Corporate PresentationDecember 2020

FORWARD-LOOKING STATEMENTS

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This press release contains forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995 and other federal securities laws. The use of words such as “intended”, "may," "might," "will," "would," "should," "expect," "believe," "estimate," and other similar expressions are intended to identify forward-looking statements. For example, all statements Sio makes regarding costs associated with its operating activities are forward-looking. All forward-looking statements are based on estimates and assumptions by Sio’s management that, although Sio believes to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that Sio expected. Such risks and uncertainties include, among others, the impact of the Covid-19 pandemic on our operations, the initiation and conduct of preclinical studies and clinical trials; the availability of data from clinical trials; the development of a

suspension-based manufacturing process for Axo-Lenti-PD; the scaling up of manufacturing, the expectations for regulatory submissions and approvals; the continued development of our gene therapy product candidates and platforms; Sio’s scientific approach and general development progress; and the availability or commercial potential of Sio’s product candidates. These statements are also subject to a number of material risks and uncertainties that are described in Sio’s most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on November 13, 2020, as updated by its subsequent filings with the Securities and Exchange Commission. Any forward-looking statement speaks only as of the date on which it was made. Sio undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.

SIO: AIMING FOR TRANSFORMATIVE

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40+ employees across NYC and Raleigh

Gene therapy expertise in neurogenerative diseases

Partnered with leading gene therapy academic

organizations including the NIH and UMass

Focusing on preclinical and analytical development in our

new North Carolina lab facility

PLATFORM PARTNERSHIPS PEOPLE

Combining cutting-edge science with bold imagination to develop genetic medicines that aim to radically improve the lives of patients

Serve the rare disease and Parkinson’s patient

communities as a resource and partner

Partnered with top AAV and Lentiviral manufacturers

including Viralgen and Oxford Biomedica

Clinical data in Parkinson’s disease with 21 patients

across 5 dose cohorts

Use both AAV and Lentiviral vectors tailored

to each disease

Potential to be first-in-class (GM1/2) and best in class

(PD) gene therapy

LEADERSHIP AND ADVISORS TEAM WITH BROAD CNS AND GENE THERAPY EXPERIENCE

Pavan Cheruvu, MDChief Executive Officer

David Nassif, JDChief Financial Officer & General Counsel Gavin Corcoran, MD FACP

Chief R&D OfficerParag Meswani, PharmD

Chief Commercial Officer

Frank Torti, MDChairperson

Berndt ModigBoard Member

Atul Pande, MDLead Independent Director

Senthil SundaramBoard Member

Eric Venker, MD, PharmDBoard Member

Kristiina Vuori, MD, PhDBoard Member

Pavan Cheruvu, MDBoard Member

Guanping Gao, PhDChief AAV Scientific Advisor

Man

agem

ent

Advi

sor

Board of Directors

THREE CLINICAL-STAGE GENE THERAPY PROGRAMS

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Candidate Indication Vector Gene Phase

AXO-Lenti-PD

Research Pre-clinical Clinical

Parkinson’s disease Lentivirus TH, CH1, AADC

AXO-AAV-GM1 GM1 gangliosidosis AAV9 GLB1

AXO-AAV-GM2 Tay-Sachs/Sandhoffdisease

AAVrh.8 HEXA, HEXB

Phase 2

Phase 1/2

Phase 1/2

Geographic rights: WorldwideFDA Designations: Orphan Drug Designation

Rare Pediatric Disease Designation

Geographic rights: WorldwideFDA Designations: Orphan Drug Designation

Rare Pediatric Disease Designation

Geographic rights: Worldwide

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AXO-Lenti-PD Program Update

AXO-Lenti-PD has the potential to provide clinically meaningful benefits to patients with advanced PD continuing to progress on medical therapy

Clinically Meaningful Data Next Steps

• Complete the development of suspension process clinical trial material

• File the IND in the US and IMPD in EU

• Dose patients with the higher dose in the open label SUNRISE-PD study

• Proceed to a controlled study (EXPLORE-PD) with the appropriate dose based on the results of SUNRISE-PD

• Cohort 2 shows:• Favorable safety profile similar to cohort 1 & Prosavin• Positive assessments focused on the change in motor

function and activities of daily living• Large change from baseline in UPDRS II and III - 14

and 21 points, respectively• Clinically meaningful improvement in Hauser Diary

OFF and good ON time• Reduction in the LEDD in the face of the stabilization

or improvement

• Totality of data supports moving to a higher dose and greater putaminal coverage

• Achieved with a 3-fold increase in volume administered

Rare fatal pediatric diseasesFirst clinical-stage gene therapies for GM1 gangliosidosis, Tay-Sachs and Sandhoff diseases

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GM1 GANGLIOSIDOSIS AND GM2 GANGLIOSIDOSIS (TAY-SACHS/SANDHOFF DISEASE): DEVASTATING PEDIATRIC DISEASES

• Mutation in the HEXA or HEXB gene leads to impaired β-hexosaminidase A heterodimer (α-β) enzyme

• HEXA gene mutation: Tay-Sachs disease• HEXB gene mutation: Sandhoff disease

• Accumulation of GM2 ganglioside in the central nervous system leads to significant neurological disease

• Naturally occurring models: feline and sheep

• Mutation in the GLB1 gene leads to impaired β-galactosidase enzyme

• Accumulation of GM1 ganglioside in multiple organ systems causes significant defects:

• Severe progressive neurological decline• Hepatosplenomegaly• Blindness and ocular deficits• Osteoporosis and skeletal dysfunction

• Naturally occurring model: feline

Fatal, pediatric lysosomal storage disorders with monogenic autosomal recessive inheritance pattern

Combined Prevalence: ~750-1,350 US+EU patients with NO APPROVED TREATMENTS

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GM1 Gangliosidosis Tay-Sachs/Sandhoff Disease

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

50 1 62 3 74 8

NATURAL HISTORY OF INFANTILE GM1 GANGLIOSIDOSIS AND TAY-SACHS/SANDHOFF DISEASE1,2

GM1 GangliosidosisTay-Sachs/Sandhoff

Perc

ent S

urvi

val

Age (years)

Dysphagia Requiring

Feeding Tube Lose Head Control

~50% mortality by 3.5 years

~75% mortality by 5 yearsCannot Sit

AloneLose Head

Control

OsteoporosisBlindnessSeizure Onset

Clinical course illustrates rapidly progressive and uniformly fatal nature of both diseases

1: Bley, et al, Pediatrics. 2011; 128(5):1233-1241.2: Utz, et al, Mol Genet Metab. 2017; 121(2):170-179.

Life expectancy curve derived from natural history study in GM2 patients

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ATTRACTIVE TARGETS FOR GENE THERAPY: WELL-UNDERSTOOD BIOLOGY UNDERLYINGBOTH DISEASES

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Broad distribution achieved via one-time administration

Underlying neurobiology supports the use of gene

therapy for long-term enzyme restoration

Clinically relevant biomarkers paired with

well-accepted neurodevelopmental

measures

GM1 Ganglioside β-galactosidase

GM2 Ganglioside

β-Hexosaminidase A(α-β heterodimer)

GM3 Ganglioside GM1 Gangliosidosis

HEXA Gene: Tay-Sachs disease

GM2 Gangliosidosis

HEXB Gene: Sandhoff diseaseGLB1 Gene

AXO-AAV-GM1: GENE THERAPY FOR GM1 GANGLIOSIDOSIS

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Only Clinical-Stage Gene Therapy Program Targeting the Full Spectrum of Patients with Type I and Type II GM1 Gangliosidosis

GM1 Gangliosidosis AXO-AAV-GM1 Gene Therapy Rationale

• One time delivery of a functional copy of the GLB1 gene via intravenous administration of AAV9 vector system

• Intravenous delivery addresses the multisystem manifestations of GM1 gangliosidosis

• Only gene therapy to demonstrate restoration of wild-type survival in a naturally-occurring GM1 feline model

• Positive six-month enzyme activity and preliminary clinical outcomes data in late-infantile/juvenile (Type II) children treated with low-dose gene therapy (1.5x1013 vg/kg)

• High dose cohort (4.5x1013 vg/kg) initiated in November 2020; two patients now dosed without complications

• Fatal, pediatric lysosomal storage disorder with monogenic autosomal recessive inheritance pattern that affects ~450-900 US+EU patients

• Single gene (GLB1) defect leads to decreased β-galactosidase enzyme activity and ganglioside accumulation

• Disease hallmark is progressive neurodegeneration due to storage of GM1 ganglioside in lysosomes

• Late infantile/juvenile (Type II) have a life expectancy of 10-20 years

• Currently no treatments available

INTRAVENOUS DELIVERY TO ADDRESS THE MULTISYSTEM MANIFESTATIONS OF GM1 GANGLIOSIDOSIS

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CEREBRAL ATROPHY

HEPATOSPLENOMEGALY

CHERRY-RED SPOT

SKELETAL DYSPLASIA

CARDIAC ABNORMALITIES

Cisterna magna Delivery Intravenous Delivery

Invasiveness Medium Minor

CNS Distribution

Outer surface of brain and spinal cord*

Whole brain and spinal cord

Body Distribution

Low, highly variable vector delivery to body organs

• Heart• Liver-Spleen• Gastrointestinal• Musculoskeletal• Peripheral nerves

*Data on file

ONLY GENE THERAPY TO DEMONSTRATE RESTORATION OF WILD-TYPE SURVIVAL IN A GM1 FELINE MODEL1

13

0

1

2

3

4

5

6

7

8

9

10

1 6 11 16 21 26 31 36

Clin

ical

Rat

ing

Scor

e

Age (months)

Normal GM1 feline + one-time gene therapy GM1 feline

GM1 Felines Treated with 1.5E13 vg/kg via Intravenous Injection at 5 Weeks of Age

IV infusion

1: UMass Data on File; WPRE included in construct administered to felines Note: Felines were treated with the first-generation construct and the AXO-AAV-GM1 vector has been optimized prior to dosing patients in the ongoing clinical trial.

INDEPENDENT STUDY CONFIRMS AAV9 IV ROUTE OF ADMINISTRATION HAS SUPERIOR CNS DISTRIBUTION IN GM1 FELINES

All feline animals were treated with 1.5e13 vg/kg and used a similar vector backbone

1: Data from Auburn University.Note: Felines were treated with a vector that includes a WPRE component; AXO-AAV-GM1 does not include this component.

INDEPENDENT STUDY DEMONSTRATES AAV9 GENE THERAPY IV ROUTE OF ADMINISTRATION IS MOST EFFECTIVE IN EXTENDING SURVIVAL AND IMPROVING CLINICAL FUNCTION

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All feline animals were treated with 1.5e13 vg/kg and used a similar vector backbone

1: Data from Auburn University.Note: Felines were treated with a vector that includes a WPRE component; AXO-AAV-GM1 does not include this component.

EXTENSIVE PRECLINICAL DATA SUPPORT DIFFERENTIATED CLINICAL APPROACH

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AAV9 outperforms AAVRh10 acrossadministration routesOptimized Vector

Intravenous administration has superior CNSdistribution and βGal activity with potential toaddress multisystem manifestations

Optimized Delivery

Restoration of white and grey matter, and corticalvolume, as measured by MRI observed in felinemodel

Restored Cortical Volume

Only gene therapy to demonstrate restoration of wildtype survival in naturally occurring feline modelSuperior Outcomes

Independent preclinical studies show consistent superiority of vector, delivery and efficacy with AXO-AAV-GM1 IV delivery

Stabilization of neuromuscular decline and survival prolongation observed in naturally occurring feline model

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ROUTE OF ADMINISTRATION • Intravenous

CLINICAL MEASURES (TYPE II)

• Safety and tolerability

• Developmental changes and disease progression measured by: Vineland-3 Adaptive Behavior Scales, Bayley Scales of Infant Development (Type I only) and Clinical Global Impressions Scale

• Changes to MRI/MRS

• Motor function and disease severity

• Skeletal survey, swallow/speech assessment

• Exploratory objectives include systemic and CSF biomarkers and neurological symptoms

NEXT STEPS

• High dose cohort (4.5x1013 vg/kg) initiated in November 2020; two patients now dosed without complications

• Continued dosing of infantile (Type I) and late-infantile/juvenile (Type II) patients in high-dose cohort of ongoing study

• Obtain data in both Type I and Type II children as part of clinical and regulatory strategy to obtain broad indication

Low-Dose Cohort1.5 x 1013 vg/kg Type I (infantile) and Type II

(juvenile)

STAGE 1: DOSE-RANGING STAGE 2: EFFICACY STUDY

High-dose Cohort4.5 x 1013 vg/kg

6-month data readout December 2020

Stage 1 and Stage 2 will include a mix of Type I (infantile) and Type II (late-infantile/juvenile)

AXO-AAV-GM1: CLINICAL STUDY DESIGN

ClinicalTrials.gov Identifier: NCT03952637

Ongoing

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Biomarkers of Disease Activity• Rates severity and improvement based on clinical opinion from 1-7

• 1 = “normal” or “very much improved since initiation of treatment”

• “7” = “among the most extremely ill patients” or “very much worse since the initiation of treatment”

• Stabilization in CGI relative to natural history has not been reported previously

1Normal, not

at all ill

2Minimally

ill

3Mildly ill

4Moderately

ill

5Markedly

ill

6Severely

ill

7Very

severely ill

Clinical Global Impression Scale (CGI)

Vineland-3 Adaptive Behavior Assessment (VABS-III)• GM1 presents with regression in function or loss of achieved milestones

• Vineland-3 is a measure of adaptive behavior that is widely used to assess intellectual ability in patients with neurodevelopmental disabilities

• Evaluates communication, daily living, and social skills

• VABS-III demonstrates predictable decline in natural history studies and stabilization has not been reported previously.

Ability

Scor

e

Growth Scale Value (GSV)

GSV Score has predictable relationship to ability

• Level of residual enzyme correlates inversely with the severity of the disease

• 10-20% enzyme activity threshold thought to aid in clearance of stored lysosomal substrates and associated with slower disease progression of various lysosomal storage disorders.

• Lower the level of enzymatic activity, the more severe the phenotype

(1) Lang et al., Mol Genet Metab, 2020; (2) NIH data on file; (3) Utz et al., Mol Genet Metab, 2017; (4) Yogalingam et al., J. Biol. Chem. 2019.

AXO-AAV-GM1: CLINICALLY MEANINGFUL ASSESSMENTS OF THERAPEUTIC RESPONSE

AXO-AAV-GM1: 6-Month Data ReadoutBiomarkersClinical and Functional Outcomes

OVERALL SAFETY SUMMARY (6-MONTH DATA)

• AXO-AAV-GM1 was generally safe and well-tolerated at the low dose (1.5x1013 vg/kg) delivered intravenously in Type II (late-infantile and Juvenile) patients.

• There have been no serious adverse events (SAEs) related to gene therapy. o One SAE was described: a single patient experienced bacterial sepsis due to a PICC line infection,

which was considered to be unrelated to the investigational drug product, and which resolved within a few days following line removal and administration of IV antibiotics.

• The most common adverse events were considered mild to moderate. Transient AST elevations were observed in 4 subjects, none of which required clinical intervention or had associated clinical sequelae. There were no other adverse events indicative of impaired liver function including serum bilirubin, GGT, and ALT. No clinically relevant changes were observed in platelet count.

• The favorable safety profile in the low-dose cohort supports continued enrollment of patients in the high-dose cohort (4.5x1013 vg/kg), in which two patients have now been dosed without complications.

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β-galactosidase ENZYME ACTIVITY IN SERUM ACROSS 9 DISTINCT TIMEPOINTS Increase from baseline between 71-138% (mean: 110%) during the 6-month observation period

21

123

106

74

132138

123

109114

71

0

20

40

60

80

100

120

140

160

Day 7 Day 14 Day 21 Day 30 Day 45 Day 60 Day 75 Day 90 Day 180

% I

NCR

EASE

FRO

M B

ASEL

INE

IN S

ERU

M

BETA

-GAL

ACTO

SIDA

SE E

NZY

ME

ACTI

VITY

Data Collection Timepoint

% Change from Baseline

N = 5

Cohort Mean: 110%

β-galactosidase ACTIVITY IN SERUM BY SUBJECT:Enzyme activity restored to 23-57% (mean: 38%) of normal* reference levels at Month 6

22.7

56.5

25.7

37.3

48.5

0.0

10.0

20.0

30.0

40.0

50.0

60.0%

of N

orm

al R

efer

ence

Lev

els

22

DAY 180 DAY 180 DAY 180 DAY 180 DAY 180

*The reference level was defined by the lowest level of enzyme activity in serum from 30 healthy adult volunteers using the samevalidated assay of beta-galactosidase enzyme activity as was used to assess the patients in the study.

001-003 001-006 001-008001-004 001-007

N = 5

Cohort Mean: 38%

BIOMARKER SUMMARY: Positive Increase in β-Galactosidase Serum Levels Over Six Months

• Serum beta-galactosidase enzyme activity was sampled at 9 distinct timepoints between Day 7 and Month 6

• The proportional increase from baseline across the patients ranged between 71-138% (mean: 110%) during the 6-month observation period, representing an approximate doubling in enzyme activity after gene transfer. At Month 6, serum enzyme activity increased by an average of 71% from baseline (range: 33%-127%) across the five patients.

• At month 6, serum enzyme activity on average was restored to 38% of normal reference levels at Month 6, with individual patients ranging from 23-57% of these normal levels.

• The reference level was defined by the lowest level of serum enzyme activity consistent with a normal clinical presentation in 30 healthy adult volunteers using a validated assay of beta-galactosidase enzyme activity.

• Cerebrospinal fluid (CSF) samples were collected in all patients over the 6-month period. Development and validation of biomarker assays for CSF is currently ongoing.

23

FLOOR AND UPRIGHT MOBILTY SCORES BY SUBJECT AT MONTH 6All subjects demonstrate disease stability

5 5 5 55 5 5 5 5 5 5 55 5

0

1

2

3

4

5

24 34 44 54 64 74 84

Floo

r Mob

ility

Sco

re

Age (in months)001-003 001-004 001-006 001-007 001-008

24

5 5 5 5

2 2 2 2

3 3 3 3

4 4 4 44 4 4 4

0

1

2

3

4

5

24 34 44 54 64 74 84

Upr

ight

Mob

ility

Sco

re

Age (in months)001-003 001-004 001-006 001-007 001-008

Motor Scoring- Floor Mobility: 0 = Unable to roll1 = Rolls Independently2 = Sits with support3 = Sits without support4 = Scoots independently when sitting5 = Crawls in 4-point independently

Upright Mobility Scale: 0 = Non-ambulatory, dependent for wheeled mobility (WC or stroller)1 = Able to pull to stand, unable to ambulate2 =Ambulates only with the assistance of another person (with or without a mobility aid) due to unsteady gait3 =Ambulates independently with mobility aid due to unsteady gait4 =Independent ambulation, may be unsteady5 =Ambulation is normal for age

Visit Schedule: ScreeningDay 30Day 90Day 180

CLINICAL GLOBAL IMPRESSION SCALE (CGI) AT MONTH 6Improved in 4/5 patients and remained stable in the 5TH child over evaluation period.

2

4

3 3 3

0

1

2

3

4

5

6

7

CGI-S

ever

ityat

Bas

elin

e

25

SCREENING (SCR)

4 4 4 4 44

3 3 3 3

4

3 3 3 3

0

1

2

3

4

5

6

7

CGI-C

ompa

red

to B

asel

ine

D30D90

D180SCR SCR SCR SCR

CGI Baseline Severity :1 = Normal2 = Borderline ill 3 = Mildly ill4 = Moderately ill5 = Markedly ill6 = Severely ill7 = Among the most extremely ill patients.

CGI Compared to Baseline: 1 = Very much improved 2 = Much improved3 = Minimally improved 4 = No change5 = Minimally worse 6 = Much worse7 = Very much worse

D30D90

D180 D30D90

D180 D30D90

D180 D30D90

D180

001-003 001-006 001-004 001-007

001-008

001-003 001-003001-004 001-004001-006 001-006 001-007 001-007001-008 001-008

VINELAND-3: GROWTH VALUE SCORES DEFINITIONS BY DOMAIN

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VINELAND-3: SUBDOMAIN GROWTH SCALE VALUE SCORES MONTH 6 (1/2)

117 117 121

8782 82

100

118113109 109 106

107114

109

0

30

60

90

120

150

180

24 36 48 60 72 84

Receptive Communication

27

142

154

166

87 87

69

125 126133

137 133136

125 134

135

0

30

60

90

120

150

180

24 36 48 60 72 84

Expressive Communication

4247

10 2940 42

2529 32

2940 42

0

30

60

90

120

150

180

24 36 48 60 72 84

Written Communication[1]

3644

10

37 37 34

3436

31

36 37 34

0

30

60

90

120

150

180

24 36 48 60 72 84

Community[1]

41 45

1034 38 42

38 39 42

39 39 42

0

30

60

90

120

150

180

24 36 48 60 72 84

Domestic[1]

110 110117

7670

75

93100 99

100 10096

102106

101

0

30

60

90

120

150

24 36 48 60 72 84

Personal

Age in Months

Gro

wth

Sca

le V

alue

Sco

re

001-003 001-006 001-008 001-004 001-007

Com

mun

icat

ion

Dai

ly L

ivin

g Sk

ills

Visit Schedule: Screening, Baseline, Day 180

[1] Domestic, Community and Written subdomains are applicable to subjects 3 years and older. Subject 004 turned 3 years old between Day 90 and Day 180.

VINELAND-3: SUBDOMAIN GROWTH SCALE VALUE SCORES MONTH 6 (2/2)

113

97106

73 73 70

8896 99

9297 93

9197 99

0

30

60

90

120

150

180

24 36 48 60 72 84

Interpersonal Relationships

28

10696

108

62 62 58

8393 95

93 9593

87 9692

0

30

60

90

120

150

180

24 36 48 60 72 84

Play and Leisure Time

6857

67

46 45 4651

6459

55 57 5657 59 57

0

30

60

90

120

150

180

24 36 48 60 72 84

Coping Skills

120 118 117

75 72

54

108 112 112

100108

117105112 112

0

30

60

90

120

150

180

24 36 48 60 72 84

Fine

148 148155

8681

68

118 118 119

128 124 126

128 125 126

0

30

60

90

120

150

180

24 36 48 60 72 84

Gross

Age (in Months)

Gro

wth

Sca

le V

alue

Sco

re

001-003 001-006001-004 001-007

001-008

Soci

aliza

tion

Mot

or

Visit Schedule: Screening, Baseline, Day 180

AXO-AAV-GM1 LOW-DOSE TYPE II PATIENT COHORT: 6-MONTH SUMMARY• Generally well-tolerated with a favorable safety

profile• Serum beta-galactosidase enzyme activity

increased in all patients at all timepoints between Day 7 and Month 6, representing an approximate doubling in enzyme activity after gene transfer

• All five children demonstrated signs of clinical disease stability across multiple measures of neurodevelopment

• High-dose cohort (4.5x1013 vg/kg) for Type II patients initiated in November 2020 with two patients dosed without complications; study ongoing 29

AXO-AAV-GM2: GENE THERAPY FOR GM2 GANGLIOSIDOSISStage 1: Clearance of investigational new drug application received November 2020

30

The Only Gene Therapy in Development That has Already Been Tested in Human Patients Through an Expanded Access Protocol

Tay-Sachs / Sandhoff Disease AXO-AAV-GM2

• One-time delivery of two vectors using AAVrh8 vector encoding HEXA and HEXB genes directly to the CNS

• Dual intrathalamic and intrathecal routes of administration allow for transduction across entire neuraxis

• Reported the first evidence of disease stabilization in two infants with Tay-Sachs disease following administration

• Therapy has been generally well-tolerated to date, with no serious adverse events

• Fatal, pediatric lysosomal storage disorder with monogenic autosomal recessive inheritance pattern that affects ~250-450 US+EU patients

• Well-characterized natural history demonstrating developmental regression, blindness and epilepsy with focal seizures

• Caused by a mutation in the HEXA or HEXB genes, which prevents β-hexosaminidase A enzyme formation

• Infantile (Type I) is the most common form of the disease; patients have a life expectancy of 3-4 years

• Currently no treatments available

NATURAL HISTORY OF INFANTILE GM2: TAY-SACHS AND SANDHOFF DISEASES

31

AGE (months)

Clinical course illustrates rapidly progressive and uniformly fatal nature of infantile form of both diseases

Bley, et al, Pediatrics. 2011; 128(5):1233-1241.Jarnes Utz, et al, Mol Genet Metab. 2017; 121(2):170-179

43210

Sitting without propping

Transfer from hand to hand

Head control

Reach for object

Seizure onset

Blindness

Deafness

Gain

Gain

Gain

Gain

Loss

Loss

Loss

Loss

Endpoints include: • Motor milestone gain / loss • Auditory assessments• Visual assessments• MRI changes

Most early motor milestones are gained and subsequently

lost within a ~1-year time frame

AXO-AAV-GM2: COMBINED INTRAPARENCHYMAL AND CSF DOSING DELIVERS OPTIMAL OUTCOMES

32

Bilateral Thalamic + Unilateral ICV (BiTh/ICV) Injections in SD Cats Transduce Entire Neuraxisand Dramatically Improve Function with Significantly Increased Survival (P < 0.0001)

Neuraxial Distribution of Reconstituted Enzyme with Combination Delivery(cross sections stained for HEXA enzyme activity)

Rockwell, et al. ASN Neuro. 2015: 1-13UMMS data on file

CASE STUDY: PATIENT TSD-002 DOSED WITH AXO-AAV-GM2 VIA EXPANDED ACCESS

33

A Mildly Symptomatic Infantile Tay-Sachs Disease Patient Dosed Bilaterally into Thalamus and Cisterna Magna

• Total 4.6x1013 vg as equimolar mix of rAAVrh8HexA and HexB split between thalamus (bilateral) and intrathecal

• Immune Suppression: Rituximab, Sirolimus, Prednisone beginning 6 days prior to administration

• Current status:

• Clinically well at present with a stable exam

• No evidence of seizures or exaggerated startle responses

Cisterna magna and

Lumbar spinal cord

Birth

3 to 4 months – Disease onset• Cherry red spot on macula

10 months• Clinically stable

6 months – Screened

Age: 7-month-old, female

Family History: Two untreated older siblings with Tay Sachs disease• Siblings exhibited rapid disease progression,

clinical regression and seizure onset at 12-18 months of age

Thalamus

7 months – Dosed

34

PRE-TREATMENT

3 MONTH POST-TX

6 MONTH POST-TX

CM = Contrast Media FA = Fractional AnisotropyRD = Radial Diffusivity

No injury to thalamus;

Normal new myelin

deposition

Nestrasil, et al, Molecular Genetics and Metabolism. 2018

CASE STUDY: PATIENT TSD-002 SHOWED NORMAL BRAIN ANATOMY AND INCREASED MYELINATION CONSISTENT WITH NORMAL BRAIN DEVELOPMENT AT THIS AGE

048

1216202428323640444852566064

Baseline Week 1 Week 2 Week 3 Month 1 Month 2 Month 3 Month 6 Month 12

CHO

P IN

TEN

D S

core

Time from Administration TSD-001 TSD-002 Clinically Meaningful Improvement Range

FIRST TWO PATIENTS DOSED WITH AXO-AAV-GM2: STABILIZATION OF MOTOR SKILLS AS MEASURED BY CHOP INTEND*

35

Clinically Meaningful Improvement: Total scores sustained >40 points indicates a clinically meaningful improvement

*CHOP INTEND (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) is a 16-item measure of motor skills with a total range of 0 – 64, where zero equals no response and 64 equals a complete response

AXO-AAV-GM2: CLINICAL STUDY DESIGN

36

Low-Dose(n=1)

Registrational study using target dose from Stage 1

(n≈8-10)

Mid-dose(n≈4)

High-dose(n≈3)

STAGE 1: DOSE-ESCALATION STAGE 2: EFFICACY STUDY

ROUTE OF ADMINISTRATION

• Vector administered via a catheter directly into the thalamus on both sides and into the CSF through an intrathecal (IT) catheter:

o 75% of the intended intrathecal dose will be administered into the cisterna magna

o 25% of the intended dose will be infused to the thoracolumbar area

CLINICAL MEASURES (TYPE

II)

• Safety and tolerability

• Enzyme activity in CSF and serum

• GM2 ganglioside levels in CSF

• Changes to MRI/MRS

• Motor function and disease severity

• Exploratory objectives include other systemic and CSF biomarkers and neurological symptoms

NEXT STEPS• IND cleared November 2020

• Expects to begin patient identification and site startup activities in preparation for dosing promptly

AAV PROGRAM PARTNERSHIPS WITH LEADING GLOBAL GENE THERAPY INSTITUTIONS

37

• Rare disease programs originated from University of Massachusetts Medical School and Auburn University

• Andelyn Biosciences: premier manufacturer of AAV technology; formed by Nationwide Children’s Hospital

• Viralgen: Leading CDMO built as a joint venture between AskBio and Columbus Venture Partners in Spain

• Secured cGMP capacity and resources to support development and commercialization

Adult neurodegenerative diseasesParkinson’s disease

38

AXO-LENTI-PD: GENE THERAPY FOR PARKINSON’S DISEASE

39

Moderate to Advanced Parkinson’s disease AXO-Lenti-PD

• One-time treatment using a lentiviral vector with three key genes to produce endogenous dopamine

• Development plan integrates robust preclinical and clinical data from 1st generation vector, ProSavin

• SUNRISE-PD Cohort 1: 17-22 point improvement from baseline in UPDRS III “OFF” scores at 6 and 12 months

• Cohort 2: Positive 6-month data demonstrating 21-point improvement from baseline in UPDRS III “OFF” score

• Addressable market of > 200k patients

• Progressive and chronic disease that impacts more than 1 million patients in the US

• 50% of people with PD develop motor problems after 5 years, despite best medical treatment

• >80% experience ON/OFF fluctuations

• Levodopa, the gold standard therapy, causes treatment side effects such as dyskinesias and has a high pill burden with modest improvements of 4-8 points in UPDRS III “OFF” Scores

• Substantial opportunity to improve motor function and quality of life

Clinical Data From 21 Patients Across 5 Different Dose Cohorts Demonstrates Dose Dependent Efficacy and Favorable Safety Profile

OVERVIEW OF AXO-LENTI-PD

40

AXO-Lenti-PD encodes three enzymes required for endogenous dopamine synthesis• Tyrosine hydroxylase (TH) and Cyclohydrolase 1 (CH1): converts tyrosine to L-dopa• Aromatic L-amino acid decarboxylase (AADC): converts L-dopa to dopamine

Utilizes a lentiviral vector with large gene packaging capacity to accommodate all three genes

Tyrosine Levodopa DopamineCH1

TH AADC

Stereotactic delivery via one-time infusion directly into the putamen• Neuroimaging with MRI performed before and after procedure to ensure localization• No intraoperative MRI required for localization

AXO-LENTI-PD: RE-ENGINEREED VECTOR LEVERAGES PROSAVIN NONCLINICAL AND CLINICAL EXPERIENCE

41

AADC CH1

IRES

CMVp TH WPRE

IRES

ProSavinSIN LTR SIN LTR

AADCCH1 WPRE

IRES

AXO-Lenti-PDSIN LTR

CMVp TH

SIN LTR

ProSavin AXO-Lenti-PD

• CH1 moved closer to promoter to enhanceexpression

• TH and CH1 joined by flexible linker to ensure co-localization

VECTOR DESIGN

PROSAVIN CLINICAL EFFICACYMean UPDRS-III OFF Change from

Baseline to 12 Months• Cohort 1: -7 points (-27%)

• Cohort 2: -11 points (-29%)

• Cohort 3: -15 points (-29%)

ProSavin - PHASE 1/2 STUDY

n=3n=6

n=6

15 patients treated with ProSavin to inform AXO-Lenti-PD’s development plan

Cohort 11.9 x 107 TU

Cohort 24.0 x 107 TU

Cohort 31.0 x 108 TU

• 5-10x improvement indopamine production in vitro with AXO-Lenti-PD

• Enhanced PK and PD observed in vitro and in vivo with AXO-Lenti-PD

• Evidence of dose-dependent efficacy and biomarker activity vs. control observed in animal models of disease (MPTP macaque monkeys)

• Long-term studies showed no evidence of carcinogenicity in multiple species

PRE-CLINICAL DATA

1: Stewart, et al, Hum Gene Ther Clin Dev. 2016;27(3):100-110.2: Palfi, et al. The Lancet. 2014;383(9923):1138-1146

AXO-Lenti-PD – Optimized Vector ConstructSUNRISE-PD Phase 2 Clinical Study

Dose Escalation

Cohort 14.2 x 106 TU

600 µL total infusion volume

Volume Expansion Cohort 3

4.2 x 107 TU1800 µL total infusion volume

AXO-Lenti-PDEXPLORE-PD Phase 2

Clinical Study

Randomized, double-blinded clinical trial with

highest safe dose vs. sham surgical procedure

N=2 N=4 Evaluates safety, tolerability, and efficacy of higher volume and flow rate

Cohort 21.4 x 107 TU

600 µL total infusion volume

ENROLLMENT CRITERIA• Patients with advanced, idiopathic Parkinson Disease• Age: 30-70• Hoehn & Yahr (H&Y) OFF Stage: 3-4• UPDRS Part III (motor) OFF score: 30-60• Levodopa equivalent daily dose (LEDD): ≥ 900 mg• ≥ 2.5 hours diary “OFF” time (Cohort 2)

Cohort 3 and EXPLORE-PD Clinical Study

AXO-LENTI-PD CLINICAL DEVELOPMENT PLAN: CURRENT STATUS

42

SYSTEMATIC DATA COLLECTION EVALUATING PATIENT OUTCOMES

• Adverse event collection• Focused ongoing surveillance of gene therapy

Safety and Tolerability

• Hauser Patient Diary• UPDRS Part III OFFMotor Function

• UPDRS Part II OFFActivities of Daily

Living

• Levodopa Equivalent Daily Dose (LEDD) Effect on Current Medication Regimen

Hauser Diary is completed by the patient at home every 30 mins over 3 consecutive days.• OFF• ON without troublesome dyskinesia• ON with troublesome dyskinesia• ON without dyskinesia• Sleep

UPDRS II and III evaluations• Objective scale completed by a trained

neurologist after a 12-hour Levodopa washout to evaluate patients without the effects of background medical therapy

LEDD: calculated based on patient’s daily medication doses of Levodopa & other dopamine agonists

43

AXO-LENTI-PD COHORT 1 AND COHORT 2 CHANGE FROM BASELINE TO 6 MONTHS

Patient Hauser Diary OFF Time (hrs)

Hauser Diary“Good ON” Time

(hrs)

LEDD Change(mg)

UPDRS Part II (ADL)OFF

UPDRS Part III (MOTOR)

OFF

1001 +2.8 -2.4 -98 -26 -20

1003 -0.5 +2 -150 -13 -14

Cohort 1 Mean +1.2 -0.2 -124 (11%) -19.5 (65%) -17 (29%)

2002 -0.6 +0.6 0 -12 -22

2004 -0.2 +0.1 -700 - -

2006 -3.9 +3.5 -466 - -

2007 -4.6 +4.5 +81 -15 -19

Cohort 2 Mean -2.3 +2.2 -271 (13%) -13.5 (71%) -20.5 (40%)

• Patient 2004 – Declined to participate in UPDRS OFF evaluations at 6-month assessment. We do not expect this patient to participate in future UPDRS evaluations.

• Patient 2006 – Unable to complete UPDRS OFF assessments due to COVID-related site closure.• Patients 2002, 2006, and 2007 are expected to participate in future assessments provided all sites are open.44

AXO-LENTI-PD: POTENTIALLY TURNING BACK THE CLOCK FOR PATIENTS WITH PARKINSON’S DISEASE

45

-25

-20

-15

-10

-5

0

5

10

15

20

25

CHANGE FROM BASELINE ON UPDRS PART III “OFF” SCORE

ProSavin Low-dose ProSavin Medium-dose ProSavin High-DoseALPD Low-dose ALPD Medium-dose Expected Natural History*

Baseline Month 12 Month 24 Month 36 Month 48 Month 60Month 6

*UPDRS III Off score is expected to worsen by 3-4 points per year as the PD progresses; Palfi, et al. Lancet. 2014

Impr

ovem

ent

Wor

seni

ng

TOTALITY OF AXO-LENTI-PD DATA ACROSS COHORTS SUGGESTS CONSISTENT PATIENT BENEFIT

• Generally well-tolerated with no serious adverse events related to therapySafety and Tolerability

•17-21-point mean improvement in the UPDRS Part III (motor) OFF score at 6 months Improved Motor Function

•Increase in “Good” ON time” and decrease in “OFF” time•Increased ON time without dyskinesia and ON time with non-

troublesome dyskinesia•Decrease in ON time with troublesome dyskinesia

Improved Dyskinesias

•Improvement in UPDRS Part II (activities of daily living) OFF score•Decrease in LEDD Improved Quality of Life

46

Next Steps File Investigational New Drug (IND) with US FDA File Investigational Medicinal Product Dossier (IMPD) in EU

Gating item for filing Developing reliable, suspension-based manufacturing process

Volume Expansion Cohort 3

4.2 x 107 TU1800 µL total infusion

volume

AXO-Lenti-PDEXPLORE-PD Phase 2

Clinical Study

Randomized, double-blinded clinical trial with

highest safe dose vs. sham surgical procedure

Cohort 3 and EXPLORE-PD Clinical Study

ENROLLMENT CRITERIA • Bilateral idiopathic PD

• Age: 30-80

• H&Y OFF Stage: 3-4

• Levodopa equivalent daily dose (LEDD): ≥ 450 mg

• ≥ 2.5 hours diary “OFF” time

AXO-LENTI-PD CLINICAL DEVELOPMENT PLAN: NEXT STEPS

Evaluates safety, tolerability, and efficacy of higher volume

and flow rate

47

AXO-LENTI-PD: POTENTIALLY BEST-IN-CLASS INVESTIGATIONAL THERAPY FOR PARKINSON’S DISEASE

48

AXO-Lenti-PDOther

Dopaminergic Gene Therapy

Deep Brain Stimulation

Restores 3 critical enzymes in endogenous dopamine synthesis pathway1 One-time striatal infusion without need for intra-operative MRI2

5+ years of durable efficacy in the clinic5

10+ years of demonstrated safety and tolerability in the clinic5

Potential (based on MoA) to significantly reduce reliance on long-term oral levodopa therapy1,2,5 Potential to improve motor function without worsening troublesome side effects of therapy (e.g. dyskinesias)2,5

No implanted hardware or requirement for long-term device interrogation and maintenance2,3,4,5

1: Stewart, et al, Hum Gene Ther Clin Dev. 2016;27(3):100-110.2. Palfi, et al. The Lancet. 2014;383(9923):1138-11463: Christine, et al. Ann Neurol. 2019.4: VerciseTM DBS Summary, Timmermann, et al. Lancet. 2015 and Deuschl ,et al, N Engl J Med. 2006; DBS Package Inserts.5.. Palfi, et al. The Lancet . 2018 and Data on file

AXO-LENTI-PD HAS THE POTENTIAL TO BECOME A MULTIBILLION-DOLLAR GENE THERAPY OPPORTUNITY

49

~150 K~70 K

~700 K

0 K

100 K

200 K

300 K

400 K

500 K

600 K

700 K

800 K

Base Case (Patients Aged 30-80with H&Y Stage 3-4)

Patients with Dementia Label Expansion Opportunities Total Potential Market

Tota

l Ind

icat

ed A

XO-L

enti-

PD P

opul

atio

n in

US

and

EU5

TOTAL ADDRESSABLE MARKET

~480 K

Source: LEK Consulting, Internal Analysis, NCBI, etc.

Corporate PresentationNovember 2020