result of CFH mutations increases the time to

degrade C3 convertase, which drives complement pathway upregulation. In the

second panel, GEM103, the company’s recombinant CFH protein demonstrates

equivalent activity to endogenous FH in a cleavage assay. In the far right panel,

injection of GEM103 into the eye in NHP results in the stable expression of

supra-physiological levels of CFH in the primate eye.


Company Overview. Gene Therapy Research Institute (GTRI) is a Japanese

biotechnology company developing gene therapies for neurological disorders.

They have two lead programs: sporadic ALS (AAV.GTX-ADAR2) and Parkinson’s

Disease (AAV2-AADC, AAV2-TH-GCH). Both programs are currently in preclinical

testing, with Phase I/II studies expected to begin in 2020. GTRI also has earlier

stage preclinical programs in Spinocerebellar Degeneration Type 1 (SCA1),

Alzheimer’s Disease, GLUT1 Deficiency and Tay-Sachs Disease (a type of

GM2 Gangliosidosis).

The company has developed 2 novel vectors. AAV.GTX is designed for CNS

diseases and penetrates the blood-brain barrier. Preclinical testing has shown

better expression in nerve cells than the current gold-standard vector for CNS,

AAV9. Their AAV.GT5 vector is designed for metabolic diseases, and exhibits

higher expression in hepatocytes compared with other AAV vectors. No immune

reactions to neutralizing antibodies have been detected.

.

AAV.GTX entering the clinic for sporadic ALS in 2020. The company’s planned

Phase I/II study in sporadic ALS will employ the AAV.GTX vector and will deliver

the ADAR2 protein through an intrathecal injection. ADAR2 is an RNA-editing

enzyme that is involved in proper editing of glutamate receptors; mutation or

downregulation of the gene is thought to result in the glutamergic deficit and

calcium influx that is classically seen in ALS patients and implicated in motor

neuron death. The company is plans to use this study to apply for approval in

Japan under its conditional approval system around the middle of 2022.

GTRI’s PD gene therapy packages three proteins in two recombinant vectors

for administration as a single injection. GTRI’s unique method will have one

AAV2 vector housing the tyrosine hydrolase (TH) and cyclohydrolase (GCH) genes

and another AAV2 vector housing the larger aromatic amino acid decarboxylase

(AADC) gene. The three genes contribute to the biosynthesis of dopamine.

The distinct vectors will be delivered as a mixture via one intracranial injection into

the striatum. The goal of therapy is to generate tonic dopamine production that may

reduce involuntary movements and decrease oral levodopa usage. GTRI plans to

initiate a Phase I/II study in 2020 and believes the results will support conditional

approval in Japan by the end of 2022.

Gene Therapy Research Institute (Private)


EXHIBIT 110

GTRI’s Clinical Pipeline

EXHIBIT 111

Upcoming Catalysts


Sporadic ALS AAV.GTX-ADAR2Phase I/II trial initiation in 1H20

Potential approval in mid-2022 (JPN)

Parkinson’s

Disease

AAV2-AADC,

AAV2-TH-GCH

Phase I/II trial initiation in mid-2020

Potential approval by YE22 (JPN)


Krystal Biotech is developing novel “off-the-shelf” non-invasive modified

HSV-1 gene therapy products for the treatment of severe monogenic skin

diseases, aesthetic conditions, and chronic skin diseases (Exhibit 112).

The company developed a fully-integrated vector platform that employs

non-integrating, replication-incompetent HSV-1 vectors to directly deliver

transgenes of interest to the skin via topical application with high transduction

efficiency. The ~150 Kb genome of HSV-1 confers a large payload capacity,

accommodating multiple genes and effectors.

The company’s pipeline includes the following gene therapy products:

• KB103: Bercolagene telserpavec delivers a functional copy of the COL7A1

transgene to the compromised skin of patients with dystrophic epidermolysis

bullosa (DEB) to restore expression of functional collagen VII protein

• KB105: Delivers the wildtype TGM1 gene to keratinocytes for the treatment of

Autosomal Recessive Congenital Ichthyosis (ARCI) associated with TGM1

• KB301: Modified vector platform containing the human collagen gene is

formulated into an intradermal solution for the treatment of aesthetic defects

• KB104: Modified vector encoding optimized human SPINK5 for the treatment of

Netherton Syndrome

• KB5XX: The KB500 series includes vectors modified to carry anti-inflammatory

antibody effectors (full length and Ab fragments), formulated into a topical gel

for the treatment of chronic skin diseases such as atopic dermatitis

and psoriasis

KB103, KRYS’ lead pipeline candidate, is currently in Phase I/II development

for DEB. KB103 met the primary efficacy endpoints of functional COL7 expression

(observed as early as 2 days post treatment) and observation of NC1 and NC2

reactive anchoring fibrils in the two patients treated in the Phase I trial.

Combined analysis of Phase I and II efficacy data of KB103 in DEB

demonstrated complete closure of 7/8 KB103-treated wounds. The average

time to 100% wound closure was 20 days. Two patients in the Phase I study

achieved durable wound closure of 184 days and 174 days; preliminary Phase II

data indicate a 101 day duration of wound closure at the 120-day time point.

No treatment-related adverse events, immune responses, or blistering were

reported following initial or repeat doses of KB103. Analysis of blood and urine

samples confirmed the absence of viral shedding, clinical lab abnormalities, and

antibodies to COL7.

Preliminary in vitro and preclinical proof-of-concept and safety data with KB105

further support the notion that the proprietary off-the-shelf HSV-1 platform has the

flexibility to be adapted across multiple target genes of interest for the treatment of

a variety of dermatologic conditions.

Krystal Biotech (KRYS): Not Covered (Page 1 of 2)

Source: Krystal Biotech Q3 2019 Corporate Presentation. Bustos M et al. 2019 SID Annual Meeting. Piper Jaffray Research.

EXHIBIT 112

Krystal Biotech’s Pipeline


Krystal’s off-the-shelf system is differentiated from the majority of

competitive approaches that employ autologous, ex vivo genetically modified

cell therapies to treat severe skin diseases on multiple levels, including:

• Streamlined treatment approach is less invasive, expensive, and

time-consuming for patients and providers

• Reduced costs associated with manufacturing and supply chain

• Readily available for use in multiple patients

• Relative ease of administration by dermatologists in outpatient settings

Drug product preparation is conducted in-house at Krystal’s end-to-end GMP

manufacturing facility using upstream production and downstream purification

processes that are scalable from clinical phases to commercial production, and

compliant with global regulatory requirements.

Krystal Biotech (KRYS): Not Covered (Page 2 of 2)

Source: Krystal Biotech Q3 2019 Corporate Presentation. Bustos M et al. 2019 SID Annual Meeting. Piper Jaffray Research.

EXHIBIT 114

Off-the-shelf vs Autologous Ex Vivo Cell Therapy Production and Administration for Dermatologic Diseases

EXHIBIT 113

Upcoming Catalysts

Indication Drug Upcoming Catalysts

DEB KB103

• Commence pivotal Phase III trial in 2H19

• Commence EU trial in 1H20

• File BLA in 2H20

ARCI KB105• Commence phase I/II trial in 2H19; interim data

• Initiate pivotal trial in 1H20

Aesthetics KB301/302 • File IND in 2H19

Netherton KB104 • File IND in 1H20

- -• Break ground on second GMP manufacturing

facility in 1H20


MeiraGTx is a clinical stage gene therapy company with a diverse pipeline

that spans several ocular disorders, neurodegenerative disease, and salivary

gland disease, and incorporates a proprietary Riboswitch technology, which

precisely controls target gene protein production.

The pipeline includes:

• AAV-RPE65: AAV vector containing the RPE65 gene for the treatment of

RPE65-deficiency

• AAV-CNGB3 and AAV-CNGA3: AAV vector containing the CNGB3 gene or

CNGA3 gene for the treatment of achromatopsia

• AAV-RPGR: AAV vector containing the RPGR gene for the treatment of XLRP

• AAV-GAD: AAV vector containing the GAD gene for the treatment of PD

• AAV-AQP1: AAV vector containing the AQP1 gene for the treatment of

radiation-induced xerostomia

AAV-RPE-65 is the company’s lead ophthalmic gene therapy program.

It is administered as a subretinal injection of an RPE65-expressing vector for the

treatment RPE65-deficiency. The company plans to discuss registrational criteria

with the FDA for AAV-RPE65 in RPE65 deficiency by YE19, following the positive

Phase I/II readouts we saw earlier this year. In the Phase I/II trial of AAV-RPE-65,

a total of 15 patients were treated: 9 adults in 3 dose escalation cohorts and

6 pediatric patients in an expansion cohort. The study met its primary endpoint of

safety and tolerability at 6 months and met statistical significance across multiple

secondary endpoints including improvements in retinal sensitivity (p<0.01 for both

adult and pediatric cohorts). Visual acuity was also improved following AAV-RPE65

treatment (p=0.02 for adults, and p=0.03 for children).

The company’s achromatopsia program consists of two therapeutics.

AAV-CNGB3 is designed to restore cone function in achromatopsia patients with

mutations in CNGB3 and is administered by subretinal injection. The FDA and

EMA have granted orphan drug designation, rare pediatric disease designation,

Fast Track designation, and PRIME designation for this therapy. This program is

being developed under a co-development agreement with Janssen. Data from the

Phase I/II trial of AAV-CNGB3 for achromatopsia, which is currently ongoing, are

expected in 2019/20. A total of 23 patients have been enrolled, including

11 adults in dose escalation cohorts and 12 children in a pediatric expansion

cohort. Additionally, data from the Phase I/II trial for the second candidate,

AAV-CNGA3, are expected in 2022. A total of 18 pediatric patients are expected to

enroll in this trial. This product utilizes a synthetic promoter to yield robust gene

expression, which accounts for the larger amount of protein production needed to

restore cone function in patients with a CNGA3 mutation. It is also being developed

under the Janssen agreement.

MeiraGTx (MGTX): Van Buren, OW (Page 1 of 2)


MeiraGTx Pipeline

EXHIBIT 115


Meira’s is also developing AAV-RPGR for the treatment of the subset of XLRP

caused by mutations in RPGR. The FDA and EMA have granted orphan drug

designation and Fast Track designation. This program is being developed under

agreement with Janssen. Data from the ongoing Phase I/II trial of AAV-RPGR in

XLRP are expected in 2021. A total of 36 adult and pediatric patients are expected

to enroll.

In neurological disorders, the company’s main focus is Parkinson’s disease.

Nearly 1 million people in the US alone (and 10M people worldwide) are affected

by PD, making it the second-most common neurodegenerative disease after

Alzheimer’s disease. There are currently no approved gene therapies for PD.

However, Duodopda has been approved as a first line therapy for PD, and is a gel

for continuous intestinal administration of a mixture of levodopa and carbidopa.

MeiraGTx aims to replace this continuously administered drug with a one-time

gene therapy, AAV-GAD. AAV-GAD delivers the glutamic acid decarboxylase

(GAD) gene directly to subthalamic nucleus (STN) neurons and is designed to

rebalance excitation and inhibition by bypassing the circuitry disrupted by

dopamine loss. Expression of GAD should increase production of inhibitory GABA,

thereby normalizing the hyperactive motor circuits as a way to improve symptoms

in PD patients without affecting other brain regions. The company recently

completed a Phase II clinical study of AAV-GAD in 45 PD patients. The study met

its primary endpoint at 6 months of a change from baseline in off-medication

Unified Parkinson Disease Rating Scale (UPDRS) motor score (8.1 point

improvement for AAV-GAD vs 4.7 point improvement for sham, p<0.03).

The number of responders with clinically meaningful improvements of 9 points or

greater in UPDRS motor score was 50% in AAV-GAD treated patients and 14% in

the sham cohort at 6 months (p<0.03), which increased to 62% and 24% at

12 months, respectively (p<0.02). Moreover, there was a correlation between levels

of a biomarker for the formation of new polysynaptic pathways that link the STN to

motor cortical regions (GADRP, p<0.009). The company plans to discuss

registrational criteria with the FDA for AAV-GAD in PD by YE19.

In addition to a robust clinical pipeline, the company has developed in-house

manufacturing capabilities provided by a wholly-owned cGMP manufacturing

facility located in London. The facility allows for faster start up time, capabilities for

scaling to multiple programs and vector types, and acceleration of processing times

due to its modular design. The company is looking to expand its manufacturing

capacity in the near-term and is planning to produce plasmids in-house as well.

MeiraGTx (MGTX): Van Buren, OW (Page 2 of 2)


Upcoming Catalysts

EXHIBIT 116


Parkinson’s Disease AAV-GADMeet with FDA to discuss

registrational criteria by YE:2019

REP65 Deficiency AAV-RPE65Meet with FDA to discuss

registrational criteria by YE:2019

Achromatopsia AAV-CNGB3Data from the Phase I/II trial by

late 2019/early 2020

X-Linked Retinitis

PigmentosaAAV-RPGR Phase I/II data in 2021

Achromatopsia AAV-CNGA3 Phase I/II data in 2022

Radiation-Induced

XerostomiaAAV-AQP1 Phase I/II data in 2022


Company Overview. Orchard Therapeutics is a commercial-stage

biopharmaceutical company utilizing ex vivo autologous hematopoietic stem cell

(HSC) gene therapy to transform the lives of patients with rare diseases, with

current franchises spanning neurometabolic disorders, primary immune

deficiencies, and hemoglobinopathies (see below). To produce long-lasting effects,

the company uses a lentiviral vector to introduce functional exogenous copies of a

non- or dysfunctional gene into a patient’s own HSCs, which are isolated and

treated in an ex vivo process and then re-administered to the patient.

Deep portfolio of product candidates. Strimvelis is an EU marketed

gammaretroviral-based product for the treatment of adenosine deaminase severe

combined immunodeficiency (ADA-SCID), and ORTX has six lentiviral product

candidates in clinical-stage development, with several additional candidates in

preclinical development. ORTX anticipates near-term regulatory submissions for

approval of three advanced clinical-stage product candidates: OTL-101 for the

treatment of ADA-SCID, OTL-200 for metachromatic leukodystrophy (MLD), and

OTL-103 for the treatment of Wiskott-Aldrich syndrome (WAS).

Orchard Therapeutics (ORTX): Not Covered


EXHIBIT 117

Orchard’s Gene Therapy Pipeline

EXHIBIT 119

Upcoming Catalysts


ADA-SCID OTL-101 Regulatory filings expected 1H20

MLD OTL-200 EMA filing expected 1H20

WAS OTL-103 FDA/EMA regulatory filings expected in 2021

EXHIBIT 118

Ex Vivo Gene Delivery to HSCs Can Correct Multiple Diseases

Applicability across multiple diseases. Genetically modified HSCs have

wide-ranging uses for a number of indications (see above) given their ability to

differentiate into multiple cell types, which facilitates targeting of diverse

physiological systems, including the CNS, immune system, and red blood cell

lineage. By leveraging the innate self-renewing capability of HSCs as well as the

ability of lentiviral vectors to achieve stable integration of a modified gene into the

HSC genome, these therapies have the potential to provide a durable effect

following a single administration of product.


Company Overview. Passage Bio is harnessing decades of gene therapy

expertise to streamline the development of novel therapies for genetic neurological

diseases. Their co-founder and Chief Scientific Advisor, Jim Wilson, MD, PhD is a

world-renowned authority on gene therapy. Passage has a formal research,

collaboration, and license agreement with the Gene Therapy Program (GTP) and

Orphan Disease Center at the University of Pennsylvania, and currently has a

portfolio that includes treatments for GM1 gangliosidosis, frontotemporal dementia

(FTD) and Krabbe disease, which are primed to enter the clinic throughout 2020.

UPenn and Passage Bio Partnership Model. Under the unique partnership

model, UPenn’s GTP is responsible for all pre-clinical and IND-enabling studies,

after which Passage Bio takes responsibility for all clinical development. Passage

Bio’s partnership with UPenn gives them access to the initial 5 programs

(2 undisclosed) and the option to license 7 additional programs using next-gen

capsids. In return, UPenn receives an upfront payment, sponsored research

agreement funding, along with royalties and milestones from development and

potential sales. During clinical development, UPenn’s Orphan Disease Center is

responsible for the ongoing GM1 natural history study.

Preclinical biomarker data for AAV-GLB1 in GM1 and AAV-PGRN in FTD are

early indicators of efficacy. Initial studies of AAV-GLB1 in mice have shown

improvements in HEX activity upon administration. Additionally, preclinical work in

non-human primates (NHP) using AAV-PGRN has demonstrated 5–10x increases

of PGRN levels in the cerebral spinal fluid (CSF), compared with PGRN levels in

healthy human subjects (Exhibit 121). Both programs are expected to initiate

clinical development in 2020.

Passage Bio (Private)


EXHIBIT 120

Passage’s Gene Therapy Pipeline

EXHIBIT 122

Upcoming Catalysts


GM1 AAV-GLB1 Enter Phase I clinical development 1H20

FTD AAV-PGRN Enter Phase I clinical development 1H20

Krabbe

DiseaseAAV-GALC Enter Phase I clinical development 2H20

EXHIBIT 121

CSF Levels of PGRN After AAV-PGRN Treatment of NHPs vs Healthy Humans


Indication Program Preclinical Phase I Phase II Phase III

GM1 AAV-GLB1

FTD AAV-PGRN

Krabbe

DiseaseAAV-GALC


Rocket Pharmaceuticals, founded in 2015, is a clinical stage biotechnology

company with a robust pipeline of AAV- and LVV-based gene therapy programs

with potential to be first-in-class for rare and devastating pediatric diseases.

The company has generated a group of promising proprietary therapies, including:

• RP-A501: AAV9 vector containing the lysosome-associated membrane protein

2 B (LAMP2B) gene for the treatment of Danon Disease (DD)

• RP-L102: LVV containing Fanconi anemia complementation group A (FANCA)

gene for the treatment of Fanconi Anemia (FA)

• RP-L301: LVV containing the pyruvate kinase L/R (PKLR) gene for the

treatment of Pyruvate Kinase Deficiency (PKD)

• RP-L201: LVV containing the integrin subunit beta-2 gene (ITGB2) for the

treatment of Leukocyte Adhesion Deficiency-1 (LAD-1)

• RP-L401: LVV carrying the TCIRG1 gene, which encodes the a3 subunit of

vacuolar H+-ATPases, to treat infantile malignant osteopetrosis (IMO)

RP-A501 is Rocket’s lead AAV-based candidate for the treatment of

Danon Disease. Currently, there are no targeted therapies in development for DD.

DD is caused by mutations in the LAMP2B gene, which plays an important role in

autophagy. This mutation prevents clearance of cell debris which causes

pathological accumulation and often leads to profound cardiomyopathy. There are

approximately 40,000 patients with DD in the US and EU that could be treated by

Rocket’s RP-A501. RP-A501 is an AAV-delivery vector containing the LAMP2B

gene and has distinct tropism for the heart and skeletal muscle, which are target

tissues for the disease. Backed by strong preclinical proof-of-concept, Rocket

began recruiting for the Phase I clinical trial for RP-A501 in 1Q19 and dosed the

first patient in 2Q19. The company intends to enter registrational studies next year.

If successful, approval of RP-A501 may be supported by 2024, which puts it on

track to be the first targeted therapy approved for DD. We believe RP-A501 could

be a very significant sales opportunity for Rocket as it has the potential to reach

$10B+ in US and EU sales by 2035.

RP-L102 is Rocket’s lead LVV-based candidate for the treatment of

Fanconi Anemia. FA is caused by mutations in the FA core protein complex

(FANCA/B/C/E/F/G/L/M). In particular, mutations in the FANCA protein account for

over 70% of cases. It is characterized by bone marrow failure often before the age

of 10 and is commonly comorbid with blood malignancies and developmental

disabilities. The current SoC is allogeneic hematologic stem cell transplant (HSCT),

but is not suitable for all patients due to the intrinsic DNA repair defects in FA

patients. HLA-matches may also be unavailable for some patients. Another

complication of HSCT is that about 30% of patients display increased sensitivity to

graft-versus-host-disease (GvHD). As an alternative to HSCT, Rocket is developing

RP-L102 which delivers the functional FANCA gene via a lentivirus vector to

potentially provide a cure for this devastating disease.

Rocket Pharma (RCKT): Not Covered (Page 1 of 2)


Rocket’s Pipeline

EXHIBIT 123


If successful, RP-L102 could be a first-in-class, curative therapy for Fanconi

Anemia. Importantly, RP-L102 may be superior to SoC HSCT because it could be

given prior to the development of a potentially fatal bone marrow failure, whereas

HSCT is given to patients whose bone marrow has already dangerously failed.

Rocket is currently evaluating two methodologies for RP-L102 in FA: Process A

and Process B. Process B differs from Process A in that it administers higher

doses of virus, utilizes transduction enhancers, and employs a commercial-grade

vector. Long-term data (30+ months follow-up) in patients treated by Process A and

initial data for Process B are expected by YE19. A registrational Phase II trial is

expected to begin by YE19 as well. If successful, RP-L102 may represent a

~$200MM peak sales opportunity for the company.

RP-L301 is a preclinical stage drug candidate for the treatment of PKD that is

entering the clinic in 2019. Patients with Pyruvate Kinase Deficiency (PKD) have a

mutation in the pyruvate kinase L/R (PKLR) gene, which is critical for ATP

production in red blood cells. As a result, these patients develop splenomegaly,

pallor, jaundice, and excess iron in the blood. Rocket’s RP-L301 is an LVV-based

therapy in which expression of PKLR cDNA is driven by the constitutive human

PGK promoter. The LVV is expected to enter the clinic this year based on strong

preclinical evidence of safety and efficacy. We believe RP-L301 may be a

$100MM+ opportunity that could reach $250MM+ by 2028. We note that Agios

Pharmaceuticals (AGIO; covered by Van Buren) is currently evaluating mitapivat,

an oral, small molecule PKR activator for PKD and thalassemia, which has

demonstrated a durable increase in hemoglobin in ~50% of PKD patients. While

successful development of mitapivat could limit Rocket’s market opportunity, we

believe the opportunity is still meaningful given that half of patients may not derive

benefit from mitapivat. Additionally, management believes that patients may prefer

a singular gene therapy treatment as opposed to a twice-daily oral treatment, which

may allow RP-L301 to penetrate further into the PKD market.

RP-L201 is an LVV-based gene therapy for the treatment of LAD-1. Leukocyte

Adhesion Deficiency-1 (LAD-1) is a devastating immune disorder that can range in

severity with a majority of the most-severe patients facing mortality before the age

of 3 years. The disease is caused by mutations in the ITGB2 gene that encodes

CD18, a component of the Beta-2 integrin that is critical for the adherence of

leukocytes to blood vessels and surrounding tissues. This defect results in the

patient’s leukocytes being unable to exhibit cytotoxic activities, which significantly

increases susceptibility to bacterial and fungal infections. Infections lead to death in

about half of patients before the age of 2. Rocket is developing RP-L201, which is

an LVV vector encoding the ITGB2 gene, to treat LAD-1. The company estimates

RP-L201 may treat 25–50 LAD-1 patients per year. Rocket began recruiting for the

Phase I/II clinical trial for RP-L201 in 1Q19 and expects to dose its first patient

soon. We expect data for the Phase I portion of the trial by the end of 2019.

If successful, we estimate a launch by 2023, resulting in a ~$30MM opportunity

by 2028.

Rocket Pharma (RCKT): Not Covered (Page 2 of 2)


Upcoming Catalysts

EXHIBIT 124


Danon Disease RP-A501 IND ready for Phase I by early 2020

Fanconi Anemia RP-L102 Initial data from Process B in 2H19

Pyruvate Kinase

Deficiency (PKD)RP-L301 Initiation of Phase I in 2H19

Leukocyte Adhesion

Deficiency (LAD)RP-L201 Initial data from Phase I in 2H19


Sarepta Therapeutics is a biopharmaceutical company that develops

therapies for rare neurodegenerative disorders. The company’s research and

development efforts span several therapeutic modalities including RNA, gene

therapy, and gene editing. Sarepta has one exon skipping product on the market to

treat DMD with mutations in exon 51, EXONDYS51. Gene therapy has become a

primary focus for Sarepta, with 14 different programs in the pipeline (see below).

Lead gene therapy program delivers truncated dystrophin

(“microdystrophin”) protein via AAV for DMD. Sarepta’s SRP-9001, houses the

microdystrophin (MD) protein in their proprietary AAVrh74 vector and implements a

MHC7 promotor. The vector has been optimized to reduce immunogenicity and the

promoter shows enhanced expression in skeletal and cardiac muscles. SRP-9001

is currently being tested in a randomized controlled trial of 40 DMD patients (dosed

at 2x1014 vg/kg). Dosing is expected to be completed by YE19, with 12-month

expression and functional data anticipated by YE20. A trial using commercial

supply of SRP-9001 is expected to launch in 1H20.

Data from a previous open-label trial (n=4) showed improvements in biomarkers

(such as CK-levels, which are inversely correlated with muscle degradation) and

functional metrics, summarized in Exhibit 127, below.

Other companies are also developing truncated-dystrophin gene therapies, namely

Pfizer and Solid Biosciences (PFE, SLDB, not covered). However, both suffered

setbacks following serious safety events related to complement-activation (both

use AAV9 vector). As a result, Sarepta has a comfortable lead in time-to-market.

Sarepta Therapeutics (SRPT): Brill, OW (Page 1 of 2)


EXHIBIT 125

Sarepta’s Current Gene Therapy Pipeline

EXHIBIT 127

Key Metrics from OL Microdystrophin Gene Therapy Study (n=4)

SRP-9001 Construct

EXHIBIT 126

Wild-type Dystrophin gene = 14 kb

Microdystrophin gene = 3.6 kb

1. Clinical update from March 25, 2019. *** NorthStar Ambulatory Test.


Sarepta’s second gene therapy in Limb-Girdle Dystrophy Type 2E (LGMD-2E),

has shown promising results thus far. SRP-9003 employs the same vector and

promoter (AAVrh74 and MHCK7) as the company’s DMD gene therapy but

delivers the full-length β-sarcoglycan gene. It is currently being investigated in an

open-label trial. Early biomarker data in 3 LGMD2E patients who were dosed at

5x1013 vg/kg showed an average of 51% of muscle fibers showing β-sarcoglycan

expression (primary endpoint ≥20%) and significant CK reductions of >90%.

Average expression by Western Blot was 36% of normal. One patient exhibited

high liver transaminase levels, which was controlled using steroids. A longer

steroid taper was implemented to prevent LFT elevations moving forward.

Accelerated approval based on β-sarcoglycan expression is possible.

Unlike SRP-9001, which delivers a truncated dystrophin protein, SRP-9003

packages the whole, naturally-occurring (β-sarcoglycan) gene – meaning

accelerated approval based on biomarker expression should be possible.

One KOL suggested that β-sarcoglycan levels akin to asymptomatic carriers

(~30%–50%) may be sufficient for approval. Initial mean expression levels (36%),

are within this range. We await future updates on durability of effect and safety.

LGMD-2E opportunity is modest but de-risk other LGMD programs (2A, B, C,

D, L). By our estimates, the LGMD-2E gene therapy could generate $400M for

Sarepta. However, Sarepta also has earlier stage programs in LGMD subtypes 2A,

B, C, D and L. Successful development of the LGMD2E program should have

positive read through to the broader LGMD gene therapy pipeline (which have the

same vector, similar promoter and treat a similar disease pathology) – see middle

right. Our conservative estimates put the overall LGMD opportunity at ~$3B.

Manufacturing capabilities. Sarepta plans to use an adherent cell-based

manufacturing method that should allow for an easier transition to commercial

product. They have agreements with Brammer Bio (now Thermo Fisher) that gives

them preferred access and reserved space for commercial production of their

microdystrophin gene therapy. The iCellis adherent cell unit bioreactors will be

utilized for manufacturing. Additionally, Sarepta also has an agreement with

Paragon Biosciences (now Catalent), who will manufacture their LGMD gene

therapies and provide overflow production space.

Sarepta Therapeutics (SRPT): Brill, OW (Page 2 of 2)

Source: Sarepta Therapeutics. Piper Jaffray Research.

EXHIBIT 129

Upcoming Catalysts

Indication Gene/Drug Upcoming Catalyst

Duchenne

Muscular

Dystrophy

Casimersen NDA Filing – 2H19

SRP-9001DMD RCT study data readout – YE20;

Commercial product RCT initial data – YE20

LGMD-2E SRP-9003 Updated OL data from trial at WMS – Oct. 2019

EXHIBIT 128

Sarepta’s LGMD Gene Therapy Programs: Genes, Vectors, and Promoters


Once a wild card, RARE’s gene therapy platform continues to deliver...

RARE announced the acquisition of Dimension Therapeutics in September 2017,

adding the company’s AAV gene therapy platform to RARE’s treatment modality

base of small molecules, proteins, and mRNA programs, and providing an optimal

set up to treat a number of rare monogenic, metabolic diseases by selecting the

best treatment strategy for each indication. Since this time, clinical programs

DTX301 (AAV8-OTC) for ornithine transcarbamylase deficiency and DTX401

(AAV8-G6Pase) for glycogen storage disease type Ia have demonstrated initial

proof-of-concept results with treatment generally well tolerated in patients.

…and has further expanded with a now budding pipeline of preclinical

candidates. The gene therapy pipeline continues to grow, with UX701 (AAV8-

ATP7B or AAV9-ATP7B) for Wilson disease expected to enter the clinic in 2020.

Initial excitement was highlighted at the R&D day in April 2019 for up and coming

program UX055 (AAV9-CDKL5), a rare genetic neurological disorder, and a

potential pivot from the normal liver-based metabolic indications.

Ultragenyx Pharmaceutical (RARE): Raymond, OW (Page 1 of 2)

Source: RARE. Piper Jaffray Research.

EXHIBIT 131

Upcoming Catalysts


OTC

DeficiencyDTX301 Initial Cohort 3 data (1E13 GC/kg) expected 3Q19

GSDIa DTX401 Initial Cohort 2 data (6E12 GC/kg) expected 3Q19

Wilson

DiseaseUX701 IND filing expected in 2020

EXHIBIT 130

RARE’s Gene Therapy Pipeline

Both mammalian transient transfection and producer cell line platforms

provide a nice setup for scalable manufacturing. RARE has established an

internal non-GMP process to develop gene therapy manufacturing processes for

each indication at full scale in house, and then transfer the process to a contract

manufacturing organization for full clinical and/or commercial development.

However, management has noted that they plan to build their own in-house GMP

manufacturing facility to support future gene therapy manufacturing needs.

Additional details are still TBD.

For platforms, RARE utilizes both a mammalian transient transfection system with

HEK293 cells for smaller indications (eg, OTC deficiency, GSDIa) and HeLa

producer cell lines for larger indications (eg, Hemophilia A - partnered with Bayer,

Wilson disease). RARE believes the HeLa system is the future for gene therapy

manufacturing, and has made a substantial investment to maximize the potential of

the HeLa platform, developing a production system that they’ve branded HeLa 2.0.

This system significantly shortens the time to producer cell generation, boosts

titers, increases product quality and scale, and contributes to an accelerated

product development timeline.


Highlighting positive Phase I/II updates for DTX301 in the treatment of OTC

deficiency. At the last major update for the program last September, RARE

toplined results for the second dose cohort treated at 6E12 GC/kg from the ongoing

Phase I/II study of DTX301 for the treatment of ornithine transcarbamylase (OTC)

deficiency. The update was similar to results from Cohort 1 (treated at

2E12 GC/kg), with one of three patients achieving a clinically meaningful change in

the rate of ureagenesis. The study moved to dosing Cohort 3 patients last year at

the highest dose (1E13 GC/kg), with topline results expected in 3Q19.

• Like Cohort 1, Cohort 2 was one for three in responses. Six patients in total

have been treated with DTX301 (Cohort 1, n=3; Cohort 2, n=3), with two

responders reported, one from each dosing cohort. The two responders

(Exhibit 132) continue to demonstrate sustained normalization of ureagenesis at

weeks 78 (patient 1) and 52 (patient 4), and have been able to discontinue both

alternate pathway medications and protein-restricted diets

• Safety continues to look benign. DTX301’s safety profile continues to look

favorable, with no infusion-related AEs or SAEs reported. Similar to Cohort 1,

patient 4 in Cohort 2 has had mild ALT elevations that have successfully been

controlled with two courses of tapering steroids, which is par for the course with

gene therapies

• Still looking for a dose. After completing a review of Week 12 data, the DMC

recommended RARE begin dosing of Cohort 3 patients (1E13 GC/kg), with

management indicating success would be 2 of 3 patients achieving a clinically

meaningful increase in the rate of ureagenesis at that dose. If this mark is hit,

RARE would add another three patients at that dose, and then use the data to

plan a potentially registrational Phase III study. We expect an initial update on

Cohort 3 patients in 3Q19

Ultragenyx Pharmaceutical (RARE): Raymond, OW (Page 2 of 2)

Source: RARE. Piper Jaffray Research.

EXHIBIT 132

Durable Normalization in Ureagenesis in Patients with OTC Deficiency

Cohort 1, Patient 1 (2E12 GC/kg)

Cohort 2, Patient 4 (6E12 GC/kg)


uniQure is a biotechnology company that focuses on developing liver-

directed and CNS-targeted gene therapies. They currently have one gene

therapy in a pivotal trial for Hemophilia B with a second program for Huntington’s

disease entering the clinic this year. uniQure also has preclinical assets in

development for Fabry disease and spinocerebral ataxia type 3 (SCA Type 3).

Pivotal data from lead program, AMT-061, for Hemophilia B expected in 2020.

AMT-061 utilizes the AAV5 vector and an engineered variant of the Factor IX (FIX)

called the Padua variant as the functional gene. FIX is implicated in the blood

clotting pathway and enables proper clotting function. uniQure is currently running

a Phase III pivotal trial of ~55 hemophilia B patients that are serving as their own

controls following a 6-month lead-in phase to treatment. This trial design is very

similar to that of the ongoing Phase Iib trial, which has shown strong efficacy and

durability of response out to 36 weeks.

.

Phase IIb OL data in 3 patients indicate strong efficacy and durability of

response. Data from the Phase IIb trial in (n=3) Hemophilia B patients looks better

than its Hemophilia-B gene therapy competitor, Spark Therapeutics (ONCE, not

covered) across all times points (see below). Specifically, FIX activity levels, which

correlate with number of bleeding events, have been consistently higher for

uniQure’s therapy over ~36 weeks of follow-up. AMT-061 also appears to be

durable as FIX activity does not fluctuate significantly over time.

The hemophilia B market may be modest, but QURE is poised to dominate it.

Another differentiating factor for AMT-061 beyond better efficacy and durability of

response is that immunogenicity is very low and patients are not screened out

based on presence of neutralizing antibodies. In the Phase Iib trial, 2 out of 3

patients safely received treatment despite the presence of neutralizing antibodies.

Current Piper Jaffray estimates indicate the Hemophilia B gene therapy market

could be ~$1B – and uniQure could capture the lion’s-share with superior efficacy,

safety, and a first movers advantage.

uniQure (QURE): Brill, OW (Page 1 of 2)


EXHIBIT 133

uniQure’s Current Pipeline

EXHIBIT 134

Phase II Trial Comparison of Hemophilia B Gene Therapies

12 wks 26 wks 36 wks 52 wks

Sparks Therapeutics ~24% ~30% ~30% 35.5%

uniQure 38% 47% 45% NA

Sparks Therapeutics ~38% ~43% ~42% ~60%


Sparks Therapeutics* ~12% ~18% ~15% <10%


*Includes patients before SPK-9001 protocol adjustment

FIX Activity to Normal

Average

Highest

Lowest


AMT-130, is a gene therapy for Huntington’s disease (HD) that aims to reduce

mHTT aggregation. AMT-130 utilizes an AAV5 vector housing a CAG promoter

that drives expression of a novel miRNA (“miQURE”) that targets mutated

huntington gene (mHTT) aggregates and exon 1 protein fragments. Exon 1 is

implicated in the production of the most toxic inclusion body generating fragments.

The miQURE oligomer is designed in such a way that it produces negligible

“passenger strands” in order to prevent off-target effects. Upon expression,

miQURE is incorporated in the cytoplasmic RNA-induced silencing complex (RISC)

and helps degrade the mHTT mRNA; a similar RNAi effect also occurs in the

nucleus to cause cell-wide lowering of mHTT aggregates.

A Phase I/II trial of AMT-130 in HD will commence in 2H19. The RCT will

include ~25 patients with early manifestations (Stage 1) of HD that are at risk for a

rapidly progressive disease (≥44 HTT CAG repeats). Safety and efficacy – in the

form of motor function, CSF mHTT protein levels and other biomarkers – will be

monitored over 9–18 months. AMT-130 has received orphan drug designation by

the FDA and EMA, and Fast Track Designation in the US.

Robust preclinical suggestive of durable mHTT knock down with AMT-130.

AMT-130 showed transduction throughout the brains of mini-pigs which translated

to strong mHTT lowering that was durable from 6- to 12-months (Exhibit 135).

Cortical neurons are affected in mid-to-late stage HD, meaning AMT-130 may be

effective in this population. Minipig brains are ~5x larger than NHP brains and

provide a more realistic model of human brains.

Earlier stage assets also look promising. Preclinical data presented on

AMT-150, their gene therapy for SCA3, at AAN 2019 showed that an intrathecal

AMT-150 injection resulted in strong transduction, and reductions of mutant ataxin-

3 levels in the cerebellum and the brainstem, of 53% and 65%, respectively.

uniQure possesses in-house manufacturing capabilities. QURE’s large-scale

manufacturing capability allows them to produce commercial grade product

throughout development and to scale-up to commercial supply quickly.

uniQure (QURE): Brill, OW (Page 2 of 2)


EXHIBIT 136

Upcoming Catalysts

Indication Gene/Drug Upcoming Catalyst

Hemophilia B AMT-061 Top-line data from Ph3 – YE20

Huntington’s

DiseaseAMT-130

Initial Phase I/II biomarker and safety data –

YE19 or early 2020

EXHIBIT 135

AMT-130 Shows mHTT Lowering Across Various Regions of the Brain

Company Model Region %∆ mHTT from naïve Time Period

uniQure

(AMT-130)Mini-pigs

putamen ~68%

12-mosthalamus >50%

caudate >70%

cortical neurons 47% (6-mos) ~28%-47%


Appendix

06.


Ongoing Gene Therapy Trials

by Indication

06.1


Gene Therapies Landscape: Dermatology


Company Ticker Indication Drug Vector Development Stage Analyst

Abeona Therapeutics ABEO Recessive Dystrophic EB EB-101 Retrovirus Phase III

Abeona Therapeutics ABEO Recessive Dystrophic EB EB-102 AAV Preclinical

Amryt Pharma AMYT Recessive Dystrophic EB AP103 Non-viral GT Preclinical

BioVec Pharma Private Epidermolysis Bullosa - Retrovirus Preclinical

Fibrocell Science FCSC Recessive Dystrophic EB FCX-007 Lentivirus Phase I/II

GlaxoSmithKline GSK Epidermolysis Bullosa - - Preclinical

Holostem Terapie Avanzate Srl Private Recessive Dystrophic EB Hologene 7 Retrovirus Phase II

Immusoft Corp. Private Epidermolysis Bullosa - - Preclinical

Krystal Biotech KRYS Dystrophic EB KB103 HSV-1 Phase I/II

Krystal Biotech KRYS Junctional EB KB-107 Hsv-1 Preclinical

Temprian Therapeutics Private Vitiligo - Non-viral GT Preclinical

ViroMed Co KOSDAQ 084990 Wounds pIKO AAV Preclinical

Canton Biotechnologies Private WoundsCA5 HIF

(DNA electroporation)Non-viral GT Preclinical


Gene Therapies Landscape: Hematology (Page 1 of 2)



Aruvant Sciences Private

Beta-thalassemia

ARU-1801 Lentivirus Preclinical

bluebird bio BLUE LentiGlobin Lentivirus Phase III Van Buren

CSL Behring CSLLY CAL-H - Preclinical

Errant Gene Therapeutic Private Thalagen - Preclinical

Orchard Therapeutics plc ORTX OTL-300 Lentivirus Phase I/II

Audentes Therapeutics BOLD

Crigler-Najjar Syndrome

AT342 AAV8 Phase I/II Raymond

Genethon SA Private - AAV Preclinical

Logicbio Therapeutics LOGC LB-301 AAV Discovery/Preclinical

BioMarin Pharmaceutical BMRN

Hemophilia A

valoctocogene

roxaparvovec

(Valrox, BMN 270)

AAV5 Phase III Raymond

Expression Therapeutics PrivateEx vivo stem cell-LV-

FVIII gene therapyLentivirus Preclinical

Expression Therapeutics Private AAV-FVIII AAV Preclinical

Sangamo Therapeutics SGMO SB-525 - Phase I/II

Spark Therapeutics ONCE SPK-8011 AAV5 Phase III

Spark Therapeutics ONCE SPK-8016 AAV5 Phase II

Takeda Pharmaceutical Co TAK TAK-754 (SHP654) - Phase I

Ultragenyx Pharmaceutical RARE DTX201 AAV Phase II Raymond

UniQure QURE AMT-180 AAV5 Preclinical Brill


Gene Therapies Landscape: Hematology (Page 1 of 2)



Spark Therapeutics ONCE

Hemophilia B

Fidanacogene

elaparvovec

(SPK-9001)

AAV Phase III

UniQure QURE AMT-061 AAV5 Phase III Brill

Freeline Therapeutics Private FLT-180a AAV Phase I/II

Expression Therapeutics Private AAV-FIX AAV Preclinical

Takeda Pharmaceutical Co TAK SHP648 - Preclinical

Logicbio Therapeutics LOGC LB-101 AAV Discovery/Preclinical

Catalyst Biosciences CBIO CB 2679d-GT AAV8 Preclinical

Adverum Biotechnologies ADVM Hereditary angioedema ADVM-053 - Preclinical Van Buren

Rocket Pharmaceuticals RCKT

Fanconi Anemia

RPL-102 Lentivirus Phase I

Genethon SA Private - - Phase II

Abeona Therapeutics ABEO ABO-301 AAV Preclinical

bluebird bio BLUE

Sickle Cell Disease

LentiGlobin Lentivirus Phase II Van Buren

bluebird bio BLUE Bcl11a shmiR Lentivirus Phase I Van Buren

Aruvant Sciences Private ARU-1801 Lentivirus Phase I/II

Généthon SA Private

Wiskott-Aldrich

- Lentivirus Phase II

Orchard Therapeutics ORTXOTL-103

(GSK2696275)Lentivirus Phase III


Gene Therapies Landscape: Inborn Errors of Metabolism – Lysosomal Storage Disorders (Page 1 of 2)



Rocket Pharma RCKT Danon disease (GSDIIb) RP-A501 AAV9 Phase I

Abeona Therapeutics ABEO

Fabry disease

- AAV Preclinical

Amicus Therapeutics FOLD- - Preclinical

AVROBIO AVROAVR-RD-01 Lentivirus Phase I/II

Freeline Therapeutics Private FLT190 AAV Preclinical

Sangamo Therapeutics SGMO ST-920 AAV6 Preclinical

UniQure QURE AMT-190 AAV5 Preclinical Brill

Axovant Sciences Private

GM1

AXO-AAV-GM1 AAV Ph 1/2

Lysogene LYS LYS-GM101 AAVrh10 Preclinical

Passage Bio Private AAV-GM1 AAV Preclinical

Axovant Sciences AXVT GM2 AXO-AAV-GM2 AAV Ph 1/2


MPS IIIA

(Sanfilippo type A)

ABO-102 AAV9 Phase I/II

Esteve Pharmaceuticals SA Private EGT-101 AAV9 Phase II

Lysogene SAS/Sarepta

TherapeuticsSRPT LYS-SAF302 AAVrh10 Phase III Brill

Orchard Therapeutics ORTX OTL-201 Lentivirus Preclinical


Gene Therapies Landscape: Inborn Errors of Metabolism – Lysosomal Storage Disorders (Page 2 of 2)




MPS IIIB

(Sanfilippo type B)


Esteve Pharmaceuticals SA Private EGT-201 AAV9 Preclinical

Orchard Therapeutics ORTX OTL-202 Lentivirus Preclinical

bluebird bio BLUE

MPS I

(Hurler Syndrome)

LVV-IDUA HSC LVV Preclinical Van Buren

Immusoft Corp Private ISP-001 - Preclinical

Regenxbio RGNX RGX-111 AAV9 Phase I/II

Sangamo Therapeutics SGMO SB-318 AAV6 Phase I/II

Tamid Bio Private Tamid-001 AAV Preclinical

Esteve Pharmaceuticals SA Private

MPS II

(Hunter Syndrome)

EGT-301 AAV9 Preclinical

Regenxbio RGNX RGX-121 AAV9 Phase II

Sangamo Therapeutics SGMO SB-913 AAV6 Phase II


Pompe disease

- AAV Preclinical

Actus Therapeutics Private ACTUS-101 AAV2/8 Phase II

Amicus Therapeutics FOLD - AAV Preclinical

Audentes Therapeutics BOLD AT845 AAV8 Preclinical Raymond

AVROBIO AVRO AVR-RD-03 Lentivirus Preclinical

Sarepta Therapeutics (Lacerta) SRPT - AAV Discovery Brill

Spark Therapeutics ONCE SPK-3006 AAV Preclinical


Gene Therapies Landscape: Inborn Errors of Metabolism – Neurology



Abeona Therapeutics ABEOBatten Disease (CLN1)

Infantile


Amicus Therapeutics FOLD AAV-CLN1 AAV9 Discovery/Preclinial

Regenxbio RGNXBatten Disease (CLN2)

Late Infantile

RGX-181 AAV9 Preclinical

Spark Therapeutics ONCE SPKTPP-1 rAAV Preclinical

Abeona Therapeutics ABEOBatten Disease (CLN3)

Juvenile


Amicus Therapeutics FOLD AAV9-CLN3 AAV9 Phase I/II

Amicus Therapeutics FOLD Batten Disease (CLN6) scAAV9-CB-CLN6 AAV9 Phase I/II

Amicus Therapeutics FOLD Batten Disease (CLN8) - - Preclinical

bluebird bio BLUE CALD Lenti-D Lentivirus Phase III/Pivotal Van Buren

Ultragenyx Pharmaceutical RARE GSD1a DTX401 AAV Phase I/II Raymond


Gene Therapies Landscape: Inborn Errors of Metabolism – Other



ApicBio Private A1AT Deficiency Apb-101 - Preclinical

Adrenas PrivateCongenital Adrenal

HyperplasiaBBP-631 AAV Preclinical

Selecta Biosciences SELBOTC Deficiency

SEL-313 AAV Preclinical

Ultragenyx Pharmaceutical RARE DTX301 AAV Phase I/II Raymond

American Gene Technologies

InternationalPrivate

PKU

- Lentivirus Preclinical

BioMarin Pharmaceutical BMRN BMN 307 AAV5 Preclinical Raymond

Generation Bio Corp. Private - ceDNA Preclinical

Homology Medicines FIXX HMI-102 AAVHSC Preclinical

Homology Medicines FIXX HMI-103 AAVHSC Preclinical

Rubius Therapeutics RUBY RTX-134 Lentivirus Preclinical

Ultragenyx Pharmaceutical RARE UX-501 AAV8 Preclinical Raymond

Aligen Therapeutics SL Private

Wilson disease

CM-1186 AAV Preclinical

Ultragenyx RARE UX701 AAV Preclinical Raymond

Vivet Therapeutics SAS Private VTX-801 AAV Preclinical


Gene Therapies Landscape: Infectious Disease



Benitec Biopharma Ltd Private Hepatitis B BB-103 AAV Preclinical

Excision BioTherapeutics Private Hepatitis B EBT106 AAV Preclinical


InternationalPrivate HIV AG-103-T Lentivirus Preclinical

Enzo Biochem, Inc ENZ HIV HGTV-43 Stealth Vector Phase I/II

Excision BioTherapeutics Private HIV EBT-101 AAV Preclinical

NIAID Private HIV AAV8-VRC07 AAV8 Phase I

Excision BioTherapeutics PrivateSimplexvirus (HSV)

infectionsEBT-104 AAV Preclinical

Excision BioTherapeutics PrivateSimplexvirus (HSV)

infectionsEBT-105 AAV Preclinical

Inovio Pharmaceuticals INO Zika Virus Infections INO-002 non-viral GT Phase I Raymond


Gene Therapies Landscape: Immunodeficiency



Orchard Therapeutics ORTXADA-SCID

Strimvelis LentivirusApproved/Marketed

(EU)

Orchard Therapeutics ORTX OTL-101 Lentivirus Phase III/Pivotal

Orchard Therapeutics ORTX X-CGD

(chronic granulomatous

disease)

OTL-102 Lentivirus Phase I/II

Genethon SA Private OTL-102 Lentivirus Phase I/II

Mustang Bio MBIO X-SCID MB-017 Lentivirus Phase I/II


Gene Therapies Landscape: Musculoskeletal (Page 1 of 2)



Milo Biotechnology PrivateBecker Muscular

DystrophyAAV1-Follistatin AAV Phase I/II

Audentes Therapeutics BOLD

DMD

AT702, AT751, AT753 AAV9 and 8 Preclinical Raymond

Exonics Therapeutics Private - AAV Preclinical

Genethon SA Private - AAV Preclinical

Milo Biotechnology Private AAV1-Follistatin AAV Phase I/II

Pfizer PFE PF-06939926 AAV Phase I/II

Sarepta Therapeutics SRPTSRP-9001

(AAVrh74-MHCK7)AAV Phase I/II Brill

Sarepta Therapeutics SRPT AAV-GALTG2 AAV Phase I/II Brill

Solid Biosciences SLDB SGT-001 AAV Phase I/II

Tolerion Private - - Preclinical

Milo Biotechnology Private Inclusion body myositis AAV1-Follistatin AAV Phase I/II

Sarepta Therapeutics SRPT LGMD2B MYO-201 AAV Phase I/II Brill

Sarepta Therapeutics SRPT LGMD2C MYO-103 AAV Preclinical Brill

Sarepta Therapeutics SRPT LGMD2D MYO-102 AAV Phase I/II Brill

Sarepta Therapeutics SRPT LGMD2E MYO-101 AAV Phase I/II Brill

Sarepta Therapeutics SRPT LGMD2L MYO-301 AAV Preclinical Brill


Gene Therapies Landscape: Musculoskeletal (Page 2 of 2)



Audentes Therapeutics BOLD Myotonic Dystrophy type 1 AT-466 AAV Preclinical Raymond

Axovant Sciences AXVTOPMD

AXO-AAV-OPMD AAV Preclinical

Benitec Biopharma Private BB-301 AAV Preclinical

Biogen BIIB SMA BIIB-089 - Preclinical Raymond

Novartis/Avexis NVS SMA Type 1AVXS-101

(Zolgensma)AAV9 Filed

Novartis/Avexis NVS SMA Type 2AVXS-101

(Zolgensma)AAV9 Phase I/II

Audentes Therapeutics BOLD XLMTM AT132 AAV8 Phase I/II Raymond


Gene Therapies Landscape: Neurology (Page 1 of 3)



Apic Bio Private ALS APB-102 - Preclinical

Axovant Sciences AXVT ALS - C9ORF72AXO-AAV-ALS/

AXO-AAV-FTDAAV Discovery/Preclinical

CavoGene Lifesciences Private ALS SYNCAV-1 - Preclinical

MeiraGTx MGTX ALS AAV-UPF1 AAV Preclinical Van Buren

NeuExcell Therapeutics Private ALS NXLAAV-002 AAV Preclinical

Novartis/Avexis NVS ALS - SOD1 AVXS-301 AAV Preclinical

Oxford Biomedica OXBDF ALS - - Preclinical

ViroMed Co Ltd 084990.KQ ALS VM-301 AAV Preclinical

Voyager Therapeutics VYGR ALS - SOD1 VY-SOD102 AAV Preclinical

Brainvectis SAS Private

Alzheimer's disease

BVCYP-01 AAV Preclinical

CavoGene Lifesciences Private SynCav-2 - Preclinical

NeuExcell Therapeutics Private NXLAAV-001 AAV Preclinical

Sangamo Therapeutics SGMO - - Preclinical

Telocyte Private TEL-01 AAV Preclinical

Voyager Therapeutics VYGR - AAV Preclinical

Aspa Therapeutics Private

Canavan Disease

BP-812 - Preclinical

Pfizer PFE - - Phase I/II

Pfizer PFE - - Preclinical





Pfizer PFE

Friedreich's Ataxia

- - Preclinical

PTC Therapeutics PTCT PTC-FA - Phase I/II

Voyager Therapeutics VYGR VY-FXN01 AAV Preclinical

Axovant Sciences AXVTFrontotemporal Dementia

AXO-AAV-FTD AAV Preclinical

Passage Bio Private AAV Preclinical

AskBio Private

Huntington's Disease

- AV Preclinical

Brainvectis SAS Private BVCYP-01 AAV Preclinical

NeuExcell Therapeutics Private NXLAAV-003 AAV Preclinical

Spark Therapeutics ONCE - AAV Preclinical

Takeda Pharmaceutical Co TAK - - Preclinical

uniQure QURE AMT-130 AAV Preclinical Brill

Voyager Therapeutics VYGR VY-HTT01 AAV Preclinical





Apollo Therapeutics Private

Parkinson's Disease

- - Preclinical

AskBio Private - AAV Phase I/II

Axovant Sciences AXVTAXO-LENTI-AADC-

TH-CH1Lentivirus Phase I/II

Copernicus Therapeutics Private AAV-GDNF - Preclinical

Gene Therapy Research Inst Co Private AAV-AADC-TH-CH1 AAV Preclinical

MeiraGTx MGTX AAV-GAD AAV Phase I/II Van Buren

Prevail Therapeutics PRVL PR001 AAV9 Preclinical/IND Active

SanBio Co SNBIF SB-623 - Preclinical

Takara Bio TYO: 4974 - - Phase I/II

Takeda Pharmaceutical Co TAK - - Preclinical

Voyager Therapeutics VYGR VY-AADC AAV Phase I/II

uniQure QURE SCA-Type 3 - AAV Preclinical Brill


Gene Therapies Landscape: Ophthalmology (Page 1 of 2)



agtc AGTC Achromatopsia

(ACHM-A3)

AAV-CNGA3 AAV Phase I/II

MeiraGTx MGTX AAV-CNGA3 AAV Preclinical Van Buren

agtc AGTC Achromatopsia

ACHM-B3

AAV-CNGB3 AAV Phase I/II

MeiraGTx MGTX AAV-CNGB3 AAV Phase I/II Van Buren

Aevitas Therapeutics PrivateAMD

AVTS-001 AAV Preclinical

Gemini Therapeutics Private GR-1008 AAV Preclinical

Gemini Therapeutics Private

Dry AMD

GR-1017 AAV Preclinical

Gyroscope Therapeutics Private GT-005 - Phase I/II

NanoScope Technologies Private VMCO-1 - Preclinical

Nightstar Therapeutics/Biogen NITE/BIIB NSRBEST-1 AAV Preclinical Raymond

SanBio Co SNBIF SB-623 - Preclinical

Adverum Biotechnologies ADVM

Wet AMD

ADVM-022 AAV Phase I/II Van Buren

Amarna Therapeutics Private AMA003 - Preclinical

Benitec Biopharma BNTC BB-201 AAV Preclinical

Hemera Biosciences Private HMR-59 - Phase I/II

iTherapeutics Corp. Private - - Preclinical

Oxford Biomedica OXBDF OXB-201 - Phase I/II

Regenxbio TGNX RGX-314 - Phase I/II

4D Molecular Therapeutics 4DMT

Choroideremia

4D-110 AAV Preclinical

Nightstar/Biogen NITE/BIIB NSR-REP1 AAV2 Phase III Raymond

Spark Therapeutics ONCE SPK-7001 - Phase I/II


Gene Therapies Landscape: Ophthalmology (Page 2 of 2)



GenSight Biologics GSGTF Leber's Hereditary Optic

Neuropathy

GS010 AAV Phase III

Spark Therapeutics ONCE SPK-LHON AAV Preclinical

Horama SA PrivatePDE6B Retinitis

pigmentosaHORA-PDE6B AAV Phase I/II

Horama SA Private RLBP1 Retinal Dystrophy HORA-RLBP1 AAV Preclinical

MeiraGTx MGTX RPE65-deficiency AAV-RPE65 AAV Phase I/II Van Buren

Horama SA PrivateRPE65-mediated IRD

HORA-RPE65 AAV Phase I/II

Spark/Novartis ONCE/NVS Luxterna AAV Approved/Marketed

Copernicus Therapeutics Private

Stargardt disease

- - Preclinical

Generation Bio Corp. Private - - Preclinical

Nightstar/Biogen NITE/BIIB NSR-ABCA4 AAV Preclinical

Sanofi/Oxford Biomedica OXBDF SAR422459 (StarGen) - Phase I/II

Sanofi SA SNY Usher Syndrome Type 1B SAR421689 - Phase I/II

agtc AGTC

XLRP

AAV-RPGR AAV Phase I/II

Biogen BIIB BIIB112 AAV8 Phase I/II Raymond

IVERIC bio Private - - Preclinical

MeiraGTx MGTX AAV-RPGR AAV Phase I/II Van Buren

agtc AGTCX-linked retinoschisis

(XLRS)AAV-RS1 AAV Phase I/II


Gene Therapies Landscape: Additional Indications



Cardiovascular Disease

Audentes BOLD CASQ2-CPVT AT307 - Phase I/II Raymond

Renova Therapeutics Private HFrEF RT-100 - Phase I/II

Oncology

Tocagen TOCA Glioma Toca 511 and Toca FC Retrovirus Phase III/Pivotal

Tocagen TOCA Metastatic solid tumor Toca 511 and Toca FC Retrovirus Phase I/II

Otology

Akouos Private Hearing loss Anc80AAV AAV Preclinical

Novartis NVS Hearing loss CGF166 - Phase I/II

Miscellaneous

Intellia Therapeutics NTLAAmyloid transthyretin

amyloidosis- - Preclinical

MeiraGTx MGTX Xerostomia (dry mouth) A00X - Phase I/II Van Buren

Rocket RCKTInfantile Malignant

OsteopetrosisRP-L401 - Preclinical


Ongoing Gene Therapy Trials

by Company

06.2


Gene Therapies Landscape: Companies



4D Molecular Therapeutics PrivateChoroideremia 4D-110 AAV Preclinical

Cystic Fibrosis 4D-710 AAV Preclinical


Batten Disease (CLN1), Infantile ABO-202 AAV9 Phase I/II

Batten Disease (CLN3), Juvenile ABO-201 AAV9 Phase I/II

Cystic Fibrosis ABO-401 AAV Preclinical

Fabry disease - AAV Preclinical

Fanconi Anemia ABO-301 AAV Preclinical

MPS IIIA (Sanfilippo type A) ABO-102 AAV9 Phase I/II

MPS IIIB (Sanfilippo type B) ABO-101 AAV9 Phase I/II

Pompe disease - AAV Preclinical

Recessive Dystrophic EB EB-101 Retrovirus Phase III

Recessive Dystrophic EB EB-102 AAV Preclinical

Actus Therapeutics Private Pompe disease ACTUS-101 AAV2/8 Phase II

Adrenas BBIO Congenital Adrenal Hyperplasia BBP-631 AAV Preclinical

Adverum Biotechnologies ADVMHereditary angioedema ADVM-053 - Preclinical

Van BurenWet AMD ADVM-022 AAV Phase I/II





Aevitas Therapeutics Private AMD AVTS-001 AAV Preclinical

Akouos PrivateHearing loss Anc80AAV AAV Preclinical

Balance disorders Anc80AAV AAV Preclinical

Aligen Therapeutics SL Private Wilson disease CM-1186 AAV Preclinical

Amarna Therapeutics Private Wet AMB AMA003 - Preclinical


InternationalPrivate

HIV AG-103-T Lentiviral Preclinical

PKU - Lentiviral Preclinical

Amicus Therapeutics FOLD

Batten Disease (CLN1), Infantile - - Discovery/Preclinical

Raymond

Batten Disease (CLN3), Juvenile AAV9-CLN3 AAV9 Phase I/II

Batten Disease (CLN6) scAAV9-CB-CLN6 AAV9 Phase I/II

Batten Disease (CLN8) - - Preclinical

CDKL5 Deficiency - - Preclinical

Fabry disease - Preclinical

Pompe disease - AAV Preclinical

Amryt Pharma AMYT Recessive Dystrophic EB AP103 non-viral GT Preclinical

Apic Bio PrivateALS APB-102 - Preclinical

A1AT Deficiency Apb-101 - Preclinical

Apollo Therapeutics Parkinson's disease - Preclinical

Applied Genetic Technologies

Corp.AGTC

Achromatopsia (ACHM-A3) AAV-CNGA3 AAV Phase I/II

Achromatopsia (ACHM-B3) AAV-CNGB3 AAV Phase I/II

XLRP AAV-RPGR AAV Phase I/II

X-linked retinoschisis (XLRS) AAV-RS1 AAV Phase I/II





Aruvant Sciences PrivateSickle Cell Disease ARU-1801 Lentivirus Phase I/II

Beta-thalassemia ARU-1801 Lentivirus Preclinical

AskBio PrivateHuntington's - AV Preclinical

Parkinson's disease - AAV Phase I/II

Aspa Therapeutics Private Canavan Disease BP-812 - Preclinical

Audentes BOLD

CASQ2-CPVT AT307 - Phase I/II

Raymond

Crigler-Najjar Syndrome AT342 AAV8 Phase I/II

DMDAT702, AT751,

AT753AAV9 and 8 Preclinical

Myotonic Dystrophy type 1 AT-466 AAV Preclinical

Pompe disease AT845 AAV8 Preclinical

XLMTM AT132 AAV8 Phase I/II

AVROBIOAVRO

Cystinosis AVR-RD-04 Lentivirus Preclinical

Fabry disease AVR-RD-01 Lentivirus Phase I/II

Gaucher AVR-RD-02 Lentivirus Preclinical

Pompe disease AVR-RD-03 Lentivirus Preclinical

Axovant Sciences Ltd AXVT

ALS - C9ORF72AXO-AAV-ALS/

AXO-AAV-FTDAAV Discovery/Preclinical

Frontotemporal dementia AXO-AAV-FTD AAV Preclinical

GM1 AXO-AAV-GM1 AAV Ph 1/2

GM2 AXO-AAV-GM2 AAV Ph 1/2

OPMD AXO-AAV-OPMD AAV Preclinical

Parkinson's diseaseAXO-LENTI-AADC-

TH-CH1Lentivirus Phase I/II





Benitec Biopharma Ltd Private

Hepatitis B BB-103 AAV Preclinical

Oculopharyngeal muscular

dystrophyBB-301 AAV Preclinical

Wet AMD BB-201 AAV Preclinical

Biogen BIIBX-Linked Retinitis Pigmentosa

(XLRP)BIIB112 AAV8 Phase II/III Raymond

BioMarin Pharmaceutical BMRNHemophilia A

Valoctocogene

roxaparvovec

(Valrox, BMN 270)

AAV5 Phase IIIRaymond

PKU BMN 307 AAV5 Preclinical

BioVec Pharma Private Epidermolysis Bullosa - Retrovirus Preclinical

bluebird bio BLUE

Beta-thalassemia LentiGlobin Lentivirus Phase III

Van Buren

CALD Lenti-D Lentivirus Phase III/Pivotal

MPS I (Hurler Syndrome) LVV-IDUA HSC LVV Preclinical

Sickle Cell Disease LentiGlobin Lentivirus Phase II

Sickle Cell Disease Bcl11a shmiR Lentivirus Phase I

Brainvectis SAS PrivateAlzheimer's disease BVCYP-01 AAV Preclinical

Huntington's BVCYP-01 AAV Preclinical

Catalyst Biosciences CBIO Hemophilia B CB 2679d-GT AAV8 Preclinical





CavoGene Lifesciences PrivateAlzheimer's disease SynCav-2 - Preclinical

ALS SYNCAV-1 - Preclinical

Copernicus TherapeuticsPrivate Stargardt disease - - Preclinical

Parkinson's disease AAV-GDNF - Preclinical

CRISPR Therapeutics AG CRSPBeta-thalassemia, SCD CTX001 - Preclinical

Cystic Fibrosis - - Preclinical

CSL Behring CSLLY Beta-thalassemia, SCD CAL-H - Preclinical

Editas Medicine EDIT Cystic Fibrosis - AAV or LNP Preclinical

Enzo Biochem ENZ HIV HGTV-43 Stealth Vector Phase I/II

Errant Gene Therapeutics Private Beta-thalassemia Thalagen - Preclinical

Esteve Pharmaceuticals SA Private

MPS II (Hunter Syndrome) EGT-301 AAV9 Preclinical

MPS IIIA (Sanfilippo type A) EGT-101 AAV9 Phase II

MPS IIIB (Sanfilippo type B) EGT-201 AAV9 Preclinical

Excision BioTherapeutics Private

Hepatitis B EBT106 AAV Preclinical

HIV EBT-101 AAV Preclinical

Simplexvirus (HSV) infections EBT-104 AAV Preclinical

Simplexvirus (HSV) infections EBT-105 AAV Preclinical

Exonics Therapeutics Private DMD - AAV Preclinical

Expression Therapeutics Private

Hemophilia AEx vivo stem cell-LV-

FVIII gene therapyLentivirus Preclinical

Hemophilia A AAV-FVIII AAV Preclinical

Hemophilia B AAV-FIX AAV Preclinical





Fibrocell Science FCSC Recessive Dystrophic EB FCX-007 lentivirus Phase I/II

Freeline Therapeutics PrivateFabry disease FLT190 AAV Preclinical

Hemophilia B FLT-180a AAV Phase I/II

Gemini Therapeutics PrivateDry AMD GR-1017 AAV Preclinical

AMD GR-1008 AAV Preclinical

Gene Therapy Research

Inst CoPrivate Parkinson's disease AAV-AADC-TH-CH1 AAV Preclinical

Generation Bio Corp. PrivatePKU - ceDNA Preclinical

Stargardt disease - - Preclinical

Genethon SA Private

Crigler-Najjar Syndrome - AAV Preclinical

DMD - AAV Preclinical

Fanconi Anemia - - Phase II

Wiskott-Aldrich - Lentivirus Phase II

X-CGD OTL-102 lentivirus Phase I/II

GenSight Biologics SA GSGTF LHON GS010 AAV Phase III

GlaxoSmithKline GSK Epidermolysis Bullosa - - Preclinical

Gyroscope Therapeutics Private Dry AMD GT-005 - Phase I/II

Hemera Biosciences Private Wet AMD HMR-59 - Phase I/II

Holostem Terapie Avanzate Srl Private Recessive Dystrophic EB Hologene 7 retrovirus Phase II

Homology Medicines FIXXPKU HMI-102 AAVHSC Preclinical

PKU HMI-103 AAVHSC Preclinical





Horama SA Private

PDE6B Retinitis pigmentosa HORA-PDE6B AAV Phase I/II

RPE65-mediated IRD HORA-RPE65 AAV Phase I/II

RLBP1 Retinal Dystrophy HORA-RLBP1 AAV Preclinical

Immusoft Corp. PrivateEpidermolysis Bullosa - Preclinical

MPS I (Hurler Syndrome) ISP-001 * Preclinical

iTherapeutics Corp. Private Wet AMD - - Preclinical

IVERIC bio ISEEBEST1 Related Retinal Diseases IC-200 - Preclinical

RHO-adRP IC-100 AAV Preclinical

Krystal Biotech KRYSDystrophic EB KB103 HSV-1 Phase I/II

Junctional EB KB-107 HSV-1 Preclinical

Lamellar Biomedical Private Cystic Fibrosis CF-NA non-viral GT Preclinical

Logicbio Therapeutics LOGC

Crigler-Najjar Syndrome LB-301 AAV Discovery/Preclinical

Hemophilia B LB-101 AAV Discovery/Preclinical

Methylmalonic acidemia (MMA) LB-001 AAV Preclinical

Lysogene LYS GM1 LYS-GM101 AAVrh10 Preclinical

Lysogene SAS/

Sarepta TherapeuticsSRPT MPS IIIA (Sanfilippo type A) LYS-SAF302 AAVrh10 Phase III





MeiraGTx MGTX

Achromatopsia (ACHM-A3) AAV-CNGA3 AAV Preclinical

Van Buren

Achromatopsia (ACHM-B3) AAV-CNGB3 AAV Phase I/II

ALS AAV-UPF1 AAV Preclinical

Parkinson's disease NLX-P101 AAV Phase I/II

RPE65-deficiency AAV-RPE65 AAV Phase I/II

Wet AMD A-006 Preclinical

XLRP (RPGR) AAV-RPGR AAV Phase I/II

Milo Biotechnology Private

Becker Muscular Dystrophy AAV1-Follistatin AAV Phase I/II

DMD AAV1-Follistatin AAV Phase I/II

Inclusion body myositis AAV1-Follistatin AAV Phase I/II

Mustang Bio MBIO X-SCID MB-017 lentivirus Phase I/II

NanoScope Technologies Private Dry AMD VMCO-1 - Preclinical

NeuExcell Therapeutics Private

ALS NXLAAV-002 AAV Preclinical

Alzheimer's disease NXLAAV-001 AAV Preclinical

Huntington's NXLAAV-003 AAV Preclinical

Nightstar Therapeutics/

BiogenNITE/BIIB

Dry AMD NSRBEST-1 AAV Preclinical

Choroideremia NSR-REP1 AAV2 Phase III

Stargardt disease NSR-ABCA4 AAV Preclinical

XLRP NSR-XLRP AAV8 Phase I/II





Novartis NVS Hearing loss CGF166 Phase I/II

Novartis/Avexis NVS/AVXS

ALS - SOD1 AVXS-301 AAV Preclinical

SMA Type 1AVXS-101

(Zolgensma)AAV9 Filed

SMA Type 2AVXS-101

(Zolgensma)AAV9 Phase I/II

Orchard Therapeutics ORTX

ADA-SCID Strimvelis lentivirusApproved/Marketed

(EU)

ADA-SCID OTL-101 lentivirus Phase III/Pivotal

Beta-thalassemia OTL-300 Lentivirus Phase I/II

Metachromatic leukodystrophy OTL-200 Lentivirus Phase III/Pivotal

MPS IIIA (Sanfilippo type A) OTL-201 Lentivirus Preclinical

MPS IIIB (Sanfilippo type B) OTL-202 Lentivirus Preclinical

Wiskott-AldrichOTL-103

(GSK2696275)Lentivirus Phase III

X-CGD OTL-102 lentivirus Phase I/II

Oxford Biomedica OXBDFALS - - Preclinical

Wet AMD OXB-201 Phase I/II

Passage Bio PrivateFrontotemporal dementia AAV Preclinical

GM1 AAV-GM1 AAV Preclinical





Pfizer PFE

Canavan Disease - - Phase I/II

Canavan Disease - - Preclinical

DMD PF-06939926 AAV Phase I/II

Friedreich's Ataxia - - Preclinical

Prevail Therapeutics PRVL

Parkinson's disease PR001 AAV9 Preclinical/IND Active

Neuronopathic Gaucher Disease PR001 AAV9 Preclinical

FTD-GRN PR006 AAV9 Preclinical

Synucleinopathies PR004 AAV9 Preclinical

PTC Therapeutics PTCT

AADC Deficiency AGIL-AADC AAV Phase III/Pivotal

Friedreich's Ataxia PTC-FA - Phase I/II

Friedreich's Ataxia GIL-FA AAV Phase I/II

Regenxbio RGNX

Batten Disease (CLN2),

Late InfantileRGX-181 AAV9 Preclinical

HoFH RGX-501 AAV Phase I/II

Wet AMD RGX-314 - Phase I/II

MPS I (Hurler Syndrome) RGX-111 AAV9 Phase I/II

MPS II (Hunter Syndrome) RGX-121 AAV9 Phase II

Renova Therapeutics Private HFrEF RT-100 - Phase I/II

Rocket Pharmaceuticals RCKT

Danon disease (GSDIIb) RP-A501 AAV9 Phase I

Fanconi Anemia RPL-102 Lentivirus Phase I

Infantile Malignant Osteopetrosis RP-L401 - Preclinical

LAD-1 Program RP-L201 LVV Phase I

Pyruvate Kinase Deficiency RP-L301 LVV Preclinical





Rubius Therapeutics RUBY PKU RTX-134 Lentivirus Preclinical

SanBio Co SNBIFDry AMD SB-623 - Preclinical

Parkinson's disease SB-623 - Preclinical

Sangamo Therapeutics SGMO

Alzheimer's disease - - Preclinical

Beta-thalassemia

Sickle Cell DiseaseST-400

- Phase II

Fabry disease ST-920 AAV6 Preclinical

Hemophilia A SB-525 - Phase I/II

Hemophilia B SB-FIX - Phase I/II

MPS I (Hurler Syndrome) SB-318 AAV6 Phase I/II

MPS II (Hunter Syndrome) SB-913 AAV6 Phase II

Sanofi SA SNY Usher Syndrome Type 1B SAR421689 - Phase I/II Raymond

Sanofi SA/Oxford BiomedicaSNY/

OXBDFStargardt disease SAR422459 - Phase I/II

Sarepta Therapeutics SRPT

DMDSRP-9001

(AAVrh74-MHCK7)AAV Phase I/II

BrillDMD AAV-GALTG2 AAV Phase I/II

LGMD2B MYO-201 AAV Phase I/II

LGMD2C MYO-103 AAV Preclinical

LGMD2D MYO-102 AAV Phase I/II

LGMD2E MYO-101 AAV Phase I/II

LGMD2L MYO-301 AAV Preclinical

Sarepta Therapeutics (Lacerta) SRPT Pompe disease - AAV Discovery Brill





Selecta Biosciences SELBMethylmalonic acidemia (MMA) SEL-302 - Preclinical

OTC Deficiency SEL-313 AAV Preclinical

Solid Biosciences SLDB DMD SGT-001 AAV Phase I/II

Spark Therapeutics ONCE

Batten Disease (CLN2), Late

InfantileSPKTPP-1 rAAV Preclinical

Choroideremia SPK-7001 - Phase I/II

Hemophilia A SPK-8011 AAV5 Phase III

Hemophilia A with inhibitors SPK-8016 AAV5 Phase II

Hemophilia B

Fidanacogene

elaparvovec

(SPK-9001)

AAV Phase III

Huntington's - AAV Preclinical

Leber's Hereditary Optic

NeuropathySPK-LHON AAV Preclinical

Pompe diseaseSPK-3006

(AAV-sec-GAA)AAV Preclinical

Spark Therapeutics/Novartis ONCE/NVS RPE65-mediated IRD Luxterna AAV Approved/Marketed

Takara Bio Parkinson's disease - - Phase I/II

TakedaTAK

Hemophilia A TAK-754 (SHP654) - Phase I

Hemophilia B SHP648 - Preclinical

Huntington's - - Preclinical

Parkinson's disease - - Preclinical

Talee Bio PrivateCystic Fibrosis TL-101 AAV Preclinical

Cystic Fibrosis TL-102 Lentivirus Preclinical





Tamid Bio Private MPS I (Hurler Syndrome) Tamid-001 AAV Preclinical

Telocyte Private Alzheimer's disease TEL-01 AAV Preclinical

Temprian Therapeutics Private Vitiligo - non-viral GT Preclinical

The National Institute of

Allergy and Infectious

Diseases

Private HIV AAV8-VRC07 AAV8 Phase I

Tocagen TOCA

GliomaToca 511 and

Toca FCretrovirus Phase III/Pivotal

Metastatic solid tumorToca 511 and

Toca FCretrovirus Phase I/II

Tolerion Private DMD - - Preclincal

Ultragenyx Pharmaceutical RARE

GSD1a DTX401 AAV Phase I/II

Raymond

Hemophilia A DTX201 AAV Phase II

OTC Deficiency DTX301 AAV Phase I/II

PKU UX-501 AAV8 Preclinical

Wilson disease UX701 AAV Preclinical

UniQure QURE

Fabry disease AMT-190 AAV5 Preclinical

Brill

Hemophilia A AMT-180 AAV5 Preclinical

Hemophilia BAMT-061 (Padua

variant of Factor IX)AAV5 Phase III

Huntington's AMT-130 AAV Preclinical

SCA-Type 3 xxx AAV Preclinical

ViroMed Co Ltd 084990.KQALS VM-301 AAV Preclinical

Wounds pIKO AAV Preclinical





Vivet Therapeutics SAS Private Wilson disease VTX-801 AAV Preclinical

Voyager Therapeutics VYGR

Alzheimer's disease (Tauopathy program) AAV Preclinical

ALS - SOD1 VY-SOD102 AAV Preclinical

Friedreich's Ataxia VY-FXN01 AAV Preclinical

Huntington's VY-HTT01 AAV Preclinical

Parkinson's disease (advanced) VY-AADC AAV Phase I/II


Risks associated with all companies described in this report are common to other biotech companies.

Clinical risk. Success in clinical trials will be essential for companies to market their products, but success in the clinic is not guaranteed.

Regulatory risk. The FDA, EMA or other regulatory bodies may have a different view on the benefit-risk balance demonstrated in clinical testing than the company

seeking approval. Companies may be required to do additional trials, which may make the development of the candidates more time- and cost-prohibitive.

Commercial risk. The cell therapy space that companies operate in is very specific and challenging as there are multiple competitors and significant pricing pressure.

Additionally, if cell therapies are successfully developed, they will be entering a market that has have several other modalities available and/or close by in development.

Clinical and/or regulatory success does not guarantee commercial success.

Financing risk. Pipeline development and commercial plans will require capital and time. In addition to cash flow from marketed products and funding from partners,

companies may need to raise more money through an equity offering, which may negatively impact the stock price.

Intellectual property risk. Protection of a company’s drugs and processes is dependent on issued or pending patents and in-house knowledge. One or more parties

often challenge the intellectual property estate of a successful product, claiming priority for other patents or that the patents are invalid or infringe. Significant expense on

legal protection could be required in the future, with no guarantee of success.

Risks



BioInsights Report Library


Date Title Topic

10/31/18 Oncology Series: Assessing Heme-Oncs’ Early CAR-T Experience & Potential Competition CAR-T Cells

11/26/18 BioInsights: A Deep Dive on Anti-VEGFs and Next-Gen Therapies for Wet AMD & DME Ophthalmology - Retinal Diseases

12/27/18Hematology Series – Sickle Cell Disease (SCD): A Deep Dive on the Current Management of Sickle

Cell Disease and Therapies in Clinical TrialsHematology - Sickle Cell Disease

01/31/19 Oncology Series: Bispecific Antibodies – Long “Emerging,” Now Ready for Prime Time Bispecific Antibodies

03/04/19 Investing in Gene Editing – Early Days, but Huge Therapeutic Potential Gene Editing

03/29/19 Rare Disease Series: Disease Modifying Therapies in Cystic Fibrosis Cystic Fibrosis

04/29/19Oncology Series – Cell Therapy Compendium: Cell Type Considerations For The Next Generation Of

Cellular TherapyCell Therapies

05/30/19 Oncology Series – Targeting DNA Damage Response (DDR) Pathways Through Precision Oncology DNA Damage Response

06/25/19 Targeting FcRn – A Deep Dive Into a Rapidly Advancing Therapeutic ApproachFcRn and IgG-mediated

Autoimmune Disorders

07/31/19 Medical Dermatology From “A to V”: A Rapidly Evolving Landscape Medical Dermatology


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