proqr corporate presentation · proqr therapeutics corporate presentation– 2 this press release...
TRANSCRIPT
CREATING MEDICINESfor patientsin need
Date:March 2020
Nasdaq:PRQR
Forward looking statements
ProQR Therapeutics – Corporate Presentation 2
This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "could," "estimate," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," "should," "will," "would" and similar expressions. Such forward-looking statements include, but are not limited to, statements regarding QR-421a, and the clinical development and the therapeutic potential thereof, our other programs and business operations, including timing of commencing clinical trials and enrollment of patients therein, the expected impact of the COVID-19 on our business operations, including our research and development plans and timelines and the supply chain for our clinical and development programs, and our financial position and cash runway. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this press release. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, the risks, uncertainties and other factors in our filings made with the Securities and Exchange Commission, including certain sections of our annual report filed on Form 20-F. These risks and uncertainties include, among others, the cost, timing and results of preclinical studies and clinical trials and other development activities by us and our collaborative partners whose operations and activities may be
slowed or halted by the COVID-19 pandemic; the likelihood of our clinical programs being executed on timelines provided and reliance on our contract research organizations and predictability of timely enrollment of subjects and patients to advance our clinical trials and maintain their own operations; our reliance on contract manufacturers to supply materials for research and development and the risk of supply interruption from a contract manufacturer; the potential for future data to alter initial and preliminary results of early-stage clinical trials; the unpredictability of the duration and results of the regulatory review of applications or clearances that are necessary to initiate and continue to advance and progress our clinical programs; the ability to secure, maintain and realize the intended benefits of collaborations with partners; the possible impairment of, inability to obtain, and costs to obtain intellectual property rights; possible safety or efficacy concerns that could emerge as new data are generated in research and development; and general business, financial and accounting risks and litigation. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the future, except as required by law.
ProQR at a glance
ProQR Therapeutics – Corporate Presentation 3
Patient-centric RNA THERAPEUTICS platform company, developing drugs for RARE DISEASES with well understood causality
Broad RNA platform in other therapeutic areas
• Fully owned and in house developed Axiomer® RNA editing platform with very broad applicability
• Majority ownership in CNS spin-out company Amylon
• Minority stake in DEBspin-out company Wings Therapeutics
Platform for RNA therapies targeting inherited blindness
Sepofarsen (QR-110) for LCA10 with positive clinical data
• Phase 1/2 top-line results show rapid, significant and durable improvement in vision
• Pivotal Phase 2/3 Illuminate trial ongoing
QR-421a for Usher syndrome Exon 13
• Encouraging findings reported from interim analysis of first two cohorts of Phase 1/2 Stellar trial – dose expansion and dose escalation cohorts planned
QR-1123 for P23H adRP (in-licensed from Ionis)
• Preclinical activities and natural history study completed by Ionis
• Phase 1/2 Aurora trial ongoing; Initial data expected in 2021
Pursuing deep pipeline in ophthalmology with many targets that can progress into clinical development rapidly
Cash runway• Expected to fund operations
into H2 2022
RNA therapies for genetic disease
4
Taking away the underlying cause of disease in the RNA
An RNA therapy repairs the RNA, without changing the patient’s DNA.
The cell can now perform its function like a normal cell
In genetic disease a mistake in a gene, called a mutation, is copied
into the RNA thereby causing disease
In healthy cells parts of the DNA, called genes, are copied into RNAs so the cell can perform its function
Nucleus DNA
RNA
RNA Therapy
Normal cell(retina)
Diseased cell(retina)
Treated cell(retina)
ProQR Therapeutics – Corporate Presentation
RNA therapies for inherited retinal diseases
ProQR Therapeutics – Corporate Presentation 5
Reverse blindness with 1 - 2 routine injections per year
RNA TherapyIntravitreal administration
RNA Therapy characteristics
• Personalized medicine designed to repair a specific mutation
• No changes made to the DNA
• Robust improvements in vision observed in clinical trial
• Favorable benefit/risk profile observed in clinical trial
• Naked molecules, no vectors needed for delivery
• Intravitreal injection under local anesthesia
• RNA molecules reach the entire retina, ability to treat peripheral retinal disease
ProQR RNA therapy development pipeline
ProQR Therapeutics – Corporate Presentation 6
DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS
LATE STAGE/REGISTRATIONAL
TRIALS
Ophthalmology
Sepofarsen (QR-110) for LCA10 p.Cys998X
QR-421a for Usher syndrome 2A exon 13
QR-1123 for P23H adRP - discovered by Ionis
QR-504a for FECD3
QR-411 for Usher syndrome 2A PE40
QR-1011 for Stargardt’s disease c.5461-10T>C
QRX-461 for Usher syndrome undisclosed mutation
QRX-136 for LCA undisclosed mutation
ProQR’s VISION2023
2 3 7APPROVED PRODUCTS
LATE STAGE PROGRAMS
EARLY STAGE PROGRAMS
A FULLY INTEGRATED INHERITED RETINAL DISEASE COMPANY BY 2023
ProQR Therapeutics – Corporate Presentation 7
Eyes on the RNA Opportunity
ProQR Therapeutics – Corporate Presentation 8
Foundation of common characteristics, irrespective of the target• Intravitreal administration is
routine procedure• Acceptable safety profile• Broad distribution throughout
the entire retina• Long half life allowing for
infrequent dosing
ProQR projects its RNAtechnology can addressabout 25% of the mutations at a molecular level
>300 genes causing Inherited Retinal Diseases, described with >50 pathogenic mutations per gene, leading to >15,000 targets.
The opportunity: >100 tangible targets remain after further filtering for disease state and population size
Sepofarsen (QR-110) for LCA10
ProQR Therapeutics – Corporate Presentation 9
LCA10
Lose sight in first years of life
No therapy available
p.Cys998X mutation affects ~2,000 patients in the Western world
RNA therapy: sepofarsen
Goal: Restore vision/ prevent vision loss in patients with LCA10
Locally adminis-tered in the eye. Routine intra-vitreal procedure
Anticipated infrequent dosing of 2 times a year
√ Established modality in eye√ Strong preclinical proof of concept in
human retina in preclinical models√ Top-line Phase 1/2 clinical trial results
showed rapid, significant and durable efficacy and favorable benefit/risk
√ Orphan drug designation & Rare pediatric disease designation
√ FDA Fast track designation and access to EMA PRIME program
• Pivotal Phase 2/3 Illuminate trial initiated; data expected H1 2021
Phase 1/2 – trial design
ProQR Therapeutics – Corporate Presentation 10
Open label, multiple dose, dose escalation study
• Enrolled 11 LCA10 patients (age range 8-44) with 1 or 2 copies of the p.Cys998X mutation
• Intravitreal injections in one eye
• Participating sites: major sites in EU (UGhent) and US (UPenn, UIowa)
Objectives:
• Base case: Safety/tolerability & Mechanistic proof-of-concept (full-field stimulation)
• Up-side: Clinical proof-of-concept (best corrected visual acuity), Identify target dose, Mobility course feasibility in LCA10
• Explore: Additional secondary outcome measures
Top-line data, reported in October 2019:
• Validated efficacy of sepofarsen with statistically significant increase in vision in target registration dose group,
• Established efficacious dose regimen with acceptable
benefit/risk and provides strong guidance for population enrichment for the pivotal trial.
• Eligible patients will be rolled over into an extension trial where they will be offered to also get their second eye treated
= DSMC review
Adult 320/160µg dose
Adult 160/80µg dose
Pediatric 160/80µg dose
Pediatric 320/160µg dose
12 months treatment in worse eyeScreeningbaseline
Roll-over to extension+ 2nd eye treatment
DSMC
DSMC
DSMC
DSMC
DSMC
Top-line efficacy resultsPrimary and key secondary outcome measures pooled analysis n=11
Objective Assessment Direction of improvement
Responder threshold
Mean change from baseline at month 12 (SEM)
Treated (TE) Untreated (CE)
Mechanistic proof-of-concept
Full field stimulus (FST) red – log cd/m2 (n=10)
↓= improved -0.5-0.92 (0.18)
p<0.01 vs. CE-0.16 (0.16)
Full field stimulus (FST) blue – log cd/m2 (n=10)
↓= improved -0.5-0.79 (0.23)
p<0.02 vs. CE0.02 (0.11)
Clinical proof-of-concept
Best corrected visual acuity (BCVA) – LogMAR (n=11)
↓= improved -0.3-0.55 (0.26)
p<0.05 vs. CE-0.11 (0.07)
Secondaryoutcome*
Mobility course – composite score (n=10)
↑ = improved 22.5 (0.99)
p=0.1 vs. CE1.75 (0.75)
*Additional exploratory outcome measures, including OCI, PLR, OCT, PROs being analyzed
ProQR Therapeutics – Corporate Presentation 11
Example of mobility course
ProQR Therapeutics – Corporate Presentation 12
Before and after treatment
Link:https://youtu.be/YqVN3A7I1_4
BCVA stratified by dose cohortPrimary outcome measure – mean change in BCVABenefit maintained from month 3 to month 12
Mean ΔBCVALogMAR
Treated eye (SEM) Contralateral eye (SEM)
month 3 month 12 month 3 month 12
Pooled analysis (n=11)
-0.50(0.24)
-0.55(0.26)
0.0(0.04)
-0.11(0.07)
160μg/80μg (n=6) -0.81(0.41)
-0.93(0.43)
0.01(0.08)
-0.22(0.11)
320μg/160μg (n=5) -0.13(0.1)
-0.11(0.07)
0.0 (0.0)
0.01(0.04)
Phase2/3 trialtargetdose
ProQR Therapeutics – Corporate Presentation 13
160µg/80µg cohortConsistent improvement with favorable benefit/risk
Responder (%)
Treated eye Contralateral eye
US responder threshold
EU responder threshold
US responder threshold
EU responder threshold
160μg/80μg (n=6) 67% 83% 33% 33%
* = homozygous subject
Responder Rate
Safety Findings
-2.66
-1.7
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0*
US
4.0 4.02.4 2.1 2.45 0.63
BCVA baseline (LogMAR)
Chan
ge fr
om b
asel
ine
(Log
MAR
)
EU
160μg/80μg (n=6)
Tolerability No issues
Systemic safety No issues
Lens opacity 3 findings
Cataract surgery outcome 2 surgeries. Complete recovery of pre-cataract benefit 2/2 subjects
Retinal findings No issues
Safety Findings
ProQR Therapeutics – Corporate Presentation 14
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
Chan
ge in
BCV
A (L
ogM
AR)
BCVA
Treated Eye Contralateral Eye
ImprovedAcuity
ImpairedAcuity
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
Chan
ge in
FST
(cd/
m2 )
FST
Treated eye blue light Contralateral eye blue light
Treated eye red light Contralateral eye red light
MoreSensitive
LessSensitive
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Chan
ge in
Mob
ility
(lev
els)
Mobility
Treated Eye Contralateral Eye
MoreImpairment
LessImpairment
Key outcome measures change month 12 Target registration dose level: 160µg/80µg (n=6) Every six-month dosing interval-maintained benefit
ProQR Therapeutics – Corporate Presentation 15
Summary of Phase 1/2 top-line data• The Phase 1/2 trial met all primary and upside objectives
• Target dose identified
• Positive benefit/risk for safety
• Identified primary endpoint for Phase 2/3
• Final data validate Phase 2/3 assumptions• Strong, significant and durable response in target dose out to one year
(primary endpoint in Phase 2/3)
• Target population performed better than excluded population
• Mobility performance supported BCVA and is being validated as a key secondary outcome measure for the registration trial
• Six-month dosing frequency feasible
ProQR Therapeutics – Corporate Presentation 16
Sepofarsen Pivotal Phase 2/3 trial
ProQR Therapeutics – Corporate Presentation 17
Design agreed on with FDA
• Double-masked, randomized, controlled, 12-month, multiple dose study
• Could serve as the sole registration trial• Sites in North America and select EU
countries
• 30+ patients >8 years old• Multiple IVT injections in both eyes• First patient dosed in April 2019• Primary (registration) endpoint:
• Visual Acuity (ETDRS, BRVT)
• Key secondary endpoints • Mobility course• Full field stimulus testing (FST)• Ocular instability (OCI)• Optical coherence tomography (OCT)
0 month 3 month 6 month 9 month
12 month Primary Endpoint 15 month 18 month 21 month 24 month
sepofarsen: 80 µg loading dose, 40 µg maintenance dose (n=10) Safety
sepofarsen: 160 µg loading dose, 80 µg maintenance dose (n=10) Safety
Sham-procedure (n=10) Crossover
= Dose first eye = Dose second eye
Ophthalmology pipeline
• Acceptable benefit/risk safety profile (sepofarsen)• Durable response with infrequent dosing• Intravitreal administration delivers to the retina• Clinically meaningful vision improvement in a majority of
low vision patients
• Optic cup accurately predicted:• Clinically efficacious intravitreal dose level • Response to treatment• Time to onset of response
• To be further validated in future trials of sepofarsen and other IRD programs
ProQR Therapeutics – Corporate Presentation
Building on success of sepofarsen
18
DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS
LATE STAGE/REGISTRATIONAL
TRIALS
OphthalmologySepofarsen (QR-110) for LCA10 p.Cys998X
QR-421a for Usher syndrome 2A exon 13
QR-1123 for P23H adRP - discovered by Ionis
QR-504a for FECD3
QR-411 for Usher syndrome 2A PE40
QR-1011 for Stargardt’s disease c.5461-10T>C
QRX-461 for Usher syndrome undisclosed mutation
QRX-136 for LCA undisclosed mutation
QR-421a for Ush2a
ProQR Therapeutics 19
Designed to treat genetic vision loss in Usher syndrome and non-syndromic RP
RNA therapy for Usher & nsRP
Develop hearing and vision loss in childhood and are completely blind by mid adulthood
USH2A exon 13 mutations affect ~16,000 patients in Western world
Approximately 15-25% has exon 13 mutations on both alleles
√ RNA is established modality in eye√ Strong preclinical proof of concept
in patient-derived retinal model√ Orphan drug designation & Rare
pediatric disease designation√ Fast track designation
Partnership
Awarded $7.5Mfinancial support from FFB to conduct trial
For USH2A exon 13 no therapy available
Unmet need
QR-421a is targeted to• Reverse vision loss or stop
disease progression• Eventually treat asymptomatic
patients based on genetic diagnosis
Disease progression and endpoints
ProQR Therapeutics 20
100° 20° 10° 0°
Visual Acuityin Snellen
Visual field in degrees vision
20/20 20/20 No Light Perception
OutcomeMeasures
Disease Progressionwith Patient Age Hearing
impairmentNight blindness(start rod degeneration)
Loss of visual field (rod degeneration)
Loss of central vision(cone degeneration)
Mild to Moderate disease Severe disease
600Complete blindness(rods and cones degenerated)
Dark-Adapted ChromaticPerimetry
Static Perimetry Micro-Perimetry
OCT – EZ area
Best Corrected Visual Acuity
Full-field Stimulation Test
Ranges are illustrative, not exact
20/32
QR-421a Phase 1/2 trial in Usher & nsRP
ProQR Therapeutics 21
~200 day half-life allows for informative single dose FIH trial design
Stellar Phase 1/2 trial• Randomized, single ascending dose, global
multicenter, longitudinal, 24-months study
• Goals include safety and efficacy
• Inclusion criteria: visual field of ≥10o
1 month24 months total
DSMC
DSMC
COHORT 150 µg
COHORT 2100 µg
0 month
1 month 3 months0 monthDSMC = Dose in one eye = DSMC review
• Visual Field (VF) and retinal sensitivity: Microperimetry, static perimetry, dark-adapted chromatic perimetry, full-field stimulus threshold test
COHORT 2B100 µg Homozygous
COHORT 3200 µg
Interim Analysis 1
24 month masked follow-up
to measure durability of effect and inform
dosing interval
Interim Analysis 2
3 months
Key endpoints include: • Visual acuity (VA): Best-Corrected VA
and Low Luminance VA
• Retinal structure: EZ-area on SD-OCT
• Patient Reported Outcomes
Interim analysis - trial population baseline characteristics
Cohort Genotype PhenotypeVisual
impairment severity
Months of follow-up
50µg (n=4)
3 homozygous1 heterozygous
2 Usher2 nsRP
2 mild-moderate2 severe 6-11
100µg (n=4)
0 homozygous4 heterozygous
2 Usher2 nsRP
3 mild-moderate1 severe 3-4
Sham (n=6)
1 homozygous5 heterozygous
2 Usher4 nsRP
5 mild-moderate1 severe 3-9
ProQR Therapeutics 22
Safety and tolerability
• No serious ocular or non-ocular Adverse Events.
• No evidence of inflammation.
• No treatment-associated cataracts.
• No cases of cystoid macular edema or retinal thinning.
ProQR Therapeutics 23
A total of more than 1350 subject-treatment days at time of Interim Analysis
25% of treated subjects defined as responder
ProQR Therapeutics 24
1 of 3 homozygous versus 1 of 5 heterozygous subjects demonstrated benefit in multiple outcome measures v. untreated eye
Pattern of Benefit
SubjectBaseline
visual impairment
Genetic background Dose Days OCT EZ
area DAC FST BCVA
Responder 1 Moderate Homozygous 50µg 270
Responder 2 Severe Heterozygous 100µg 120
Mild-moderate disease informative
Severe disease informative= Benefit = No change
-1
0
1
2
3
4
5
6
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
0 4 8 12 16 20 24 28 32 36-3
-2
-1
0
1
2
3
0 4 8 12 16 20 24 28 32 36-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32 36
Responder 1 Concordant benefit in FST, EZ area and DAC relative to untreated eye (change from baseline)
ProQR Therapeutics 25
Waning response at later time points informs dosing interval
Direction ofImprovement
Direction ofImprovement
Direction ofImprovement
White FST, CFB (log cd/m2 left and dB right)
DAC Cyan HoV total V, CFB (dB.steradian)
EZ area, CFB (%)
Weeks Weeks Weeks
Baseline demographics• Age/Gender: 30 yo/Female• Genetic background: Homozygous• Visual impairment: Moderate
• Visual acuity (BCVA): • Left eye – 74 letters (Snellen 20/32)• Right eye (treated) – 70 letters (Snellen 20/40)
• Received a single 50µg dose
Untreated EyeTreated Eye50µg dose x 1
Responder 2Concordant improvement in FST, BCVA and DAC relative to untreated eye (change from baseline)
100µg dose x 1
ProQR Therapeutics 26
-14
-12
-10
-8
-6
-4
-2
0
2
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0 4 8 12-3-2-1012345678
0 4 8 12 16 20-10
-5
0
5
10
15
0 4 8 12 16
Direction ofImprovement
Direction ofImprovement
BCVA, CFB (ETDRS letters)
Direction ofImprovement
Untreated EyeTreated Eye
White FST, CFB (log cd/m2 left and dB right)
DAC Cyan HoV total V, CFB (dB.steradian)
Baseline demographics• Age/Gender: 60 yo/Male• Genetic background: Heterozygous• Visual impairment: Severe
• Visual acuity (BCVA): • Left eye (treated) – 33 letters (Snellen 20/250)• Right eye – 35 letters (Snellen 20/200)
• Received a single 100µg dose
Weeks Weeks Weeks
Progress against trial goals√ Establish early safety and tolerability
• Thus far, generally well tolerated with no serious adverse events
√ Characterize early examples of functional target engagement and if present, duration of benefit to inform dosing interval• 2 of 8 QR-421a-treated subjects demonstrated treatment benefit• 0 of 6 sham-treated subjects met the responder definition
√ Assess utility of various outcome measures in moderate versus advanced disease
√ Inform further dose-ranging and the subject enrichment strategy for next steps in development• Enrichment for homozygous exon 13 mutation subjects in the 100µg dose cohort• Dose escalation to a 200µg dose cohort
Characterize the contributions of drug dose and gene dose
Follow treatment-responsive subjects to characterize the duration of response and estimate the dosing interval
27
QR-1123 for P23H adRP
ProQR Therapeutics – Corporate Presentation 28
Gapmer targeting autosomal dominant RP due to the P23H mutation in RHO
P23H adRP
Progressive reduction in night & peripheral vision. Blindness is frequent in mid-adulthood
No therapy available
~2,500 patients with P23H adRP in United States
RNA therapy: QR-1123
Goal: Restore vision/prevent vision loss in patients with P23H adRP
Locally adminis-tered in the eye. Routine intra-vitreal procedure
Anticipated infrequent dosing of 4 times a year or less
√ Established modality in eye√ Strong preclinical proof of concept in vivo√ In-licensed from Ionis Pharmaceuticals√ 2-year Natural History Study is completed
and will be used to accelerate clinical development
√ Received IND clearance√ Orphan drug designation
Next steps • Phase 1/2 trial ongoing, first patient dosed• Clinical development similar to QR-421a
QR-1123 for P23H adRP
• P23H mutation in the rhodopsin (RHO) gene causes autosomal dominant Retinitis Pigmentosa (adRP)• Rhodopsin is the light sensitive pigment in
rods in the retina• P23H mutant rhodopsin is misfolded and
toxic, causing progressive loss of rods (night and peripheral vision affected)
• Eventual loss of cones (central vision) causes patients to become legally blind by ~40-50 years of age
• P23H is the most prevalent mutation associated with adRP in the US, accounting for ~2,500 patients
• QR-1123 inhibits the formation of toxic mutant version of rhodopsin protein• QR-1123 selectively binds to the mutant
RHO mRNA• Gapmer structure causes RNase H
mediated cleavage of mutant mRNA without affecting the WT mRNA
• QR-1123 slows retinal degeneration in aggressive humanized mouse models of adRP
• Potential to reverse toxic effect and restore vision in P23H adRP patients
ProQR Therapeutics – Corporate Presentation 29
Disease Background & Clinical Phenotype
Rhodopsin Rhodopsin
QR-1123
Rhodopsin
MoA QR-1123QR-1123 blocks expression of toxic P23H mutant RHO protein
Healthy people inherit two wild type copies of the rhodopsin gene
P23H mutant rhodopsin is misfolded and toxic, causing progressive loss of rods
QR-1123 suppresses P23H mRNA with an allele specific mechanism
ProQR Therapeutics – Corporate Presentation 30
mRNA Rhodopsin
protein
Rhodopsin
Outersegment
Innersegment
Nucleus
Connectingcilium
RNA
DNA
DNA
Rhodopsin
Aurora Phase 1/2 trial • Double-masked, randomized, sham controlled
• Goals include safety, tolerability and efficacy
• Up to 35 adult patients
• Initial data expected in 2021
QR-1123 Phase 1/2 trial in adRP patients
ProQR Therapeutics – Corporate Presentation 31
1 month
DSMC
75 µg n=1
0 month
150 µg n=1
12-month follow up
300 µg n=3
QR-1123: n=6 Sham: n=2
Single dose
Multiple dose(every 3 months)
DSMC
DSMC
Potential to add additional single and multiple dose cohorts at different dose levels
Key endpoints include: • Visual acuity
• Visual field
• OCT
• Patient Reported Outcomes
= Dose in one eye through intravitreal administration
QR-504a for FECD3
ProQR Therapeutics – Corporate Presentation 32
Fuchs Endothelial Corneal Dystrophy
Front of the eye disease leading to blindness in 50+ years of age
>250,000 patients with Repeat expansion in TCF4in Western world
√ RNA is established modality in eye√ Rapid delivery to corneal cells√ Strong preclinical proof of concept
in human primary cell models
Next steps • Progression into development
RNA therapy: QR-504a
For FECD3 repeat expansion in TCF4No therapy available
Strong preclinical PoC in human primary cell models. Development candidate selected
Strong PoC
Inherited blindness pipeline beyond LCA10 and Usher syndrome
ProQR Therapeutics – Corporate Presentation 33
• Sepofarsen Phase 1/2 trial completed
• Phase 2/3 pivotal Illuminate trial ongoing
• QR-421a Stellar Phase 1/2 trial interim analysis complete – dose expansion and dose escalation cohorts planned
• QR-1123 Phase 1/2 trial ongoing, first data expected 2021
• Rapidly advancing several undisclosed discovery stage ophthalmology programs into development and clinical trials
DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS
LATE STAGE/REGISTRATIONAL
TRIALS
OphthalmologySepofarsen (QR-110) for LCA10 p.Cys998X
QR-421a for Usher syndrome 2A exon 13
QR-1123 for P23H adRP - discovered by Ionis
QR-504a for FECD3
QR-411 for Usher syndrome 2A PE40
QR-1011 for Stargardt’s disease c.5461-10T>C
QRX-461 for Usher syndrome undisclosed mutation
QRX-136 for LCA undisclosed mutation
Potential broad applicability• >20,000 G-to-A mutations
described in literature• Proprietary Axiomer platform
technology can target G-to-A mutations
• Potentially broader applicability in protein modulation and stop-codon mutations
Strong IP protection• Invented in house at ProQR
laboratories• Protected with 8 patents families,
protecting Axiomer as a platform• Key collaborations with ADAR
experts in the world
Unique A-to-I RNA editing• A-to-I editing in RNA• Using endogenous ADAR• ADAR is recruited by a single
stranded Editing Oligonucleotide (EON)
• I is translated as a G, allowing to target G-to-A mutations
Axiomer® RNA editing platform
ProQR Therapeutics – Corporate Presentation 34
Editing Oligonucleotide (EON) mediated A-to-I editing
Strong team with proven track record
ProQR Therapeutics – Corporate Presentation 35
Management team Supervisory board
Daniel de BoerChief Executive Officer
Honorary former board member
Gerard PlatenburgChief Innovation Officer
Smital ShahChief Business & Financial Officer
David RodmanExecutive Vice President ofResearch & Development
Antoine Papiernik
Henri Termeer
James Shannon
Alison Lawton
Dinko ValerioChairman
Tiffany BurtVP Commercial
Leadership team
Aniz GirachChief Medical Officer
Bart Filius
Theresa Heggie
World-class Scientific Advisory Committee
36ProQR Therapeutics – Corporate Presentation
Phillip D. ZamorePhD
Peter A. BealPhD
Thaddeus DryjaMD
Cy SteinMD
NUCLEIC ACID THERAPEUTICS
Yi-Tao YuPhD
Art LevinPhD
Annemieke Aartsma RusPhD
Peter AdamsonPhD
Broad IP estate• ProQR built a broad IP estate consisting of:
• 27 fully owned patent families• 7 external licenses (MGH, INSERM, Radboud University, Ionis Pharmaceuticals, Rochester
and Leiden University)
• Patent terms (excluding possible extension):• Eluforsen for F508del through 2033• Sepofarsen for LCA10 through 2036• QR-421a for Usher exon 13 through 2037• QR-1123 for adRetinitis Pigmentosa through 2036• QR-504a for Fuchs Endothelial Corneal Distrophy through 2036• QR-411 for Usher PE40 through 2037• QR-1011 for Stargardt disease through 2038• Axiomer® platform technology through 2039
ProQR Therapeutics – Corporate Presentation 37
Several upcoming milestonesSepofarsen (QR-110) for LCA10√ Positive top-line results Phase 1/2
announced Q4 2019√ Phase 2/3 Illuminate trial initiated
• Enrollment ongoing• Update on inSight extension study expected
in H2 2020, including data on contralateral eye treatment
QR-421a for Usher syndrome 2A exon 13√ Stellar Phase 1/2 trial reported interim data• Dose expansion and dose escalation cohorts
planned
QR-1123 for P23H adRP√ Aurora Phase 1/2 trial underway Q4 2019• Initial data expected 2021
QR-504a for Fuchs’ Endothelial Corneal Dystrophy• Proof of mechanism study planned
Ophthalmology Pipeline• Rapidly advancing several discovery
and nonclinical stage ophthalmology programs to mature into development and clinical trials
ProQR Therapeutics – Corporate Presentation 38
ProQR since 2012
• Based in Leiden, the Netherlands
• 160 employees (35 nationalities)
• 2014 IPO NASDAQ: PRQR
• FD Shares outstanding: ~57 million (post October 2019 financing)
• Cash position (Q4 2019) €112.0 million; no debt
• Includes net proceeds from October 2019 of €48.6 million
• $7.5M grant funding awarded by Foundation Fighting Blindness in February 2018
• €4.7M Innovation Credit from Dutch government for sepofarsen program
• Projected cash runway into H2 2022
ProQR Therapeutics – Corporate Presentation 39
Facts and figures
IT’S INOUR RNA
Sepofarsen reference slides
ProQR Therapeutics – Corporate Presentation 41
Sepofarsen for LCA10
ProQR Therapeutics – Corporate Presentation 42
Splice correction for p.Cys998X CEP290 mRNA
In wild-type cellsCEP290 maintains cilium
structure and enables normal protein transport
In p.Cys998X-LCA10 cellsprotein transport
is hampered and the outer segment degenerates
Exclusion of the cryptic exon from the mutated
mRNA leads to wild-type CEP290 protein
Exon 27Exon 26 XExon 27Exon 26
Exon 26 Exon 27
Outersegment
Innersegment
Nucleus
Connectingcilium
pre-mRNA
DNA
mRNA
sepofarsen
mRNA
pre-mRNA Exon 26 Exon 27X
Exon 27Exon 26
sepofarsen
Exon 26 Exon 27X
Phase 1/2 – Baseline Demographics
ProQR Therapeutics – Corporate Presentation 43
160µg/80µg cohort, n=6; 2 LP only, 3 BRVT, 1 ETDRS320µg/160µg cohort, n=5; 3 LP only, 1 BRVT, 1 ETDRS
Gender 2nd CEP290 Allele Age/Group Baseline BCVA[LogMAR] Treated Eye Dose [µg]
M c.2503_2504delAC 19 / Adult LP / LP Right 160/80
M c.4723A>T 41 / Adult LP / LP Right 160/80
M c.5668G>T 44 / Adult 2.4 / 2.3 Left 160/80
F c.4438‐3delC 16 / Pediatric 2.5 / 2.5 Right 160/80
M c.6277delG 8 / Pediatric 1.9 / 2.1 Left 160/80
F c.2991+1655A>G 14 / Pediatric 0.6 / 0.6 Left 160/80
F c.3167_3168insA 21 / Adult LP / LP Right 320/160
F c.4723A>T 27 / Adult 1.1 / 0.7 Right 320/160
F c.4393C>T 24 / Adult LP / LP Right 320/160
M c.6277delG 10 / Pediatric 1.9 / 1.4 Right 320/160
F c.547_550delTACC 15 / Pediatric LP / LP Right 320/160
BRVT = Berkley Rudimentary Vision Test (1.7-4.0 LogMAR) | ETDRS = Standard Eye Chart (0.0-1.6 LogMAR)4.0 LogMAR = Light perception (LP) only | 3.0 LogMAR = Hand motion | 2.0 LogMAR = Finger counting | 1.0 LogMAR = 20/200 | 0.0 LogMAR 20/20
Disposition>4000 subject treatment-days at two dose levels
12 screened
1 screen fail
11 enrolled
6 treated 160µg/80µg
5 treated 320µg/160µg
6 completed
5 completed
roll-over to extension
ProQR Therapeutics – Corporate Presentation 44
Top-line safety summary
ProQR Therapeutics – Corporate Presentation 45
Positive benefit/risk in 160µg/80µg cohort with 50% incidence of lens opacitySubclinical retinal findings in 320µg/160µg cohort
Cataracts Cystoid Macular Edema Retinal thinning
SAE/AE 6 SAE (surgery)/2 AE 0 SAE / 2 AE 0 SAE / 2 AE
Dose-dependent incidence Yes Yes Yes
Timing (160μg/80μg cohort) 8-12 months No cases No cases
Timing (320μg/160μg cohort) 3-9 months 3-4 months 3-10 months
Treatment-responsive Yes Yes Stabilized
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
320µg/160µg cohortLess improvement with dose-limiting safety findings
BCVA baseline (LogMAR)
Chan
ge fr
om b
asel
ine
(Log
MAR
)
4.01.05 4.0
USEU
4.01.9
Responder (%)
Treated eye Contralateral eye
US responder threshold
EU responder threshold
US responder threshold
EU responder threshold
320μg/160μg (n=5) 20% 20% 0% 0%
320µg/160µg (n=5)
Tolerability No issues
Systemic safety No issues
Lens opacity 5 findings
Cataract surgery outcome 4 surgeries. Complete recovery ofpre-cataract benefit 4/4 subjects
Retinal findings 4 findings in 3 individuals
Responder Rate
Safety Findings
CME treated topically with improvement. Retinal thinning stabilized 2-3 months
ProQR Therapeutics – Corporate Presentation 46
Sustained improvement in BCVA for at least 1 yearAll responses (7/7) were maintained for a minimum of 6 months after a maintenance dose
Minimal Clinically Important Difference (MCID) (-0.3 LogMAR)
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
All treated (n=11)
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
160μg/80μg Cohort (n=6)
TE CETreated eye Contralateral eye
Chan
ge fr
om b
asel
ine
in B
CVA
(logM
AR)
ImprovedAcuity
ImpairedAcuity
ProQR Therapeutics – Corporate Presentation 47
Example of a 160µg/80µg responder7/7 trial subjects with BCVA improvement sustained that benefit during ≥6-month dosing interval
ProQR Therapeutics – Corporate Presentation 48
-2.4
-2.2
-2
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
FST (cd/m2)
TE blue light TE red light
0
0.5
1
1.5
2
2.5
3
BCVA (LogMAR)
ImprovedAcuity
ImpairedAcuity
MoreSensitive
LessSensitive
MoreImpairment
LessImpairment
Dose Dose Dose
6m interval*
*7/7 trial subjects with BCVA improvement sustained that benefit during ≥6-month dosing interval
0
2
4
6
8
10
12
14
16
18
20
Mobility (Levels)
TE
Example of homozygous subject13-letter improvement in BCVA with robust improvement in mobility and FST
ProQR Therapeutics – Corporate Presentation 49
-2.4
-2.2
-2
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
FST (cd/m2)
TE blue light TE red light
0.3
0.35
0.4
0.45
0.5
0.55
0.6
0.65
0.7
BCVA (LogMAR)
0
2
4
6
8
10
12
14
16
18
20
Mobility (Levels)
ImprovedAcuity
ImpairedAcuity
MoreSensitive
LessSensitive
MoreImpairment
LessImpairment
Dose
12m interval
Top-line efficacy dataTarget registration dose level: 160µg/80µg (n=6)
Group mean Treated eye Contralateral eye
BCVA (LogMAR) -0.93P<0.01 vs. baseline
-0.22P=N.S. vs. baseline
FST Red (Log) -0.66P<0.01 vs. baseline
0.05P=N.S. vs. baseline
FST Blue (Log) -0.63P<0.01 vs. baseline
0.12P=N.S. vs. baseline
Mobility (levels) +4.0P<0.01 vs. baseline
+2.7P<0.05 vs. baseline
ProQR Therapeutics – Corporate Presentation 50
Significance assessed by mixed effects repeated measures model
Mobility Course for LCA10
ProQR Therapeutics – Corporate Presentation 51
• Large dynamic range to accommodate lower visual acuity.
• Measures functional visual performance using a series of courses at increasing difficulty and multiple light intensities.
• > 2 levels considered meaningful.
Course Light level Score
Fail all courses 0
BRE 100% LED 1
BRE 10% LED 2
HCRE 400 lux 3
HCRE 50 lux 4
HCRE 1 lux 5
HCVNC 400 lux 6
HCVNC 250 lux 7
HCVNC 125 lux 8
HCVNC 50 lux 9
HCVNC 10 lux 10
HCVNC 4 lux 11
HCVNC 1 lux 12
LCVNC 400 lux 13
LCVNC 250 lux 14
LCVNC 125 lux 15
LCVNC 50 lux 16
LCVNC 10 lux 17
LCVNC 4 lux 18
LCVNC 1 lux 19
Low-Contrast Visual Navigation Challenge at 1, 4, 10, 50, 125, 250, 400 lux (Ora, Inc. LCVNC™)
High-Contrast Visual Navigation Challenge at 1, 4, 10, 50, 125, 250, 400 lux (Ora, Inc. HCVNC™)
High-Contrast Room Exitat 1, 50, 400 lux (Ora, Inc. HCRE™)
Backlit Room Exit at 10% and 100% backlighting intensity (Ora, Inc. BRE™)
Grading scores:
QR-421a reference slides
ProQR Therapeutics – Corporate Presentation 52
∆Exon13 Usherin protein is functional
ProQR Therapeutics – Corporate Presentation 53
Time (ms)
Wild-type range
Ampl
itude
Treated exon 13 mutant zebrafish
Exon 13 mutant zebrafish without treatment
Erwin van Wijk, Radboudumc, Nijmegen, the Netherlands
ERG with light stimulus in zebrafishUsherin protein (in red) in zebrafish retina
Treated with oligo
With usherinprotein
Without usherin protein
Visual fields:
ProQR Therapeutics – Corporate Presentation 54
Quantifying visual field defects
Usher syndrome Earlier stage disease
Later stage disease
Potentially viable photoreceptors as shown by OCT. Indicates potential area of visual functional restoration by QR-421a
Dark-adaptedchromatic (DAC)perimetry (Medmont)
Microperimetry (MAIA)
Automated perimetry (Octopus)
Visual field measurement
ProQR Therapeutics – Corporate Presentation 55
Sens
itivi
ty (d
B)
Isopter plot(Definition isopter: a line of equalretinal sensitivity in the visual field)
Positive outcome: Evidence of visual field expansion at few points of the isopter
Profile plot
Eccentricity (degrees of visual field)
Visual field measurement
ProQR Therapeutics – Corporate Presentation 56
Increased visual field
Sens
itivi
ty (d
B)
Profile plot
Isopter plot
Sens
itivi
ty (d
B)
Eccentricity (degrees of visual field)
Visual field measurement
ProQR Therapeutics – Corporate Presentation 57
Sens
itivi
ty (d
B)
Eccentricity (degrees of visual field)
Isopter plot
Profile plotIncreased visual field
Sens
itivi
ty (d
B)
Full Field Stimulus Test (FST)
• Test of most sensitive part of the retina
• White light for total retina
• Blue light for rods (mostly peripheral)
• Red light for cones (mostly central macula)
ProQR Therapeutics – Corporate Presentation 58
All study subjects
GoalDirectional improvement in treatment group
Visual Acuity
• Snellen VA chart used in Clinical Practice
Snellen Visual Acuity ETDRS/LogMAR Visual Acuity
• ETDRS Chart used as Gold Standard for assessing VA in Clinical Trials
• Alternative VA scales used for VA with low vision patients
Only applicable in severe patients
Goals (in severe patients only)
• In responder analysis an improvement of -0.2 LogMAR (2 lines, or 10-letters) is considered meaningful by EMA
• In responder analysis an improvement of -0.3 LogMAR (3 lines, or 15-letters) is considered meaningful by FDA
• Noise of assay is likely 0.1 LogMAR (1 line, or 5-letters)
ProQR Therapeutics – Corporate Presentation 59
Visual Field (VF)
• Dark Adapted Chromatic Perimetry (Medmont)
• Measure of visual field in peripheral vision
• Patients are dark adapted prior to measurement
• Measures visual field at different wavelengths (colors)
• Static visual field (Octopus)
• Measure of visual field in peripheral vision
• Gold standard in measuring VF
• Measures visual field with white light only
ProQR Therapeutics – Corporate Presentation 60
For moderate patients
Medmont device for DAC perimetry
Hill of Vision visualPerimetry data
GoalsImprovement above the noise of the assay and/or improvement in hill of vision analysis
Visual Field (VF)
• Micro perimetry (Maia)
• Measures visual field in the macula (0-20°visual field)
• Measures visual field with white light
ProQR Therapeutics – Corporate Presentation 61
For severe patients
GoalsImprovement above the noise of the assay and/or improvement in hill of vision analysis
OCT – EZ-line
• Imaging of the retina through high resolution OCT
• Visualizes anatomy of the central 6mm of the retina
• Degeneration of photoreceptor cells in the macula is visible at <20° visual field as depicted by EZ-line
ProQR Therapeutics – Corporate Presentation 62
Only applicable in severe patients
Severe Usher Syndrome
Normal OCT
GoalRestoration of the EZ line after treatment compared to baseline
Patient Reported Outcomes
• Patient Global Impression of Severity (PGI-S)Very brief questionnaire about the subject’s (eye) condition in the past week
• Patient Global Impression of Change (PGI-C)Very brief questionnaire about the change in the subject’s condition since he/she started in the study
• Veteran Administration Low Vision Visual Acuity Functioning Questionnaire (VFQ-20)20 questions rating how difficult a certain functional task is
ProQR Therapeutics – Corporate Presentation 63
A range of PRO’s applicable to all subjects in the trial
QR-1123 reference slides
ProQR Therapeutics – Corporate Presentation 64
QR-1123 is specific for P23H allele
ProQR Therapeutics – Corporate Presentation 65
Strong and specific suppression of P23H in cells QR-1123 is selective for P23H in vivo
QR-1123 preserves ONL and improves ERG in P23H rat model
ProQR Therapeutics – Corporate Presentation 66
Murray et al., 2015 IOVS 56: 6362
QR-1123 surrogate improves ERG in P23H Tg ratstrong correlation with ONL preservation
QR-1123 surrogate preserves ONLin P23H Tg rat
mRHO AS03 PBS QR-1123 surrogate Control oligo
Light level Light level
Ampl
itude
(µV)
Ampl
itude
(µV)
QR-1123 reduces retinal degeneration in humanized P23H mice
ProQR Therapeutics – Corporate Presentation 67
Optic Nerve Head (ONH)
Superior retina
Inferiorretina
Lens
Optic NerveHead
Superior Inferior
Additional Appendix
ProQR Therapeutics – Corporate Presentation 68
QR-411 for Usher syndrome
ProQR Therapeutics – Corporate Presentation 69
Designed to treat genetic eye disease in Usher syndrome
Usher
Develop hearing loss and blindness in childhood and turn completely blind by mid adulthood
PE40 mutation affects ~1,000 patients in Western world
√ RNA is established modality in eye√ Strong preclinical proof of concept
in patient retinal organoids√ Orphan drug designation
RNA therapy: QR-411
For Usher PE40no therapy available
Strong preclinical PoC in patient retinal model. Development candidate selected
Strong PoC
Next steps • IND-enabling studies expected to start
in 2020• Clinical development similar to QR-421a
QR-1011 for Stargardt’s disease
ProQR Therapeutics – Corporate Presentation 70
Stargardt’s disease
Develop blindness in childhood and turn completely blind by mid adulthood
~7,000 patients with c.5461-10T>C in ABCA4in Western world
√ RNA is established modality in eye√ Strong preclinical proof of concept
Next steps • Progression into patient retinal
organoid model
RNA therapy: QR-1011
For Stargardt’s c.5461-10T>C in ABCA4 no therapy available
Preclinical PoC and efficacy in human mini-gene models
Strong PoC
ProQR spun-off non-core activitiesWings Therapeutics
Clinical stage company focussed on development of life changing therapies for Dystrophic Epidermolysis Bullosa
• Spun out of ProQR in March 2019 with QR-313 for Exon 73 mutations and all other DEB activities
• Wings led by CEO Deborah Ramsdall, Executive Chairman Mark de Souza, PhD, and Chief Medical Officer Hal Landy, MD
• ProQR has a minority stake and will be eligible for milestone and royalty rights to commercial products
Amylon Therapeutics
Company focussed on the development of CNS products with initial focus on HCHWA-D
• ProQR incubated the activities of Amylon since 2015 and spun the company out in 2017
• The initial focus of Amylon is on its development program AT-010 for HCHWA-D, a brain disease caused by a mutation in beta-amyloid leading to stroke in mid-adulthood
• ProQR retained a majority stake in the company and will be eligible for milestone and royalty rights to commercial
ProQR Therapeutics – Corporate Presentation 71