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CREATING MEDICINESfor patientsin need
Date:January 2019
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
Sepofarsen (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• Data Phase 1/2 STELLAR trial expected mid 2019• Multiple dose adaptive trial, data expected in 2021
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 WINGStrial with interim analysis data expected 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
OphthalmologySepofarsen (QR-110) for LCA10 p.Cys998XQR-421a for Usher syndrome 2A exon 13QR-1123 for P23H adRP - discovered by IonisQR-504 for FECD3QR-411 for Usher syndrome 2A PE-40QR-1011 for Stargardt’s disease c.5461-10T>CQRX-461 for Usher syndrome undisclosed mutation
QRX-136 for LCA undisclosed mutation
Beyond OphthalmologyQR-313 for DEB exon 73QRX-704 for Huntington’s DiseaseEluforsen (QR-010) for CF F508del
FibrosisPartnered with Galapagos NVUndisclosed targets
Central Nervous SystemAmylon TherapeuticsAT-010 for HCHWA-D
PARTNERED PROGRAMS
ProQR’s VISION2023
ProQR Therapeutics – R&D Day 2019 5
2 3 7COMMERCIAL PRODUCTS
LATE STAGE PROGRAMS
EARLY STAGE PROGRAMS
A FULLY INTEGRATED INHERITED RETINAL DISEASE COMPANY BY 2023
RNA oligo therapies for inherited blindness
ProQR Therapeutics – Corporate Presentation 6
Wild-type Disease Disease + oligo
RNA
DNA
Protein
RNA
DNA
Protein
RNA
DNA
Protein
ProQR inherited blindness platform
ProQR Therapeutics – Corporate Presentation 7
Intravitreal delivery is routine procedure• Long half-life in the eye allows
for dosing quarterly or less frequent
• Chemical modification enables naked delivery
• Sepofarsen has shown placebo-like clean safety profile
Predictive optic cup model• Sophisticated organoid model
for retinal dystrophies• Accurately predicted in
sepofarsen 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
Sepofarsen (QR-110) for LCA10
ProQR Therapeutics – Corporate Presentation 8
LCA10
Lose sight in first years of life
No therapy available
p.Cys998X mutation affects ~2,000 patients in the Western World
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
√ 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 with data around YE 2020
Ongoing Phase 1/2 trial
ProQR Therapeutics – Corporate Presentation 9
Open label, multiple dose, dose escalation study, Phase 1/2
• Enrolled eleven p.Cys998X LCA10 patients in range of 8-44 yo
• 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
• Orphan drug designation in EU and US
• FDA Fast-track designation
Adult 160* µg dose
Adult 80 µg* dose
Pediatric 80* µg dose
Pediatric 160* µg dose
= DSMC review
*Loading dose is double the maintenance dose
• 3 month positive interim analysis data reported in September 2018
• >60% of patients improved on multiple efficacy endpoints
• Patients continue to be followed out to 12 months of treatment of which data is expected in H2 2019
• Eligible patients will be rolled over into an extension trial where they will be offered to also get their second eye treated
Top Line Efficacy Results
ProQR Therapeutics – Corporate Presentation 10
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 11
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
ETDRS (LogMAR -0.3 - 1.6)
BRVT (LogMAR 1.4 - 4.0)
BCVA effect was maintained for at least 6 months
ProQR Therapeutics – Corporate Presentation 12
Dose 1 Dose 2 Dose 3
Clinically meaningful (-0.3 LogMAR)Im
prov
emen
t
Mobility Course for LCA10
ProQR Therapeutics – Corporate Presentation 13
• 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 14
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 15
Responder
Non-responder
Full Field Stimulus Test (FST)
ProQR Therapeutics – Corporate Presentation 16
Impr
ovem
ent
Measured with blue and red light
BlueTreated Eye
BlueContralateral Eye
RedTreated Eye
RedContralateral Eye
Ocular instability (OCI)
ProQR Therapeutics – Corporate Presentation 17
Measuring nystagmus (involuntary eye movement)
Treated Eye Contralateral Eye Individual subject responses
Impr
ovem
ent
OCT imaging demonstrated regeneration of outer segment after sepofarsen treatment
ProQR Therapeutics – Corporate Presentation 18
No change detected in untreated eye (data not shown)
Sepofarsen Phase 1/2 in LCA10, Luxturna in LCA2
ProQR Therapeutics – Corporate Presentation 19
Sepofarsen 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
Discussion of evolving safety findings in trial PQ-110-001• At the time of the IA, no significant, unanticipated
AEs had been reported.
• Subsequently, lens opacities and CME were observed in a dose- and time-dependent manner:• Lens opacity occurred approx. 4 months
earlier in mid dose group compared to low dose group, with none observed prior to month 4;
• CME only observed in mid dose group (3-4 months into the study)
• Investigators judged that 3 of 6 lens opacities required surgical removal• 2 subjects had demonstrated improved BCVA
prior to developing the cataract. After surgery restoration of benefit was observed.
• Both subjects with CME were judged to be mild in severity and not associated with reduced visual acuity.• Both started on standard of care treatment
with partial resolution noted on one month follow-up OCT
• Dose modifications and longer dosing interval introduced in program:• After 12 month visit, all subjects will be rolled
over into an extension trial with every six month treatment with the low dose regimen.
ProQR Therapeutics – R&D Day 2019 20
ILLUMINATE study proposed dose regimens
ProQR Therapeutics – R&D Day 2019 21
Modeling based on estimated t1/2 in retina 200d from NHP
Low dose pivotal (80 µg load/40 µg maintenance*)
Lens opacity Risk
CME Risk
Expo
sure
rela
tive
to m
axim
umvi
treo
us e
xpos
ure
Days0 100 200 300 400
0
50
100
Dose (µg): 80 40 40
*Every 6 months after 3 month dose
Primary dose pivotal(160 µg load/80 µg maintenance*)
Lens opacity Risk
CME Risk
Expo
sure
rela
tive
to m
axim
umvi
treo
us e
xpos
ure
Days0 100 200 300 400
0
50
100
Dose (µg): 160 80 80
Projected human tissue exposure (200d t1/2)
ILLUMINATE study proposed dose regimens
ProQR Therapeutics – R&D Day 2019 22
Efficacy is predicted in low dose regimen
CEP290 exon skipping in organoid
Expr
essi
on le
vels
(%)
Untreate
d
26-X-27
26-27*** ****** ***
0.3 3 101
CEP290-LCA
QR-110 (µM)
120
100
80
60
40
20
0
Low dose pivotal (80 µg load/40 µg maintenance*)
Lens opacity Risk
CME Risk
Expo
sure
rela
tive
to m
axim
umvi
treo
us e
xpos
ure
Days0 100 200 300 400
0
50
100
Dose (µg): 80 40 40
*Every 6 months after 3 month dose
Pivotal Phase 2/3 trial
ProQR Therapeutics – Corporate Presentation 23
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• Expected to start 1H 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
= Dose first eye = Dose second eye
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
Ophthalmology pipeline
• Acceptable risk/benefit 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
24
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-504 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 Usher syndrome
ProQR Therapeutics – R&D Day 2019
Designed to treat genetic vision loss in Usher and non-syndromic RP
Usher
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
√ RNA is established modality in eye√ Strong preclinical proof of concept
in patient retinal model√ Orphan drug designation√ Fast track designation√ IND approved by FDA
STELLAR Phase 1/2 trial• Expect safety and efficacy results in
mid-2019• Expect results from multiple dose
adaptive trial in 2021
Partnership
Awarded $7.5M financial support from FFB to conduct trial
For USH2A exon 13 no therapy available
Unmet need
25
“Read-through” from LCA10 to Ush2a
ProQR Therapeutics – R&D Day 2019 26
Candidate Cellular MoA Target cell Active in retinal organoid
Active in animals
Active in humans
sepofarsen Restore cilium and OS
PhotoreceptorCones
Yes≤1µM Unknown Yes
QR-421a Restore cilium and OS
PhotoreceptorRods
Yes≤1µM Yes TBD
• CEP290 and Usherin are co-localized in photoreceptors
• Sepofarsen and QR-421a have similar concentration-response curves in retinal organoids
• QR-421a has additional preclinical translational PoC in animal model
CEP290
Outer segment (OS)
Inner segment (IS)
Transition zoneConnectingCilium (CC)
Usherin
Usher Syndrome disease progression
ProQR Therapeutics – Corporate Presentation
Hearing impairment
Loss of visual field(rod degeneration)
Loss of central vision(cone degeneration)
Complete blindness(rods and cones degenerated)
0 10
Night blindness(start rod degeneration)
20 30 40 50 60AGE* (YEARS)
*High within patient variability in onset and progression of disease
Ush2a (RP) v LCA10
ProQR Therapeutics – Corporate Presentation
Anatomical defect and targeted restoration of function
Macula PeripheralPeripheral
Normal LCA10 Ush2a (RP)
Normal EZ-line No EZ-line Macula EZ-line only
• LCA10 retina experiences early rod (peripheral) degeneration with limited function in the macula (presence of ONL in the macula, no EZ-line)
• Normal retina has functioning central and peripheral retina (presence of ONL and EZ-line)
• RP patients have slower degeneration starting in the peripheral retina and then progressing to the macula (presence of ONL and macular EZ-line) retina defect is in peripheral retina
Ush2a (RP) v LCA10
ProQR Therapeutics – Corporate Presentation
Anatomical defect and targeted restoration of function
Macula PeripheralPeripheral
Normal LCA10 Ush2a (RP)
Normal EZ-line No EZ-line Macula EZ-line only
• Sepofarsen targets photoreceptors that are only present in the macula
• Demonstrated visual acuity improvements, suggesting restoration of function
• Evidence of EZ-line restoration
• QR-421a targets non functioning photoreceptors in the peripheral retina
• Visual fields improvement will provide evidence of function
= Anatomical location of targeted restoration of function
QR-421a produced functional ∆exon 13 Ush2a protein in optic cups and zebra fish
ProQR Therapeutics – Corporate Presentation
AON treated zebrafish showed b-wave ERG amplitude restoration
Wild-type range
Ampl
itude
Time (ms)
AON treated Exon 13 mutant
Erwin van Wijk, Radboudumc, Nijmegen, the Netherlands
QR-421a treated optic cups from c.2299delG homozygous patient
Normal visual field
ProQR Therapeutics – Corporate Presentation
The normal field of vision extends to approximately 60°nasally, 90° temporally, 60°superiorly and 70° inferiorly
Right eyeLeft eye
TEMPORAL TEMPORAL
SUPERIOR
INFERIOR
NASAL
30° eccentricity
Visual field defects
ProQR Therapeutics – Corporate Presentation
Normal Visual Field Usher syndrome
Early stage disease
Later stage disease
Visual field defects
ProQR Therapeutics – Corporate Presentation
Normal Visual Field Usher syndrome
Ultimate treatment paradigm is to treat patients before significant visual field loss occurs
Early stage disease
Later stage disease
Potentially viable photo-receptors as shown by OCT Indicates potential area of visual functional restoration by QR-421a
Primary efficacy measures:
ProQR Therapeutics – R&D Day 2019 34
Quantifying visual field defects and EZ-line extension
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 perimetry
Microperimetry
Automated perimetry
OCT: Extension of EZChange in ellipsoid zone
Macula EZ plus peripheral extension
ProQR Therapeutics – Corporate Presentation
STELLAR Phase 1/2 trial• Single dose, double-masked, randomized,
controlled trial• Goals include safety and efficacy PoC and dose interval• ~18 adult patients with moderate to 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 (randomized 2:1 active:control per cohort)• Key trial endpoints: Visual field (Medmont DAC Perimetry,
Static VF, microperimetry) and OCT• IND open, data expected in mid-2019
QR-421a Phase 1/2 trial in Usher 2a patients
Meeting of independent DSMC
Phase 1/2Single Dose
Trial
Low dose (n=4+2 sham)
Mid dose (n=4+2 sham)
High dose (n=4+2 sham)
Open label extensionn=8-12
Washout informs dosing interval
Adaptive Sham Crossover (n=4-6)
35
6M Efficacy and dosing interval modeling
3M IA
Key trial goals/objectives• Establish safety and pharmacokinetics
• Identify dose/duration for next study
• Assess efficacy based on:
• Improvement in visual fields, particularly rod function;
• Evidence of structural improvement consistent with VF improvement as measured by OCT
• Other functional vision improvements
ProQR Therapeutics – Corporate Presentation
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 sepofarsen 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 37
Exclusive worldwide license from Ionis Pharma
QR-1123 for P23H adRP
ProQR Therapeutics – Corporate Presentation 38
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
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
Next steps • Phase 1/2 trial expected to start in 2019• 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 39
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 40
mRNA Rhodopsin
protein
Rhodopsin
Outersegment
Innersegment
Nucleus
Connectingcilium
RNA
DNA
DNA
Rhodopsin
QR-1123 is specific for P23H allele
ProQR Therapeutics – Corporate Presentation 41
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 42
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 43
Optic Nerve Head (ONH)
Superior retina
Inferiorretina
Lens
Optic NerveHead
Superior Inferior
Preliminary Phase 1/2 trial in adRPP23H patients
ProQR Therapeutics – Corporate Presentation 44
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
Low dose
Mid dose
High dose
Open label extension
= DSMC review
QR-411 for Usher syndrome
ProQR Therapeutics – Corporate Presenation 45
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
QR-411
For Usher PE40no therapy available
Strong preclinical PoC in human organoid models. Development candidate selected
Strong PoC
Next steps • IND-enabling studies expected to start in
2019• Clinical development similar to QR-421a
QR-1011 for Stargardt’s disease
ProQR Therapeutics – Corporate Presentation 46
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 retinal organoid
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
QR-504 for FECD3
ProQR Therapeutics – Corporate Presentation 47
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
QR-504
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
• Sepofarsen 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 48
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-504 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-313 for dystrophic epidermolysis bullosa
ProQR Therapeutics – Corporate Presentation 49
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• Interim PoC data from trial
expected in early 2019• Full results expected in 2019• Potential for extension
study
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
• Placebo controlled, double-blinded phase 1/2 trial• 4-8 RDEB exon 73 patients, >2yo• 10 sites in US and select EU countries• Independent DSMC
• Dosing 2 or 3 times per week depending on bandage change frequency, 5gram gel (50mg QR-313) per 100cm2 area
• Orphan drug designation in EU and US
• Endpoints• Primary: safety, tolerability and exon skip• Secondary: C7 protein detection (IF), anchoring fibrils
(TEM), wound healing (imaging), time to re-blistering
• Readouts• Interim proof of concept: exon skip, IF and TEM in
initial group of patients in early 2019• Full data on all patients in 2019
• Potential for extension study in same patients to test different dosing regimes and administration routes
ProQR Therapeutics – Corporate Presentation 50
4 weeks treatment 8 weeks follow up
End of treatmentbiopsy
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 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 51
Editing Oligonucleotide (EON) mediated A-to-I editing
Endogenous editing
EONs designed for targeted editingADAR deaminates target A in EON-target RNA helix
Axiomer® EON-directed therapeutic editing
RNAEON
I
RNA
I
A
ADAR dsRBDs
ADARdeaminase
domain
RNA RNAEON
A
ProQR Therapeutics – R&D Day 2019 52
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 for targeted editing
ProQR Therapeutics – Corporate Presentation 53
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 54
Next steps and strategy
Strong team with proven track record
ProQR Therapeutics – Sofinnova advisory board 55
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
Dinko ValerioChairman
Alison Lawton
Paul Baart
Antoine Papiernik
Henri Termeer
James Shannon
Peter AdamsonSenior Vice President Opthalmology Franchise
Tiffany BurtVP Comercial
Leadership team
Aniz GirachChief Medical Officer
World-class Scientific Advisory Committee
56ProQR 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• Sepofarsen 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 57
Several upcoming milestonesSepofarsen (QR-110) for LCA10• Complete readout Phase 1/2 in H2 2019• Start Phase 2/3 in H1 2019 with readout
around YE 2020
QR-421a for Usher syndrome exon 13• STELLAR Phase 1/2 trial to report interim
data in mid 2019• Initiate an adaptive multiple-dose trial with
projected readout in 2021
QR-1123 for P23H adRP• Phase 1/2 trial expected to start in 2019
Ophthalmology Pipeline• Rapidly advancing several discovery
and nonclinical 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
early 2019, full data in 2019
ProQR Therapeutics – Corporate Presentation 58
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 (Q3 2018): € 113.7 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
• €4.7M Innovation Credit from Dutch government for sepofarsen program
• Projected cash runway into 2021
ProQR Therapeutics – Corporate Presentation 59
Facts and figures as of September 2018
IT’S INOUR RNA