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CREATING MEDICINESfor patientsin need
Date:October 2018
Nasdaq:PRQR
Forward looking statements
ProQR Therapeutics – Corporate Presentation 2
This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including but not limited to, statements regarding our strategy, future operations, future preclinical and clinical trial plans and related timing of trials and results, research and development, future financial position, future revenues, projected costs, prospects, therapeutic potential of our product candidates, plans and objectives of management, are forward-looking statements. The words “aim,” “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.
Forward-looking statements represent our management’s beliefs and assumptions only as of the date of this presentation. We may not actually achieve the plans, intentions or expectations
disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements contained in this presentation reflect our current views with respect to future events, and we assume no obligation to update any forward-looking statements except as required by applicable law. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those that may be described in greater detail in the annual report filed on Form 20-F for the year ended December 31, 2017 that we have filed with the U.S. Securities and Exchange Commission (the “SEC”) and any subsequent filings we have made with the SEC. We have included important factors in the cautionary statements included in that annual report, particularly in the Risk Factors section, and subsequent filings with the SEC that we believe could cause actual results or events to differ materially from the forward-looking statements that we make.
ProQR at a glancePlatform for therapies targeting inherited blindness
QR-110 for LCA10 with positive clinical data
• Phase 1/2 trial expected to complete H2 2019• Phase 2/3 ILLUMINATE trial expected to start H1 2019
QR-421a for Usher syndrome Exon 13
• Completed pre-IND meeting• Initiate STELLAR trial around YE 2018, data expected
mid 2019• Multiple dose adaptive trial, data expected H2 2020
QR-1123 for P23H adRP (in-licensed from Ionis)
• Preclinical activities and natural history study completed by Ionis
• Phase 1/2 trial expected to start in 2019
Pursuing deep pipeline in ophthalmology with many targets that can progress into clinical development rapidly
ProQR Therapeutics – Corporate Presentation 3
Patient-centric RNA THERAPEUTICS platform company, developing drugs for ORPHAN DISEASES with well understood causality
Broad RNA platform in other therapeutic areas
Dystrophic Epidermolysis Bullosa
• QR-313 in active clinical trial with interim analysis data expected late 2018 / early 2019
Partnership with Galapagos on fibrosis targets using Axiomer®
RNA editing platform
Majority ownership in CNS spin-out company Amylon
ProQR development pipeline
ProQR Therapeutics – Corporate Presentation 4
DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS
LATE STAGE/REGISTRATIONAL
TRIALS
OphthalmologyQR-110 for LCA10 p.Cys998XQR-421a for Usher syndrome 2A exon 13QR-1123 for P23H adRP - discovered by IonisQRX-504 for FECD3QR-411 for Usher syndrome 2A PE-40QRX-1011 for Stargardt’s disease c.5461-10T>C
Dystrophic Epidermolysis BullosaQR-313 for DEB exon 73QRX-323 for DEB exon 80QRX-333 for DEB exon 3
Cystic FibrosisEluforsen (QR-010) for F508del
FibrosisPartnered with Galapagos NVUndisclosed targets
Central Nervous SystemAmylon TherapeuticsAT-010 for HCHWA-D
PARTNERED PROGRAMS
RNA oligo therapies for inherited blindness
ProQR Therapeutics – Corporate Presentation 5
Wild-type Disease Disease + oligo
RNA
DNA
Protein
RNA
DNA
Protein
RNA
DNA
Protein
ProQR inherited blindness platform
ProQR Therapeutics – Corporate Presentation 6
Intravitreal delivery is routine procedure• Long half-life in the eye allows
for dosing quarterly or less frequent
• Chemical modification enables naked delivery
• QR-110 has shown placebo-like clean safety profile
Predictive optic cup model• Sophisticated organoid model
for retinal dystrophies• Accurately predicted in QR-
110 trial:• Clinically efficacious
intravitreal dose level • Response to treatment• Time to onset of response
Broad distribution allows for targeting of central and peripheral diseases• Oligo’s distribute broadly to all
different cell types• Allowing for targeting central
and peripheral disease
Targeted RNA oligo therapies• RNA oligo designed to
specifically address the mutations causing the disease
• >300 genetic eye diseases described
UNIQUE PLATFORM FOR PRECISION MEDICINE
QR-110 for LCA10
ProQR Therapeutics – Corporate Presentation 7
LCA10
Lose sight in first years of life
No therapy available
p.Cys998X mutation affects ~2,000 patients in the Western World
QR-110
Goal: Restore vision/ prevent vision loss in patients with LCA10
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 human retina in preclinical models
√ Orphan drug designation√ Fast track designation
√ Phase 1/2 interim analysis showed rapid and sustained efficacy and favorable safety
• Pivotal phase 2/3 trial expected to start in H1 2019
Clinical study design – PQ-110-001
ProQR Therapeutics – Corporate Presentation 8
Open label, multiple dose, dose escalation study, Phase 1/2
• Up to twelve p.Cys998X LCA10 patients; adults and children (≥6yrs)
• Intravitreal injections in one eye
• Participating sites: major sites in EU (UGhent) and US (UPenn, UIowa)
• Primary endpoints:
• Safety, tolerability
• Secondary endpoints and exploratory efficacy:
• Visual acuity, mobility course, FST, OCI, pharmacokinetics, OCT, PRO, ERG, pupilometry
• IND and CTA (BE)
• Orphan drug designation in EU and US
• FDA Fast-track designation
1 loading dose & 3 maintenance doses over 1 year:
• 160 µg loading dose / 80 µg maintenance dose
• 320 µg loading dose / 160 µg maintenance dose
= DSMC review
Adult Mid dose
Adult Low dose
Adult High dose
Pediatric Low dose
Pediatric Mid dose
Pediatric High dose
Observation of early efficacy at low and mid dose led to:• Accelerated interim analysis• No escalation to the high dose
• Plan to start a pivotal Phase 2/3 ILLUMINATE trial in H1 2019 with parallel pediatric study
Interim results summary• The trial met its primary and secondary objectives Safe and well tolerated in >1500 subject treatment-days analyzed Mechanistic proof-of-concept confirmed by improvement in FST Clinical proof-of-concept confirmed by BCVA and supported by
improvement in mobility course The four analyzed outcome measures showed concordant improvement
• Enrollment has been completed
• 12 month data in all subjects is expected in H2 2019
• Plan to start a Phase 2/3 trial in H1 2019• Double-blind, controlled, dose range finding adaptive design• Could serve as the sole pivotal registration trial• Parallel trial in pediatric <6 years old
ProQR Therapeutics – Corporate Presentation 9
Baseline Demographics
ProQR Therapeutics – Corporate Presentation 10
Pediatric and adult patients (8-44 age range), with severely impaired vision
Sex 2nd CEP290 Allele Age / Group Baseline VA(logMAR)
TreatedEye
Dose(µg)
M c.2506_2507delGA 19 / A LP / LP RE 160/80
M c.4723A>T 41 / A LP / LP RE 160/80
M c.5668G>T 44 / A 2.3 / 2.4 LE 160/80
F c.4438‐3delC 16 / P 2.5 / 2.5 RE 160/80
M c.6277delG 8 / P 1.9 / 2.1 LE 160/80
F c.3167_3168insA 21 / A LP / LP RE 320/160
F c.4723A>T 27 / A 1.1 / 0.7 RE 320/160
F c.4393C>T 24 / A LP / LP RE 320/160
M c.6277delG 10 / P 1.9 / 1.4 RE 320/160
F c.547_550delTACC 15 / P LP / LP RE 320/160
F c.2991+1655A>G 14 / P 0.6/0.6 - 320/160
Disposition and Safety Results
Safety findings:
• Generally well tolerated with occasional mild AEs related to injection, typical to IVT.
• No SAEs.
• No early discontinuations.
• Independent DSMC agreed that there were no safety concerns.
ProQR Therapeutics – Corporate Presentation 11
10 subjects enrolled, no early terminations or SAEs
Subjects 1 2 4 3 1
# doses 0 1 2 3 4
Screened 12
> 1 month follow-up 10
> 3 month follow-up 8
> 5 month follow-up 6
> 6 month follow-up 4
Dosed 10
Top Line Efficacy Results
ProQR Therapeutics – Corporate Presentation 12
Concordant improvement in all outcome measures
Direction of improvement
Responder threshold
Change from baseline at Month 3Mean (SEM)
Treated Untreated
Visual Acuity (ETDRS/BRVT) – LogMAR (n=8) ↓= improved > -0.3 -0.67 (0.32) 0.02 (0.05)
Mobility Course – level (n=7) ↑ = improved >2 2.57 (1.19) 1.36 (1.04)
Full field stimulus red (FST red) - cd/m2 (n=7) ↓= improved -0.74 (0.35) -0.23 (0.18)
Full field stimulus blue (FST blue) - cd/m2 (n=7) ↓= improved -0.91 (0.38) -0.02 (0.11)
Nystagmus tracking (OCI) - Log10mm (n=7) ↓= improved -0.14 (0.08) -0.04 (0.06)
Best Corrected Visual Acuity (BCVA)
ProQR Therapeutics – Corporate Presentation 13
Majority of subjects had clinically meaningful improvement
Clinically meaningful (-0.3 LogMAR)
Individual subject responses
Chan
ge fr
om b
asel
ine
(Log
MAR
)
Impr
ovem
ent
p=0.011
EDTRS (LogMAR -0.3 - 1.6)
BRVT (LogMAR 1.4 - 4.0)
BCVA effect was maintained for at least 6 months
ProQR Therapeutics – Corporate Presentation 14
Dose 1 Dose 2 Dose 3
Clinically meaningful (-0.3 LogMAR)Im
prov
emen
t
Mobility Course for LCA10
ProQR Therapeutics – Corporate Presentation 15
• 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:
Mobility Course
ProQR Therapeutics – Corporate Presentation 16
Improved at month 3 and month 6
Clinically Meaningful(2 levels)
Treated Eye Contralateral Eye
Impr
ovem
ent
Dose 1 Dose 2
Individual subject responses
Change in BCVA tracks with change in Mobility
ProQR Therapeutics – Corporate Presentation 17
Responder
Non-responder
Full Field Stimulus Test (FST)
ProQR Therapeutics – Corporate Presentation 18
Impr
ovem
ent
Measured with blue and red light
BlueTreated Eye
BlueContralateral Eye
RedTreated Eye
RedContralateral Eye
Ocular instability (OCI)
ProQR Therapeutics – Corporate Presentation 19
Measuring nystagmus (involuntary eye movement)
Treated Eye Contralateral Eye Individual subject responses
Impr
ovem
ent
EZ line in normal retina shows outer segments by EZ-line, as detected by OCT
ProQR Therapeutics – Corporate Presentation
20
EZ line is missing in LCA10 retina due to lack of outer segments
Month 1
Month 2
Month 3
Baseline
Example of restoration of anatomy detected by OCTRestoration of EZ-line in subjectNormal retina
LCA10 retina
ProQR Therapeutics – Corporate Presentation
Summary of Phase 1/2 interim analysis• QR-110 was safe and well tolerated.
• Approximately 60% of subjects demonstrated improvement in BCVA and performance on mobility course.
• Improvement was seen within two months of the first dose and has been maintained throughout ongoing dosing and monitoring.
• Improvement in physiological endpoints including full field stimulation test and ocular instability was also observed.
• General concordance between all 4 endpoints
21ProQR Therapeutics – Corporate Presentation
2 scales to measure vision:
Normal visionNo light perception
Sensitivity and Range of endpoints
ProQR Therapeutics – Corporate Presentation 22
020/20
1.020/200
2.0Countingfingers
3.0Hand
motion
4.0Light
perception
0.720/100
LogMARSnellen
1.620/800
Ranges are illustrative, not exact
AverageAverage
LCA2 patientsVision at baseline
LCA10 patientsVision at baseline
Normal visionNo light perception
Sensitivity and Range of endpoints
ProQR Therapeutics – Corporate Presentation 23
020/20
1.020/200
2.0Countingfingers
3.0Hand
motion
4.0Light
perception
0.720/100
LogMARSnellen
1.620/800
OCI
Ranges are illustrative, not exact
Ocular Instability (OCI)
LCA2 patientsVision at baseline
LCA10 patientsVision at baseline
Functional vision assessed by mobility course(s)
Spark
ETDRSVision measured by BRVT or ETDRS is the gold standard
BRVT
2 scales to measure vision:
ProQR Mobility course
FSTFull Field Stimulus Test expected to be most sensitive endpoint
QR-110 Phase 1/2 in LCA10, Luxturna in LCA2
ProQR Therapeutics – Corporate Presentation 24
QR-110 Phase 1/2 in LCA10 Luxturna Phase 1 in LCA2 Luxturna Phase 3 in LCA2
Visual Acuity(ETDRS/BRVT)
Mean improvement of -0.67 LogMAR (p=0.01)62.5% improved > 0.3 LogMAR
Mean is not reported• 46% improved• 38% stable• 6% worseSource: BLA clinical review memo
Mean improvement of -0.16 LogMAR (p=0.17)
Source: FDA AdCom
Mobility course
Mean of 2.6 levels improvement57% of patients improved >2 levels
8/11 eyes showed improvement
Source: FDA AdCom
1.6 light levels improvement compared to placeboSource: FDA AdCom
FST red light
Mean Improvement of -0.74 logAAV-RPE 65-15 patient study. Mean improvement of -0.45 logJacobson et al., 2012
Improvement of -1.29 log
Source: ICER report
FST Blue light
Mean Improvement of -0.91 logAAV-RPE 65-15 patient study. Mean improvement of -1.59 logJacobson et al., 2012
AAV-RPE 65-15 patient study. Mean improvement of-1.96 logJacobson et al., 2012
OCImean change of log -0.14 mm 4 out of 7 patients improved
8 out of 12 patients improvedSource: A. M. Maguire et al 2009
Not reported
Not assessed in a head-to-head clinical trial
Preliminary design pivotal Phase 2/3 trial
ProQR Therapeutics – Corporate Presentation 25
Control group
Treatment group (dose level 2)
0 month 3 month 6 month 9 month 12 month
Treatment group (dose level 1)
• Double-blind, controlled, 12-month, dose range finding study in adaptive design
• Could serve as the sole registration trial• Sites in US and select EU countries• 30+ patients >6 years old• Multiple IVT injections initially in one eye
• Primary (registration) endpoints: • Visual Acuity (ETDRS, BRVT) • Mobility course
• Expected to start in H1 2019
• Preliminary design pending regulatory feedback
• Planning to start pediatric trial in <6 years old
Ophthalmology pipeline
• Clean safety profile (QR-110)
• 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 QR-110 and other IRD programs
ProQR Therapeutics – Corporate Presentation 26
Building on success of QR-110
DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS
LATE STAGE/REGISTRATIONAL
TRIALS
OphthalmologyQR-110 for LCA10 p.Cys998X
QR-421a for Usher syndrome 2A exon 13
QR-1123 for P23H adRP - discovered by Ionis
QRX-504 for FECD3
QR-411 for Usher syndrome 2A PE-40
QRX-1011 for Stargardt’s disease c.5461-10T>C
QR-421a for Usher syndrome
ProQR Therapeutics – Corporate Presentation 27
Designed to treat genetic eye disease in Usher syndrome
Ushers
Develop hearing loss and blindness in childhood and turn completely blind by mid adulthood
Exon 13 mutations affect ~16,000 patients in western world.
√ RNA is established modality in eye√ Strong preclinical proof of concept
in patient retina√ Orphan drug designation√ Completed pre-IND meeting
STELLAR Phase 1/2 trial• Expect to dose a first patient with QR-
421a around YE 2018 with safety and efficacy results in mid 2019
• Expect results from multiple dose adaptive trial in H2 2020
Partnership
Awarded $7.5M financial support from FFB to conduct trial
For Usher exon 13 no therapy available
Unmet need
QR-421a produced functional ∆exon 13 Ush2a protein in optic cups and zebra fish
ProQR Therapeutics – Corporate Presentation 28
AON treated zebrafish showed b-wave ERG amplitude restoration
Time (ms)
Wild-type range
Ampl
itude
AON treated Exon 13 mutant
Erwin van Wijk, Radboudumc, Nijmegen, the Netherlands
AON treated optic cups from c.2299delG homozygous patient
ProQR Therapeutics – Corporate Presentation 29
Phase 1/2Single
Ascending Dose
STELLAR Phase 1/2 trial• Single dose, dose-escalation double blind controlled trial• Goals include safety and efficacy PoC and dose interval• Up to 12 adult patients with severe eye disease• Inclusion criteria: Visual field of >10o, visual acuity of 20/32 or worse• Single Intravitreal injection in one eye, or sham treatment• Key efficacy endpoints: Medmont DAC Perimetry, Static VF, microperimetry, OCT• First dose at YE 2018, data expected in Mid 2019
Meeting of independent DSMC
QR-421a Phase 1/2 trial in Usher 2a patients
Low dose (n=2-4)
Mid dose (n=2-4)
High dose (n=2-4)
Multiple dose adaptive trial
Open label extension
Multiple dose adaptive trial• Potentially pivotal• Repeated intravitreal injections, or sham
procedures in one eye• Goal: efficacy and safety• Up to 15 sites in US and select EU countries• First dose expected in mid 2019• Data expected in H2 2020
Washout informs dosing interval
QR-1123 for P23H adRP
Announced licensing agreement in October 2018• Upfront equity payment of $2.5 million at 20% premium ($22,23 per share)• Milestone payments (cash or equity, at ProQR’s discretion) • Royalties of 20% on net sales
High confidence in RNA therapies for eye diseases• Recent clinical proof of concept for QR-110 in LCA10• Solid pre-clinical proof of concept for QR-1123 adds another high quality
program to the ophthalmology pipeline • Success in this program would allow targeting other autosomal dominant
eye diseases
ProQR Therapeutics – Corporate Presentation 30
Exclusive worldwide license from Ionis Pharma
ProQR Therapeutics – Corporate Presentation 31
QR-1123 for P23H adRPGapmer 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
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√ Majority of IND enabling activities completed√ 2 year Natural History Study is completed and
will be used to accelerate clinical development
• Phase 1/2 trial expected to start in 2019
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 32
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 33
mRNA Rhodopsin
protein
Rhodopsin
Outersegment
Innersegment
Nucleus
Connectingcilium
RNA
DNA
DNA
Rhodopsin
QR-1123 is specific for P23H allele
ProQR Therapeutics – Corporate Presentation 34
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 35
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 36
Optic Nerve Head (ONH)
Superior retina
Inferiorretina
Lens
Optic NerveHead
Superior Inferior
Preliminary Phase 1/2 trial in adRPP23H patients
ProQR Therapeutics – Corporate Presentation 37
Preliminary Phase 1/2 trial design• Multiple dose, dose-escalation double-masked
controlled trial• Goals include safety and efficacy PoC and dose interval• Up to 12 adult patients with progressed eye disease
• Intravitreal injection in one eye, or sham treatment• Key efficacy endpoints: Medmont DAC Perimetry, Static
VF, microperimetry, OCT• Pending IND acceptance study start expected in 2019
Meeting of independent DSMC
Low dose
Mid dose
High dose
Open label extension
QR-411 for Usher syndrome
ProQR Therapeutics – Corporate Presentation 38
Designed to treat genetic eye disease in Usher syndrome
Ushers
Develop hearing loss and blindness in childhood and turn completely blind by mid adulthood
PE-40 mutation affects ~1,000 patients in western world
√ RNA is established modality in eye√ Strong pre-clinical proof of
concept in patient retina√ Orphan drug designation
Next steps • Progression into development after
validation of ophthalmology pipeline in QR-110 and QR-421a
QR-411
For Usher PE-40no therapy available
Strong pre-clinical PoCin human models. Development candidate selected
Strong PoC
QRX-1011 for Stargardt disease
ProQR Therapeutics – Corporate Presentation 39
Stargardt 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 pre-clinical proof of
concept
Next steps • Progression into development after
clinical validation of ophthalmology pipeline in QR-110 and QR-421a
QR-1011
For Stargardt c.5461-10T>C in ABCA4 no therapy available
Strong pre-clinical PoCin human models.
Strong PoC
QR-504 for FECD3
ProQR Therapeutics – Corporate Presentation 40
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 pre-clinical proof of
concept in human primary cell models
Next steps • Progression into development after
clinical validation of ophthalmology pipeline in QR-110 and QR-421a
QR-504
For FECD3 Repeat expansion in TCF4No therapy available
Strong pre-clinical PoCin human primary models. Development candidate selected
Strong PoC
Inherited blindness pipeline beyond LCA10 and Usher
• QR-110 Phase 1/2 trial is expected to complete in H2 2019
• Phase 2/3 pivotal ILLUMINATE trial is expected to start enrollment in H1 2019
• QR-421a STELLAR Phase 1/2 trial is expected to readout in mid 2019
• QR-1123 Phase 1/2 trial expected to start in 2019
• Rapidly advancing several undisclosed discovery stage ophthalmology programs into developmentand clinical trials
ProQR Therapeutics – Corporate Presentation 41
DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS
LATE STAGE/REGISTRATIONAL
TRIALS
OphthalmologyQR-110 for LCA10 p.Cys998X
QR-421a for Usher syndrome 2A exon 13
QR-1123 for P23H adRP - discovered by Ionis
QRX-504 for FECD3
QR-411 for Usher syndrome 2A PE-40
QRX-1011 for Stargardt’s disease c.5461-10T>C
QR-313 for dystrophic epidermolysis bullosa
ProQR Therapeutics – Corporate Presentation 42
DEB
Limited life expectancy
Blistering from birth
First product tar-gets most common mutation affecting ~2,000 patients in western world
QR-313
Molecular targeting with potential disease-modification due to long protein half-life
√ Strong preclinical proof of concept
√ Topical formulation based on existing hydrogel
√ FDA & EMA granted orphan drug designation
Next steps • Clinical trial initiated• Report interim data from
trial expected in late 2018 / early 2019
• Report full results expected in 2019
Topically applied. Commonly used hydro-gel, containing QR-313 RNA therapy
Anticipated convenient application at home. Maximum frequency every other day
Aims to heal wounds, restore skin and improve quality of life
QR-313 phase 1/2 trial in DEB patients
• IND enabling studies completed
• Placebo controlled, double-blinded phase 1/2 trial
• 4-8 RDEB exon 73 patients, >2yo (possibility of expansion
to 15 patients for adaptive repowering)
• 10 sites in US and select EU countries
• Independent DSMC
• Dosing 4 weeks, follow-up 8 weeks
• 2 or 3 doses per week depending on bandage change
frequency, 5gram gel (50mg QR-313) per 100cm2 area
• Endpoints
• Primary: safety, tolerability and exon skip
• Secondary: C7 protein detection (IF), anchoring fibrils (TEM),
wound healing (imaging), skin strength, time to re-blistering
• Orphan drug designation in EU and US
• Readouts:
• Exon skip in 4 or more patients in late 2018 / early 2019• Wound healing, re-blistering, IF, TEM in 2019
ProQR Therapeutics – Corporate Presentation 43
4 weeks treatment 8 weeks follow up
End of treatment
biopsy
End of follow-up
biopsy
Monitor wound healing and re-blistering
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 5 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 OligoNeucleotide (EON)
• I is translated as a G, allowing to target G-to-A mutations
Axiomer® RNA editing platform
ProQR Therapeutics – Corporate Presentation 44
Editing Oligonucleotide (EON) mediated A-to-I editing
Endogenous editing
EONs designed to recruit natural ADARs
ProQR Therapeutics – Corporate Presentation 45
Axiomer® EON-directed therapeutic editing
RNAEON
I
RNAEON
A
RNA
I
A
ADAR
RNA
E O N 1 E O N 2 E O N 3
I D U A e n z y m a t i c a c t i v i t y
( % c h a n g e o v e r c o n t r o l )
0 %
2 5 %
5 0 %
E O N 1 E O N 2 E O N 3
G A G r e d u c t i o n o v e r c o n t r o l
0 %
- 2 0 %
- 4 0 %
- 6 0 %
Robust Proof of Concept in Vivo
ProQR Therapeutics – Corporate Presentation 46
Readouts for restored function in IDUA Hurler mouse model
Enzymatic activity
GAG accumulation
RNA sequence correction
GAG reduction(% change over control)
Enzymatic activity (% change over control)
Axiomer® platform technology
Current status
• Discovered and developed in house
• 5 patent family applications filed protecting the full platform
• In vitro PoC in many other models, including CFTR class I mutations
• In vivo PoC in Hurler animal model
• >20,000 disease causing G>A mutations identified
Strategy
• Axiomer® platform technology has the potential to yield large number of new medicines for currently untreatable diseases
• ProQR plans to apply Axiomer® technology in core therapeutic areas
• Active business development strategy to capture value of platform
• First partnership with Galapagos N.V. on the application of Axiomer® technology in select fibrosis targets
ProQR Therapeutics – Corporate Presentation 47
Next steps and strategy
Strong team with proven track record
ProQR Therapeutics – Corporate Presentation 48
Management and leadership team Supervisory board
Daniel de Boer*Chief Executive Officer
Honorary former board member
Gerard Platenburg*Chief Innovation Officer
Smital ShahChief Financial Officer
René BeukemaChief Corp. Development Officer & General Counsel
David RodmanExecutive Vice President ofResearch & Development
Dinko Valerio*Chairman
Alison Lawton
Paul Baart
Antoine Papiernik
Henri Termeer*
James Shannon
* Founding team
Peter AdamsonSenior Vice President Opthalmology Franchise
World-class Scientific Advisory Committee
49ProQR Therapeutics – Corporate Presentation
Scott A. ArmstrongMD, PhD
Phillip D. ZamorePhD
Thaddeus DryjaMD
Cy SteinMD
NUCLEIC ACID THERAPEUTICS
Peter A. BealPhD
Annemieke Aartsma RusPhD
Art LevinPhD
Yi-Tao YuPhD
Broad IP estate• ProQR built a broad IP estate consisting of:
• 20 fully owned patent families• 6 licenses from academia (MGH, INSERM, Radboud University and Leiden University)
• Patent terms (excluding possible extension):• Eluforsen for F508del through 2033• QR-110 for LCA10 through 2036• QR-313 for DEB exon 73 through 2036• QR-411 for Usher PE-40 through 2037• QR-421a for Usher exon 13 through 2037• Axiomer® platform technology through 2037
ProQR Therapeutics – Corporate Presentation 50
Several upcoming milestonesQR-110 for LCA10
• Complete readout Phase 1/2 in H2 2019
• Start Phase 2/3 in H1 2019
QR-421a for Usher Syndrome exon 13
• STELLAR Phase 1/2 trial to start around YE 2018, safety and efficacy data readout in mid 2019
• Expected readout multiple dose adaptive trial in H2 2020
QR-1123 for P23H adRP
• Phase 1/2 trial expected to start in 2019
Pipeline
• Rapidly advancing several discovery and non-clinical stage ophthalmology programs to mature into development and clinical trials
QR-313 for Dystrophic EB exon 73
• WINGS Phase 1/2 Interim data readout in late 2018/early 2019, full data in 2019
Axiomer® RNA editing platform technology
• Strong potential for product and business development
ProQR Therapeutics – Corporate Presentation 51
ProQR since 2012
• Based in Leiden, the Netherlands
• 130 employees (30 nationalities)
• 2014 IPO NASDAQ: PRQR
• FD Shares outstanding: ~43 million (post September 2018 financing)
• Cash position (Q2 2018): € 33.0 million; no debt
• $104.1 million financing in September 2018
• $7.5M grant funding awarded by Foundation Fighting Blindness in February 2018
• $5M grant funding awarded by EBRP and EBMRF in June 2018
• Projected cash runway into 2021
ProQR Therapeutics – Corporate Presentation 52
Facts and figures as of September 2018
IT’S INOUR RNA