proqr corporate presentation · proqr therapeutics – corporate presentation 2 this presentation...

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


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


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


Wild-type Disease Disease + oligo

RNA

DNA

Protein

RNA

DNA

Protein

RNA

DNA

Protein

ProQR inherited blindness platform


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


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


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


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)


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


Dose 1 Dose 2 Dose 3

Clinically meaningful (-0.3 LogMAR)Im

prov

emen

t

Mobility Course for LCA10


• 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


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


Responder

Non-responder

Full Field Stimulus Test (FST)


Impr

ovem

ent

Measured with blue and red light

BlueTreated Eye

BlueContralateral Eye

RedTreated Eye

RedContralateral Eye

Ocular instability (OCI)


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


No change detected in untreated eye (data not shown)

Sepofarsen Phase 1/2 in LCA10, Luxturna in LCA2


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.


ILLUMINATE study proposed dose regimens


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


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


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



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


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


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


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


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


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


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


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


Normal Visual Field Usher syndrome

Early stage disease

Later stage disease

Visual field defects


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:


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


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


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


Exclusive worldwide license from Ionis Pharma



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


• 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


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


mRNA Rhodopsin

protein

Rhodopsin

Outersegment

Innersegment

Nucleus

Connectingcilium

RNA

DNA

DNA

Rhodopsin

QR-1123 is specific for P23H allele


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


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


Optic Nerve Head (ONH)

Superior retina

Inferiorretina

Lens

Optic NerveHead

Superior Inferior

Preliminary Phase 1/2 trial in adRPP23H patients


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


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


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


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


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




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


QR-313 for dystrophic epidermolysis bullosa


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


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


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


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


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


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


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 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


Facts and figures as of September 2018

IT’S INOUR RNA

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