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CREATING MEDICINES for patients in need Nasdaq: Date: PRQR March 2020
Forward looking statements
This presentation contains forward-looking statements that disclosed in our forward-looking statements, and you should not
involve substantial risks and uncertainties. All statements, other place undue reliance on our forward-looking statements. Actual
than statements of historical facts, contained in this results or events could differ materially from the plans,
presentation, including but not limited to, statements regarding intentions and expectations disclosed in the forward-looking
our strategy, future operations, future preclinical and clinical trial statements we make. The forward-looking statements contained
plans and related timing of trials and results, research and in this presentation reflect our current views with respect to
development, future financial position, future revenues, future events, and we assume no obligation to update any
projected costs, prospects, therapeutic potential of our product forward-looking statements except as required by applicable law.
candidates, plans and objectives of management, are forward- These forward-looking statements are subject to a number of
looking statements. The words “aim,” “anticipate,” “believe,” risks, uncertainties and assumptions, including those that may
“estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” be described in greater detail in the annual report filed on Form
“target,” “potential,” “will,” “would,” “could,” “should,” “continue,” 20-F for the year ended December 31, 2018 that we have filed
and similar expressions are intended to identify forward-looking with the U.S. Securities and Exchange Commission (the “SEC”)
statements, although not all forward-looking statements contain and any subsequent filings we have made with the SEC. We have
these identifying words. included important factors in the cautionary statements
included in that annual report, particularly in the Risk Factors
Forward-looking statements represent our management’s beliefs section, and subsequent filings with the SEC that we believe
and assumptions only as of the date of this presentation. We could cause actual results or events to differ materially from the
may not actually achieve the plans, intentions or expectations forward-looking statements that we make.
ProQR Therapeutics – Corporate Presentation 2
ProQR at a glance
Platform for RNA therapies targeting Broad RNA platform
Patient-centric RNA inherited blindness in other therapeutic
areas
THERAPEUTICS Sepofarsen (QR-110) for LCA10 with positive
clinical data Fully owned and in
platform company, •
• Phase 1/2 top-line results show rapid, significant and durable house developed
developing drugs for improvement in vision Axiomer® RNA editing
RARE DISEASES • Pivotal Phase 2/3 Illuminate trial ongoing; platform with very
broad applicability
with well understood data expected H1 2021
QR-421a for Usher syndrome Exon 13 • Majority ownership in
causality CNS spin-out company
• First patient dosed in single dose Phase 1/2 Stellar trial;
Amylon
data expected late Q1 2020
• Minority stake in DEB
QR-1123 for P23H adRP (in-licensed from Ionis)
spin-out company
• Preclinical activities and natural history study completed by Ionis Wings Therapeutics
• 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
ProQR Therapeutics – Corporate Presentation 3
RNA therapies for genetic disease
Taking away the underlying cause of disease in the RNA
Normal cell Diseased cell Treated cell
(retina) (retina) (retina)
RNA Therapy
RNA
Nucleus DNA
In genetic disease a mistake in a An RNA therapy repairs the RNA,
In healthy cells parts of the DNA,
gene, called a mutation, is copied without changing the patient’s DNA.
called genes, are copied into RNAs
into the RNA thereby causing The cell can now perform its
so the cell can perform its function
disease function like a normal cell
ProQR Therapeutics – Corporate Presentation 4
RNA therapies for inherited retinal diseases
Reverse blindness with 1 - 2 routine injections per year
RNA Therapy characteristics RNA Therapy
Intravitreal administration
• 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 Therapeutics – Corporate Presentation 5
ProQR RNA therapy development pipeline
LATE STAGE/
PROOF OF
DISCOVERY PRECLINICAL DEVELOPMENT REGISTRATIONAL
CONCEPT TRIALS
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 Therapeutics – Corporate Presentation 6
ProQR’s VISION2023
A FULLY INTEGRATED INHERITED RETINAL DISEASE COMPANY BY 2023
2 APPROVED
PRODUCTS 3 LATE STAGE
PROGRAMS 7 EARLY STAGE
PROGRAMS
ProQR Therapeutics – Corporate Presentation 7
2019 Accomplishments
• Initiated the sepofarsen pivotal trial Illuminate for LCA10,
ProQR’s first pivotal trial
• Advanced two new molecules into clinical trials:
• QR-421a for Usher syndrome 2A exon 13
• QR-1123 for autosomal dominant retinitis pigmentosa (adRP)
• Received PRIME and rare pediatric disease designations
for sepofarsen
• Raised capital to extend runway into 2022
• Strengthened the Board with Bart Filius, COO & CFO Galapagos and
Theresa Heggie, head of commercial Alnylam ex-US
• Added Aniz Girach, Chief Medical Officer and Tiffany Burt, Head of
commercial to our leadership team
• Expanded pipeline with addition of several new programs for IRDs
ProQR Therapeutics – Corporate Presentation 8
2020: Generating significant momentum
• Sepofarsen for LCA10
• Phase 2/3 pivotal Illuminate trial enrolling
• Update for inSight extension study H2 2020, including data
from contralateral eye treatment
• Prepare for submission of NDA and MAA after Illuminate
readout in H1 2021
• Gear up commercial preparations for potential launch of
sepofarsen in 2022
• QR-421a for Usher syndrome type 2
• On track to report 3 month interim data from Stellar trial in
late Q1 2020 to inform next steps in development
• QR-1123 for adRP
• Report when Aurora trial is fully enrolled; on track for clinical
data read-out in 2021
• QR-504a in Fuchs’ endothelial corneal dystrophy (FECD3)
• Advance into clinical development in 2020
• Axiomer® technology: Advance our unique RNA editing platform
to support development and strategic collaborations
ProQR Therapeutics – Corporate Presentation 9
Eyes on the RNA Opportunity
The opportunity:
>100 tangible targets
remain after further filtering
for disease state and
population size
ProQR projects its RNA
Foundation of common technology can address
characteristics, irrespective about 25% of the mutations
of the target at a molecular level
• Intravitreal administration is
routine procedure >300 genes causing
• Acceptable safety profile Inherited Retinal Diseases,
• Broad distribution throughout described with
the entire retina >50 pathogenic mutations
• Long half life allowing for per gene, leading to
infrequent dosing >15,000 targets.
ProQR Therapeutics – Corporate Presentation 10Sepofarsen (QR-110) for LCA10
LCA10
Lose sight in first No therapy p.Cys998X
years of life available mutation affects
~2,000 patients in
the Western world
RNA therapy: sepofarsen
Goal: Restore Locally adminis- Anticipated
vision/ prevent tered in the eye. infrequent dosing
vision loss in Routine intra- of 2 times a year
patients with vitreal procedure
LCA10
√ Established modality in eye √ Orphan drug designation & Rare pediatric
√ Strong preclinical proof of concept in disease designation
human retina in preclinical models √ FDA Fast track designation and access to
√ Top-line Phase 1/2 clinical trial results EMA PRIME program
showed rapid, significant and durable • Pivotal Phase 2/3 Illuminate trial initiated;
efficacy and favorable benefit/risk data expected H1 2021
ProQR Therapeutics – Corporate Presentation 11Phase 1/2 – trial design
Open label, multiple dose, dose escalation study
Screening Roll-over to extension
baseline 12 months treatment in worse eye + 2nd eye treatment • Enrolled 11 LCA10 patients (age range 8-44) with
1 or 2 copies of the p.Cys998X mutation
DS
• Intravitreal injections in one eye
MC Adult 160/80µg dose
• Participating sites: major sites in EU (UGhent) and
US (UPenn, UIowa)
DS
MC Adult 320/160µg dose
Objectives:
• Base case: Safety/tolerability & Mechanistic
proof-of-concept (full-field stimulation)
DS
MC Pediatric 160/80µg dose • Up-side: Clinical proof-of-concept (best corrected
visual acuity), Identify target dose, Mobility course
DS
Pediatric 320/160µg dose feasibility in LCA10
MC
• Explore: Additional secondary outcome measures
DS
MC = DSMC review
Top-line data, reported in October 2019: benefit/risk and provides strong guidance for population
• Validated efficacy of sepofarsen with statistically significant enrichment for the pivotal trial.
increase in vision in target registration dose group, • Eligible patients will be rolled over into an extension trial
• Established efficacious dose regimen with acceptable where they will be offered to also get their second eye treated
ProQR Therapeutics – Corporate Presentation 12Top-line efficacy results
Primary and key secondary outcome measures pooled analysis n=11
Mean change from
Direction of Responder baseline at month 12 (SEM)
Objective Assessment
improvement threshold
Treated (TE) Untreated (CE)
Full field stimulus (FST) -0.92 (0.18)
Mechanistic ↓= improved -0.5 -0.16 (0.16)
red – log cd/m2 (n=10) pExample of mobility course
Before and after treatment
Link:
https://youtu.be/
YqVN3A7I1_4
ProQR Therapeutics – Corporate Presentation 14BCVA stratified by dose cohort
Primary outcome measure – mean change in BCVA
Benefit maintained from month 3 to month 12
Treated eye (SEM) Contralateral eye (SEM)
Mean ΔBCVA
LogMAR
month 3 month 12 month 3 month 12
Pooled analysis -0.50 -0.55 0.0 -0.11
(n=11) (0.24) (0.26) (0.04) (0.07)
Phase
-0.81 -0.93 0.01 -0.22 2/3 trial
160μg/80μg (n=6) target
(0.41) (0.43) (0.08) (0.11)
dose
320μg/160μg (n=5) -0.13 -0.11 0.0 0.01
(0.1) (0.07) (0.0) (0.04)
ProQR Therapeutics – Corporate Presentation 15160µg/80µg cohort
Consistent improvement with favorable benefit/risk
BCVA baseline (LogMAR) Responder Rate
4.0 2.4 2.1 2.45 0.63 * 4.0 Treated eye Contralateral eye
0
-0.1 Responder (%) US EU US EU
Change from baseline (LogMAR)
responder responder responder responder
-0.2 EU threshold threshold threshold threshold
-0.3 US
160μg/80μg (n=6) 67% 83% 33% 33%
-0.4
-0.5
Safety Findings
-0.6
-0.7 160μg/80μg (n=6)
-0.8 Tolerability No issues
-0.9 Systemic safety No issues
-1 Lens opacity 3 findings
* = homozygous subject 2 surgeries. Complete recovery of
Cataract surgery outcome
pre-cataract benefit 2/2 subjects
-1.7 Retinal findings No issues
-2.66
ProQR Therapeutics – Corporate Presentation 16Key outcome measures change month 12
Target registration dose level: 160µg/80µg (n=6)
Every six-month dosing interval-maintained benefit
BCVA FST Mobility
Impaired 0.2 Less 0.2 Less 4.5
Acuity Sensitive Impairment
4
0
0
3.5
Change in BCVA (LogMAR)
Change in Mobility (levels)
-0.2 3
Change in FST (cd/m2)
-0.2
2.5
-0.4
-0.4 2
-0.6
1.5
-0.6
-0.8 1
0.5
-0.8
-1
0
-1.2 -1 -0.5
Improved More More
Acuity Sensitive Impairment
Treated eye blue light Contralateral eye blue light
Treated Eye Contralateral Eye Treated Eye Contralateral Eye
Treated eye red light Contralateral eye red light
ProQR Therapeutics – Corporate Presentation 17Summary 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 18Sepofarsen Pivotal Phase 2/3 trial
Design agreed on with FDA
12 month
Primary Endpoint
0 month 3 month 6 month 9 month 15 month 18 month 21 month 24 month
sepofarsen: 160 µg loading dose, 80 µg maintenance dose
Safety
(n=10)
sepofarsen: 80 µg loading dose, 40 µg maintenance dose
Safety
(n=10)
Sham-procedure (n=10) Crossover
= Dose first eye = Dose second eye
• Double-masked, randomized, controlled, • 30+ patients >8 years old • Key secondary endpoints
12-month, multiple dose study • Multiple IVT injections in both eyes • Mobility course
• Could serve as the sole registration trial • First patient dosed in April 2019 • Full field stimulus testing (FST)
• Sites in North America and select EU • Primary (registration) endpoint: • Ocular instability (OCI)
countries • Visual Acuity (ETDRS, BRVT) • Optical coherence tomography (OCT)
ProQR Therapeutics – Corporate Presentation 19Ophthalmology pipeline
Building on success of sepofarsen
LATE STAGE/
PROOF OF
DISCOVERY PRECLINICAL DEVELOPMENT REGISTRATIONAL
CONCEPT TRIALS
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
• Acceptable benefit/risk safety profile (sepofarsen) • Optic cup accurately predicted:
• Durable response with infrequent dosing • Clinically efficacious intravitreal dose level
• Intravitreal administration delivers to the retina • Response to treatment
• Clinically meaningful vision improvement in a majority of • Time to onset of response
low vision patients
• To be further validated in future trials of sepofarsen and
other IRD programs
ProQR Therapeutics – Corporate Presentation 20QR-421a for Usher syndrome
Designed to treat genetic vision loss in Usher and non-syndromic RP
RNA therapy for Usher
Develop hearing and vision USH2A exon 13 mutations affect
loss in childhood and are ~16,000 patients in Western world
completely blind by mid
adulthood
Partnership Unmet need
Awarded $7.5M For USH2A exon 13 no
financial support from therapy available
FFB to conduct trial
√ RNA is established modality in eye Stellar Phase 1/2 trial
√ Strong preclinical proof of concept • 3-month interim analysis on first and
in patient retinal model second cohort expected late Q1
√ Orphan drug designation & Rare 2020, including top-line safety and
pediatric disease designation efficacy data
√ Fast track designation
√ First patient dosed
ProQR Therapeutics – Corporate Presentation 21“Read-through” from LCA10 to Ush2a
• CEP290 and Usherin are co-localized in
Outer segment (OS)
the connecting cilium of photoreceptors
CEP290
• Sepofarsen and QR-421a have similar Usherin
concentration-response curves in retinal Connecting
Cilium (CC)
organoids
Inner segment (IS)
• QR-421a has additional preclinical
translational PoC in animal model
Active in retinal Active in Active in
Candidate Cellular MoA Target cell
organoid animals humans
Restore cilium Photoreceptor Yes
sepofarsen Unknown Yes
and OS Cones ≤1µM
Restore cilium Photoreceptor Yes
QR-421a Yes TBD
and OS Rods ≤1µM
ProQR Therapeutics – Corporate Presentation 22The study population and endpoints
Visual field
in degrees 100° 20° 10° 0°
vision
STELLAR participants baseline:
• ≥10° Visual Field
Mild to Moderate disease Severe disease
• >20° visual field (more than •QR-421a Phase 1/2 trial in Usher 2a patients
~200 day half-life allows for informative FIH trial design
Interim 3 Month Interim Analysis
Analysis 24 months total
0 month 1 month expected in late Q1 2020
DS • Data reported from 8 treated
COHORT 1 MC
50 µG subjects on low and mid
4 active dose and 4 patients on sham
2 sham DS treatment
24 month masked
MC
follow-up • Data will include all safety
to measure durability
and efficacy endpoints 3 or
of effect and inform
DS more months of treatment
COHORT 2 MC dosing interval
100 µG • Option to escalate up to a
4 active cohort of 200 µg or expand
2 sham DS first 2 cohorts
MC
= Dose in one eye DS = DSMC review 0 month 1 month 3 months
MC
Stellar Phase 1/2 trial Key endpoints include:
• Single dose, double-masked, randomized, controlled visual acuity, visual field (DAC
perimetry (Medmont), automated
• Goals include safety and efficacy PoC and dose interval
perimetry (Octopus), microperimetry
• Up to 18 adult patients with moderate to severe eye disease (MAIA)), FST, OCT and Patient
• Inclusion criteria: visual field of ≥10o Reported Outcomes
ProQR Therapeutics – Corporate Presentation 24Most sensitive endpoints by subgroup
Patients with moderate disease Patients with severe disease
• Full field stimulus • Full field stimulus
(blue, red and white light) (blue, red and white light)
• Static Perimetry • Micro perimetry by Maia device
(white light) by Octopus device
• Visual Acuity
• Dark Adapted Chromatic Perimetry
• OCT(EZ)
(color light) by Medmont device
• Patient Reported Outcomes
• Patient Reported Outcomes
Detailed explanation of each endpoint can be found in the reference slides at the end of this presentation
ProQR Therapeutics – Corporate Presentation 25Objectives in STELLAR trial
Other endpoints
Primary Endpoint: Safety Pharmacodynamic signal • Visual function
Acceptable safety profile E.g. FST, DAC perimetry • Visual acuity
• DAC perimetry
• Static Perimetry
• Microperimetry
• Structural
• OCT: (EZ)
Go Signal • Other end points
• Mobility Course
to next phase of trial
• PROs
Positive outcome for the interim analysis would look similar to other early trials:
Identify active dose levels based on an improvement in a pharmacodynamic
signal and some examples of improvement in visual function
ProQR Therapeutics – Corporate Presentation 26QR-1123 for P23H adRP
Gapmer targeting autosomal dominant RP due to the P23H mutation in RHO
P23H adRP
Progressive reduction No therapy ~2,500 patients with
in night & peripheral available P23H adRP in United
vision. Blindness is States
frequent in mid-
adulthood
RNA therapy: QR-1123
Goal: Restore Locally adminis- Anticipated
vision/prevent tered in the eye. infrequent dosing
vision loss in Routine intra- of 4 times a year
patients with vitreal procedure or less
P23H adRP
√ Established modality in eye √ Received IND clearance
√ Strong preclinical proof of concept in vivo √ Orphan drug designation
√ In-licensed from Ionis Pharmaceuticals
√ 2-year Natural History Study is completed Next steps
and will be used to accelerate clinical • Phase 1/2 trial ongoing, first patient dosed
development • Clinical development similar to QR-421a
ProQR Therapeutics – Corporate Presentation 27QR-1123 for P23H adRP
Disease Background & Clinical Phenotype
• P23H mutation in the rhodopsin (RHO) gene • QR-1123 inhibits the formation of toxic
causes autosomal dominant Retinitis mutant version of rhodopsin protein
Pigmentosa (adRP) • QR-1123 selectively binds to the mutant
• Rhodopsin is the light sensitive pigment in RHO mRNA
rods in the retina • Gapmer structure causes RNase H
• P23H mutant rhodopsin is misfolded and mediated cleavage of mutant mRNA
toxic, causing progressive loss of rods (night without affecting the WT mRNA
and peripheral vision affected) • QR-1123 slows retinal degeneration in
• Eventual loss of cones (central vision) aggressive humanized mouse models
causes patients to become legally blind by of adRP
~40-50 years of age • Potential to reverse toxic effect and restore
vision in P23H adRP patients
• P23H is the most prevalent mutation
associated with adRP in the US, accounting
for ~2,500 patients
ProQR Therapeutics – Corporate Presentation 28MoA QR-1123
QR-1123 blocks expression of toxic P23H mutant RHO protein
Outer
segment
Connecting
cilium
Inner RNA
segment
DNA
Nucleus
DNA
protein
QR-1123
mRNA Rhodopsin Rhodopsin Rhodopsin Rhodopsin Rhodopsin Rhodopsin
Healthy people inherit two wild type P23H mutant rhodopsin is misfolded and QR-1123 suppresses P23H mRNA
copies of the rhodopsin gene toxic, causing progressive loss of rods with an allele specific mechanism
ProQR Therapeutics – Corporate Presentation 29QR-1123 Phase 1/2 trial in adRP patients
0 month 1 month 12-month follow up
75 µg DS
n=1 MC
Single 150 µg DS
dose n=1 MC
300 µg DS
MC
n=3
Multiple dose QR-1123: n=6
(every 3 months) Sham: n=2
= Dose in one eye through intravitreal administration Potential to add additional single and multiple dose cohorts at different dose levels
Aurora Phase 1/2 trial Key endpoints include:
• Double-masked, randomized, sham controlled • Visual acuity
• Goals include safety, tolerability and efficacy • Visual field
• Up to 35 adult patients • OCT
• Initial data expected in 2021 • Patient Reported Outcomes
ProQR Therapeutics – Corporate Presentation 30QR-504a for FECD3
Fuchs Endothelial Corneal Dystrophy
Front of the eye disease >250,000 patients with Repeat
leading to blindness in 50+ expansion in TCF4
years of age in Western world
RNA therapy: QR-504a Strong PoC
For FECD3 repeat Strong preclinical PoC in
expansion in TCF4 human primary cell
No therapy available models. Development
candidate selected
√ RNA is established modality in eye Next steps
√ Rapid delivery to corneal cells • Progression into development
√ Strong preclinical proof of concept
in human primary cell models
ProQR Therapeutics – Corporate Presentation 31Inherited blindness pipeline beyond
LCA10 and Usher syndrome
LATE STAGE/
PROOF OF
DISCOVERY PRECLINICAL DEVELOPMENT REGISTRATIONAL
CONCEPT TRIALS
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
• Sepofarsen Phase 1/2 trial completed • QR-1123 Phase 1/2 trial ongoing, first data expected
• First patient dosed in Phase 2/3 pivotal Illuminate 2021
trial; Data expected H1 2021 • Rapidly advancing several undisclosed discovery
• QR-421a Stellar Phase 1/2 trial is expected to readout stage ophthalmology programs into development
Interim Analysis in late Q1 2020 and clinical trials
ProQR Therapeutics – Corporate Presentation 32Axiomer® RNA editing platform
Editing Oligonucleotide (EON) mediated A-to-I editing
Unique A-to-I RNA editing Strong IP protection Potential broad applicability
• A-to-I editing in RNA • Invented in house at ProQR • >20,000 G-to-A mutations
• Using endogenous ADAR laboratories described in literature
• ADAR is recruited by a single • Protected with 8 patents families, • Proprietary Axiomer platform
stranded Editing Oligonucleotide protecting Axiomer as a platform technology can target G-to-A
(EON) • Key collaborations with ADAR mutations
• I is translated as a G, allowing to experts in the world • Potentially broader applicability
target G-to-A mutations in protein modulation and stop-
codon mutations
ProQR Therapeutics – Corporate Presentation 33Strong team with proven track record
Management team Supervisory board
Dinko Valerio
Daniel de Boer Chairman
Chief Executive Officer
James Shannon
Smital Shah
Chief Business & Financial Officer
Alison Lawton
David Rodman
Executive Vice President of
Research & Development
Antoine Papiernik
Gerard Platenburg
Chief Innovation Officer
Bart Filius
Leadership team Theresa Heggie
Aniz Girach
Chief Medical Officer
Honorary former board member
Tiffany Burt Henri Termeer
VP Commercial
ProQR Therapeutics – Corporate Presentation 34World-class Scientific Advisory Committee
Art Levin Annemieke Aartsma Rus
PhD PhD
Phillip D. Zamore Peter A. Beal
PhD PhD
Cy Stein Yi-Tao Yu
MD PhD
NUCLEIC ACID THERAPEUTICS
Thaddeus Dryja Peter Adamson
MD PhD
ProQR Therapeutics – Corporate Presentation 35Broad 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 36Several upcoming milestones
Sepofarsen (QR-110) for LCA10 QR-1123 for P23H adRP
√ Positive top-line results Phase 1/2 √ Aurora Phase 1/2 trial underway Q4 2019
announced Q419 • Initial data expected 2021
√ Phase 2/3 Illuminate trial initiated
• Enrollment ongoing QR-504a for Fuchs’ Endothelial Corneal
• Update on INSIGHT extension study Dystrophy
expected in H2 2020, including data on • Advance into clinical development in 2020
contralateral eye treatment
Ophthalmology Pipeline
QR-421a for Usher syndrome 2A exon 13 • Rapidly advancing several discovery
• Stellar Phase 1/2 trial to report interim and nonclinical stage ophthalmology
data in late Q1 2020 to inform next steps in programs to mature into development
development and clinical trials
ProQR Therapeutics – Corporate Presentation 37ProQR since 2012
Facts and figures
• 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 2022
ProQR Therapeutics – Corporate Presentation 38IT’S IN OUR RNA
Sepofarsen reference slides ProQR Therapeutics – Corporate Presentation 40
Sepofarsen for LCA10
Splice correction for p.Cys998X CEP290 mRNA
Outer
segment
Connecting
cilium sepofarsen
Inner mRNA
segment
pre-mRNA
Nucleus
DNA
mRNA Exon 26 Exon 27 Exon 26 X Exon 27 Exon 26 Exon 27
sepofarsen
pre-mRNA Exon 26 Exon 27 Exon 26 X Exon 27 Exon 26 X Exon 27
In wild-type cells In p.Cys998X-LCA10 cells Exclusion of the cryptic
CEP290 maintains cilium protein transport exon from the mutated
structure and enables is hampered and the mRNA leads to
normal protein transport outer segment degenerates wild-type CEP290 protein
ProQR Therapeutics – Corporate Presentation 41Phase 1/2 – Baseline Demographics
160µg/80µg cohort, n=6; 2 LP only, 3 BRVT, 1 ETDRS
320µg/160µg cohort, n=5; 3 LP only, 1 BRVT, 1 ETDRS
Baseline BCVA
Gender 2nd CEP290 Allele Age/Group Treated Eye Dose [µg]
[LogMAR]
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
ProQR Therapeutics – Corporate Presentation 42Disposition
>4000 subject treatment-days at two dose levels
6 treated
6 completed
160µg/80µg
roll-over to
12 screened 11 enrolled
extension
5 treated
5 completed
320µg/160µg
1 screen fail
ProQR Therapeutics – Corporate Presentation 43Top-line safety summary
Positive benefit/risk in 160µg/80µg cohort with 50% incidence of lens opacity
Subclinical retinal findings in 320µg/160µg cohort
Cystoid Macular
Cataracts Retinal thinning
Edema
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
ProQR Therapeutics – Corporate Presentation 44320µg/160µg cohort
Less improvement with dose-limiting safety findings
BCVA baseline (LogMAR) Responder Rate
1.9 1.05 4.0 4.0 4.0 Treated eye Contralateral eye
0
-0.1 Responder (%) US EU US EU
Change from baseline (LogMAR)
responder responder responder responder
-0.2 EU threshold threshold threshold threshold
-0.3 US
320μg/160μg (n=5) 20% 20% 0% 0%
-0.4
-0.5
Safety Findings
-0.6
-0.7 320µg/160µg (n=5)
-0.8 Tolerability No issues
-0.9 Systemic safety No issues
-1 Lens opacity 5 findings
4 surgeries. Complete recovery of
Cataract surgery outcome
pre-cataract benefit 4/4 subjects
Retinal findings 4 findings in 3 individuals
CME treated topically with improvement. Retinal thinning stabilized 2-3 months
ProQR Therapeutics – Corporate Presentation 45Sustained improvement in BCVA for at least 1 year
All responses (7/7) were maintained for a minimum of 6 months
after a maintenance dose
All treated (n=11) 160μg/80μg Cohort (n=6)
Impaired 0.2 0.2
Acuity
Change from baseline in BCVA (logMAR)
0 0
-0.2 -0.2 Minimal Clinically
Important Difference
-0.4 -0.4 (MCID) (-0.3 LogMAR)
-0.6 -0.6
-0.8 -0.8
-1 -1
Improved
-1.2 -1.2
Acuity
Treated eye Contralateral
TE eye
CE
ProQR Therapeutics – Corporate Presentation 46Example of a 160µg/80µg responder
7/7 trial subjects with BCVA improvement sustained that benefit
during ≥6-month dosing interval
BCVA (LogMAR) FST (cd/m2) Mobility (Levels)
Impaired 3 Less 0 Less 20
Acuity Sensitive Impairment
-0.2 18
2.5 -0.4
16
-0.6
14
2 -0.8
-1 12
1.5 -1.2 10
-1.4 8
1 -1.6
6
-1.8
4
0.5 -2
-2.2 2
0 -2.4 0
Improved More More
Acuity Sensitive Impairment
Dose Dose Dose
TE blue light TE red light TE
6m interval*
*7/7 trial subjects with BCVA improvement sustained that benefit during ≥6-month dosing interval
ProQR Therapeutics – Corporate Presentation 47Example of homozygous subject
13-letter improvement in BCVA with robust improvement in
mobility and FST
BCVA (LogMAR) FST (cd/m2) Mobility (Levels)
Impaired 0.7 Less 0 Less 20
Acuity Sensitive Impairment
-0.2 18
0.65
-0.4
16
0.6 -0.6
14
-0.8
0.55
-1 12
0.5 -1.2 10
-1.4 8
0.45
-1.6
6
0.4 -1.8
4
-2
0.35
-2.2 2
0.3 -2.4 0
Improved More More
Acuity Sensitive Impairment
Dose
TE blue light TE red light
12m interval
ProQR Therapeutics – Corporate Presentation 48Top-line efficacy data
Target registration dose level: 160µg/80µg (n=6)
Group mean Treated eye Contralateral eye
BCVA (LogMAR) -0.93 -0.22
PMobility Course for LCA10
• Large dynamic range to accommodate lower visual acuity. Grading scores:
Course Light level Score
• Measures functional visual performance using a series of Fail all courses 0
courses at increasing difficulty and multiple light intensities. BRE 100% LED 1
BRE 10% LED 2
HCRE 400 lux 3
• > 2 levels considered meaningful. 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
Backlit Room Exit at 10% High-Contrast Room Exit High-Contrast Visual Low-Contrast Visual
LCVNC 10 lux 17
and 100% backlighting at 1, 50, 400 lux Navigation Challenge at Navigation Challenge at
intensity (Ora, Inc. BRE™) (Ora, Inc. HCRE™) 1, 4, 10, 50, 125, 250, 400 1, 4, 10, 50, 125, 250, 400 LCVNC 4 lux 18
lux (Ora, Inc. HCVNC™) lux (Ora, Inc. LCVNC™) LCVNC 1 lux 19
ProQR Therapeutics – Corporate Presentation 50QR-421a reference slides ProQR Therapeutics – Corporate Presentation 51
∆Exon13 Usherin protein is functional
ERG with light stimulus in zebrafish
Usherin protein (in red) in zebrafish retina
With usherin Without usherin Treated
protein Wild-type range
protein with oligo
Amplitude
Time (ms)
Exon 13 mutant zebrafish without treatment
Treated exon 13 mutant zebrafish
Erwin van Wijk, Radboudumc, Nijmegen, the Netherlands
ProQR Therapeutics – Corporate Presentation 52Visual fields:
Quantifying visual field defects
Usher syndrome Earlier stage disease
Microperimetry
(MAIA) Later stage disease
Potentially viable
photoreceptors
as shown by OCT.
Indicates potential
area of visual
functional
Automated restoration by
perimetry QR-421a
(Octopus)
Dark-adapted
chromatic (DAC)
perimetry
(Medmont)
ProQR Therapeutics – Corporate Presentation 53Visual field measurement
Sensitivity (dB)
Profile plot
Positive outcome:
Evidence of visual field
expansion at few points of
the isopter
Eccentricity (degrees of visual field)
Isopter plot
(Definition isopter: a line of equal
retinal sensitivity in the visual field)
ProQR Therapeutics – Corporate Presentation 54Visual field measurement
Increased visual field
Sensitivity (dB)
Sensitivity (dB)
Profile plot
Eccentricity (degrees of visual field)
Isopter plot
ProQR Therapeutics – Corporate Presentation 55Visual field measurement
Increased visual field
Sensitivity (dB)
Sensitivity (dB)
Profile plot
Eccentricity (degrees of visual field)
Isopter plot
ProQR Therapeutics – Corporate Presentation 56Full Field Stimulus Test (FST)
All study subjects
• 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)
Goal
Directional improvement in treatment group
ProQR Therapeutics – Corporate Presentation 57Visual Acuity
Only applicable in severe patients
Snellen Visual Acuity ETDRS/LogMAR Visual Acuity 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
• Snellen VA chart used in • ETDRS Chart used as Gold Standard
Clinical Practice for assessing VA in Clinical Trials • Noise of assay is likely 0.1
LogMAR (1 line, or
• Alternative VA scales used for VA 5-letters)
with low vision patients
ProQR Therapeutics – Corporate Presentation 58Visual Field (VF)
For moderate patients
• 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)
Medmont device for DAC perimetry
• Measure of visual field in peripheral vision
• Gold standard in measuring VF
• Measures visual field with white light only
Goals
Improvement above the noise of the assay and/or
improvement in hill of vision analysis Perimetry data Hill of Vision visual
ProQR Therapeutics – Corporate Presentation 59Visual Field (VF)
For severe patients
• Micro perimetry (Maia)
• Measures visual field in the macula (0-20°
visual field)
• Measures visual field with white light
Goals
Improvement above the noise of the assay
and/or improvement in hill of vision analysis
ProQR Therapeutics – Corporate Presentation 60OCT – EZ-line
Only applicable in severe patients
• Imaging of the retina through high Normal OCT
resolution OCT
• Visualizes anatomy of the central 6mm
of the retina
Severe Usher Syndrome
• Degeneration of photoreceptor cells in
the macula is visible atPatient Reported Outcomes A range of PRO’s applicable to all subjects in the trial • 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 62
QR-1123 reference slides ProQR Therapeutics – Corporate Presentation 63
QR-1123 is specific for P23H allele
Strong and specific
suppression of P23H in cells QR-1123 is selective for P23H in vivo
ProQR Therapeutics – Corporate Presentation 64QR-1123 preserves ONL and improves ERG in
P23H rat model
QR-1123 surrogate preserves ONL QR-1123 surrogate improves ERG in P23H Tg rat
in P23H Tg rat strong correlation with ONL preservation
mRHO AS03 PBS QR-1123 surrogate Control oligo
Amplitude (µV)
Amplitude (µV)
Light level Light level
Murray et al., 2015 IOVS 56: 6362
ProQR Therapeutics – Corporate Presentation 65QR-1123 reduces retinal degeneration
in humanized P23H mice
Superior
retina
Lens Optic Nerve
Head (ONH)
Inferior
retina
Optic
Superior Nerve Inferior
Head
ProQR Therapeutics – Corporate Presentation 66Additional Appendix ProQR Therapeutics – Corporate Presentation 67
QR-411 for Usher syndrome
Designed to treat genetic eye disease in Usher syndrome
Usher
Develop hearing loss and PE40 mutation affects ~1,000
blindness in childhood and patients in Western world
turn completely blind by
mid adulthood
RNA therapy: QR-411 Strong PoC
For Usher PE40 Strong preclinical PoC in
no therapy available patient retinal model.
Development candidate
selected
√ RNA is established modality in eye Next steps
√ Strong preclinical proof of concept • IND-enabling studies expected to start
in patient retinal organoids in 2020
√ Orphan drug designation • Clinical development similar to QR-421a
ProQR Therapeutics – Corporate Presentation 68QR-1011 for Stargardt’s disease
Stargardt’s disease
Develop blindness in ~7,000 patients with
childhood and turn c.5461-10T>C in ABCA4
completely blind by mid in Western world
adulthood
RNA therapy: QR-1011 Strong PoC
For Stargardt’s c.5461- Preclinical PoC and
10T>C in ABCA4 no efficacy in human mini-
therapy available gene models
√ RNA is established modality in eye Next steps
√ Strong preclinical proof of concept • Progression into patient retinal
organoid model
ProQR Therapeutics – Corporate Presentation 69ProQR spun-off non-core activities
Wings Therapeutics Amylon Therapeutics
Clinical stage company focussed Company focussed on the
on development of life changing development of CNS products with
therapies for Dystrophic initial focus on HCHWA-D
Epidermolysis Bullosa
• Spun out of ProQR in March 2019 with QR-313 for • ProQR incubated the activities of Amylon since 2015
Exon 73 mutations and all other DEB activities and spun the company out in 2017
• Wings will be led by interim CEO Mark de Souza, • The initial focus of Amylon is on its development
former CEO of Lotus Tissue Repair and Hal Landy, program AT-010 for HCHWA-D, a brain disease
former medical advisor to Lotus Tissue Repair and caused by a mutation in beta-amyloid leading to
CMO of Enobia stroke in mid-adulthood
• ProQR has a minority stake and will be eligible for • ProQR retained a majority stake in the company and
milestone and royalty rights to commercial products will be eligible for milestone and royalty rights to
commercial
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