ProQR Corporate Presentation€¦ · AR) BCVA 1st eye 2nd eye Improved Acuity Impaired Acuity-1-0.8-0.6-0.4-0.2 0 m 2) FST More Sensitive Less Sensitive-0.5 0 0.5 1 1.5 2 2.5 3 3.5

CREATING MEDICINESfor patientsin need

Date:

August 2020

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 are based on management's beliefs and

assumptions and on information available to management only as of the

date of this presentation. Our actual results could differ materially from

those anticipated in these forward-looking statements for many reasons,

including, without limitation, the risks, uncertainties and other factors in our

filings made with the Securities and Exchange Commission, including certain

sections of our annual report filed on Form 20-F. These risks and

uncertainties include, among others, the cost, timing and results of

preclinical studies and clinical trials and other development activities by us

and our collaborative partners whose operations and activities may be

slowed or halted by the COVID-19 pandemic; the likelihood of our clinical

programs being executed on timelines provided and reliance on our

contract research organizations and predictability of timely enrollment of

subjects and patients to advance our clinical trials and maintain their own

operations; our reliance on contract manufacturers to supply materials for

research and development and the risk of supply interruption from a

contract manufacturer; the potential for future data to alter initial and

preliminary results of early-stage clinical trials; the unpredictability of the

duration and results of the regulatory review of applications or clearances

that are necessary to initiate and continue to advance and progress our

clinical programs; the ability to secure, maintain and realize the intended

benefits of collaborations with partners; the possible impairment of, inability

to obtain, and costs to obtain intellectual property rights; possible safety or

efficacy concerns that could emerge as new data are generated in research

and development; and general business, financial and accounting risks and

litigation. Given these risks, uncertainties and other factors, you should not

place undue reliance on these forward-looking statements, and we assume

no obligation to update these forward-looking statements, even if new

information becomes available in the future, except as required by law.

3

>2,000,000 people living with Inherited retinal

disease

Very few have a

treatment

ProQR Therapeutics - Corporate Presentation

RNA therapies in pipeline for >100,000 IRD patients

4

QRX-461

for Usher

Syndrome

Sepofarsen

for LCA10

QR-411

for Usher

Syndrome

QR-1123

for P23H adRP

QR-421a

for Usher

Syndrome

Other programs for

mutations causing

IRD’s

QR-1011

for Stargardt’s

Disease

QRX-136

for LCA10

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

45,000

50,000

0

~10,000

~2,000

~1,000 ~2,000

~16,000

~7,000

~500


ProQR at a glance


Patient-focused RNA THERAPEUTICS platform company, developing drugs for RARE INHERITED RETINAL DISEASES

Platform for RNA therapies targeting inherited blindness

Sepofarsen (QR-110) for LCA10 with positive clinical data

• Phase 1/2 top-line results show rapid, significant and durable improvement in vision

• Preliminary data from InSight extension study consistent with benefit seen in Phase

1/2

• Phase 2/3 Illuminate trial ongoing

QR-421a for Usher syndrome Exon 13

• Encouraging findings reported from interim analysis of first two cohorts of Phase

1/2 Stellar trial – dose expansion and dose escalation cohorts underway

QR-1123 for P23H adRP (in-licensed from Ionis)

• Phase 1/2 Aurora trial ongoing; Initial data expected in 2021

QR-504a for Fuchs Endothelial Corneal Dystrophy ready to start clinical trial

Deep pipeline in ophthalmology with targets for multiple additional programs

Cash runway expected to fund operations into 2023

RNA therapies for inherited retinal diseases


Reverse blindness with 1 - 2 routine injections per year

RNA TherapyIntravitreal administration

RNA Therapy characteristics

• Intravitreal injection under local anesthesia

• RNA molecules reach the entire retina, ability to treat

peripheral retinal disease

• Robust improvements in vision observed in clinical trial

• Favorable benefit/risk profile observed in clinical trial

• Naked molecules, no vectors needed for delivery

• Medicines designed to repair a specific mutation

• No changes have to be made to the DNA

Sepofarsen (QR-110) for LCA10

7

LCA10

Lose sight in first years of life

No approved therapy currently available

p.Cys998X mutation affects ~2,000 patients in the Western world

RNA therapy: sepofarsen

Goal: Restore vision/ prevent vision loss in patients with LCA10

Locally adminis-tered in the eye. Routine intra-vitreal procedure

Anticipated infrequent dosing of 2 times a year

√ Established modality in eye

√ Strong preclinical proof of concept in

human retina in preclinical models

√ Top-line Phase 1/2 clinical trial results

showed rapid, significant and durable

activity and was well tolerated

√ Orphan drug designation & Rare pediatric

disease designation

√ FDA Fast track designation and access to

EMA PRIME program



Sepofarsen clinical trials


LCA10

Phase 1/2 (completed)

Phase 1/2 extension(ongoing)

Phase 2/3 (ongoing)

Pediatric(planned)

Mobility(ongoing)

Phase 1/2 + extension trial design

9

Open label, extension trial, LCA10 patients with 1 or 2 copies of p.Cys998X

= DSMC review

Adult 320/160µg dose


Pediatric 160/80µg dose


12 months treatment in worse eyeScreeningbaseline

Analysis 3-month Data + 2nd eye

Extension trial 160/80µg dose

Phase 1/2 Study – 1st eye treatment only Extension Study


Target registration dose – key outcomesPhase 1/2: First eye treated, second eye untreated

10

EyeBCVA – LogMAR

(n=6)Red FST – log cd/m2

(n=6)Blue FST – log cd/m2

(n=6)Mobility course – composite

score (n=6)

Treated 1st eye

-0.93 (0.43)p=0.13 vs. 2nd eye

-0.66 (0.14)p<0.05 vs. 2nd eye

-0.63 (0.31)p=0.09 vs. 2nd eye

4.0 (1.27)p=0.06 vs. 2nd eye

Untreated 2nd eye

-0.22 (0.11) 0.05 (0.17) 0.12 (0.16) 2.7 (1.11)

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Ch

an

ge

in B

CV

A (

Lo

gM

AR

)BCVA

1st eye 2nd eye

Improved

Acuity

Impaired

Acuity

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Ch

an

ge

in F

ST (

log c

d/m

2)

FST

More

Sensitive

Less

Sensitive

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

Ch

an

ge

in M

ob

ility

(le

vels

)

Mobility

1st eye 2nd eye

More

Impairment

Less

Impairment


1st eye red light 2nd eye red light

1st eye blue light 2nd eye blue light

Phase 1/2 extension study - change from baseline to 3 months post dosing

11

Consistent treatment response in both eyes-3

-2.5

-2

-1.5

-1

-0.5

0

BCVA FST Red FST Blue

BC

VA

(Lo

gM

AR

) FS

T (L

og

cd/m

2)

*= 6 month value of 2nd eye as 3 month visit was missed due to COVID-19

X X

-3

-2.5

-2

-1.5

-1

-0.5

0

BCVA FST Red FST Blue BCVA FST Red FST BlueBCVA FST Red FST Blue

Subject P2 Subject P3 Subject P1

1st eye 2nd eye

Subject P11*

(homozygous)


Preliminary data – July 2020

Dir

ect

ion

of

imp

rove

me

nt

Subject P3: Illustration of BCVA improvement

• Baseline:

2.4 LogMAR (20/1000)

• 3 months:

1.12 LogMAR (20/125)

• Improvement:

1.28 LogMAR*

*From being worse than legally blind

to navigating freely, watching tv and

being able to see family faces.


Baseline (2.4 LogMAR) M3 (1.12 LogMAR) M9 (0.58 LogMAR)

Using “Thru My Eyes” App

https://apps.apple.com/us/app/thru-my-eyes-simulator/id1449851701

Ph 1/2 informed Ph 2/3 enrichment strategyAll subjects with baseline of Hand Motion or better responded on BCVA

* = Homozygous subject


Phase 3 population

-2.66

-1.7

-1

-0.8

-0.6

-0.4

-0.2

0

Ch

an

ge

fro

m b

ase

line

(Lo

gM

AR

)

-2.5

P1

4.0

P2

4.0

P3

2.4

P5

2.1

P4

2.45

P7

1.05

Subject

Baseline

P11*

0.63

P8

1.9

P2

4.0

P3

1.66

P1

4.0

P11*

0.48

P10

4.0

P9

4.0

P6

4.0

3 2 1 04LogMARscale

HM CF 20/200 20/20LP

1st eye at 12 months 2nd eye at 3 months (P3 at 6 months)

Dire

ction

of im

pro

vem

en

t

Mean change from baseline In Ph 3 population:

-0.53 LogMAR

FST responses: Subject with LP at baselineLP patients are responders on light sensitivity measure


-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

FST Red FST Blue FST Red FST Blue FST Red FST Blue FST Red FST Blue FST Red FST Blue

P1 P1 P6 P6 P9 P9 P10 P10 P2 P2

Change from Baseline in FST in LP Patients

1st eye at 12 months 2nd eye at 3 months

Dire

ction

of im

pro

vem

en

t

Sepofarsen pivotal Phase 2/3 trial


Actively enrolling

• Double-masked, randomized, controlled,

12-month, multiple dose study

• Could serve as the sole registration trial

• Sites in North America and select EU

countries

• 30+ patients >8 years old

• Multiple IVT injections in both eyes

• First patient dosed in April 2019

• Primary (registration) endpoint:

• Visual Acuity (ETDRS, BRVT)

• Key secondary endpoints

• Mobility course

• Full field stimulus testing (FST)

• Ocular instability (OCI)

• Optical coherence tomography (OCT)

0 month 3 month 6 month 9 month

12 month Primary Endpoint

15 month 18 month 21 month 24 month

sepofarsen: 80 µg loading dose, 40 µg maintenance dose (n=10)

Safety

sepofarsen: 160 µg loading dose, 80 µg maintenance dose (n=10)

Safety

Sham-procedure (n=10) Crossover

= Dose 1st eye = Dose 2nd eye

ILLUMINATE Study: rationale for success

• Clinically significant and durable BCVA improvement data at 12months, a

registrable endpoint

• Target patient population confirmed--all patients with Hand Motion or better in

Ph 1/2 showed VA improvement

• Target registration dose (160/80ug) confirmed

• 6 months dosing interval confirmed

• Positive Benefit:Risk confirmed in Ph 1/2

• Consistent, supportive secondary endpoints data

• 2nd eye dosing confirms Benefit:Risk, responder profile and dose interval


Pivotal trial significantly de-risked—7 reasons to believe

QR-421a for Ush2a


Designed to treat genetic vision loss in Usher syndrome and non-syndromic RP

RNA therapy for Usher & nsRP

Develop hearing and vision loss in childhood and are completely blind by mid adulthood

USH2A exon 13 mutations affect ~16,000 patients in Western world

Approximately 15-25% has exon 13 mutations on both alleles

√ RNA is established modality in eye

√ Strong preclinical proof of concept

in patient-derived retinal model

√ Orphan drug designation & Rare

pediatric disease designation

√ Fast track designation

Partnership

Awarded $7.5Mfinancial support from FFB to conduct trial

ForUSH2A exon 13 no therapy available

Unmet need

QR-421a is targeted to

• Reverse vision loss or stop

disease progression

• Eventually treat asymptomatic

patients based on genetic

diagnosis

QR-421a Phase 1/2 trial in Usher & nsRP


~200 day half-life allows for informative single dose FIH trial design

Stellar Phase 1/2 trial

• Randomized, single ascending dose, global

multicenter, longitudinal, 24-months study

• Goals include safety and efficacy

• Inclusion criteria: visual field of ≥10o

1 month24 months total

DSMC

DSMC

COHORT 150 µg

COHORT 2100 µg

0 month

1 month 3 months0 monthDSMC

= Dose in one eye = DSMC review

• Visual Field (VF) and retinal sensitivity:

Microperimetry, static perimetry, dark-

adapted chromatic perimetry, full-field

stimulus threshold test

COHORT 2B100 µg

Homozygous

COHORT 3200 µg

Interim Analysis 1

24 month masked

follow-up

to measure durability

of effect and inform

dosing interval

Interim Analysis 2

3 months

Key endpoints include:

• Visual acuity (VA): Best-Corrected VA

and Low Luminance VA

• Retinal structure: EZ-area on SD-OCT

• Patient Reported Outcomes

25% of treated subjects defined as responder


1 of 3 homozygous versus 1 of 5 heterozygous subjects demonstrated benefit in multiple outcome measures v. untreated eye

Pattern of Benefit

SubjectBaseline

visual impairment

Genetic background

Dose DaysOCT EZ

areaDAC FST BCVA

Responder 1 Moderate Homozygous 50µg 270

Responder 2 Severe Heterozygous 100µg 120

Mild-moderate disease informative

Severe disease informative= Benefit = No change

QR-421a Interim Analysis summary

Objectives for Interim Analysis

• Explore safety, tolerability and find examples

of responders to inform further development

Safety and tolerability

• A total of more than 1,350 subject-treatment

days at time of Interim Analysis

• No serious ocular or non-ocular Adverse

Events

• No evidence of inflammation, cystoid macular

edema, retinal thinning, or treatment-

associated cataracts

Activity

• 25% (2 of 8) of QR-421a-treated patients

demonstrated a benefit on 3 condordant

endpoints

• None of the patients in the sham control

group had such a response

Summary conclusion of Interim Analysis

• Encouraging responder examples suggest

early signals of target engagement and clinical

activity of QR-421a and support continuing the

trial with expansion and dose escalation to

inform path to registration


Reported in March 2020 after 3 or more months of treatment

QR-1123 for P23H adRP


Gapmer targeting autosomal dominant RP due to the P23H mutation in RHO

P23H adRP

Progressive reduction in night & peripheral vision. Blindness is frequent in mid-adulthood

No therapy available

~2,500 patients with P23H adRP in United States

RNA therapy: QR-1123

Goal: Restore vision/prevent vision loss in patients with P23H adRP

Locally adminis-tered in the eye. Routine intra-vitreal procedure

Anticipated infrequent dosing of 4 times a year or less

√ Established modality in eye

√ Strong preclinical proof of concept in vivo

√ In-licensed from Ionis Pharmaceuticals

√ 2-year Natural History Study is completed

and will be used to accelerate clinical

development

√ Received IND clearance

√ Orphan drug designation

Next steps

• Phase 1/2 trial ongoing, first patient dosed

• Clinical development similar to QR-421a

Aurora Phase 1/2 trial

• Double-masked, randomized, sham controlled

• Goals include safety, tolerability and efficacy

• Up to 35 adult patients

• Initial data expected in 2021

QR-1123 Phase 1/2 trial in adRP patients


1 month

DSMC

75 µg

n=1

0 month

150 µg

n=1

12-month follow up

300 µg

n=3

QR-1123: n=6

Sham: n=2

Single

dose

Multiple dose

(every 3 months)

DSMC

DSMC

Potential to add additional single and multiple dose cohorts at different dose levels

Key endpoints include:

• Visual acuity

• Visual field

• OCT

• Patient Reported Outcomes

= Dose in one eye through intravitreal administration

QR-504a for FECD3


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


√ Rapid delivery to corneal cells


in human primary cell models

Next steps

• Progression into development

RNA therapy: QR-504a

For FECD3 repeat expansion in TCF4No therapy available

Strong preclinical PoC in human primary cell models. Development candidate selected

Strong PoC

Inherited blindness pipeline beyond LCA10 and Usher syndrome


• Sepofarsen Phase 1/2 trial completed


• QR-421a Stellar Phase 1/2 trial interim analysis

complete – dose expansion and dose escalation

cohorts underway

• QR-1123 Phase 1/2 trial ongoing, first data

expected 2021

• Rapidly advancing several undisclosed discovery

stage ophthalmology programs into development

and clinical trials

DISCOVERY PRECLINICAL DEVELOPMENTPROOF OF

CONCEPT TRIALS

LATE STAGE/REGISTRATIONAL

TRIALS

OphthalmologySepofarsen (QR-110) for LCA10 p.Cys998X

QR-421a for Usher syndrome 2A exon 13

QR-1123 for P23H adRP - discovered by Ionis

QR-504a for FECD3

QR-411 for Usher syndrome 2A PE40

QR-1011 for Stargardt’s disease c.5461-10T>C

QRX-461 for Usher syndrome undisclosed mutation

QRX-136 for LCA undisclosed mutation

Several upcoming milestones

Sepofarsen (QR-110) for LCA10

√ Positive top-line results Phase 1/2

announced Q4 2019

√ Phase 2/3 Illuminate trial initiated

• Enrollment ongoing

√ Update on InSight extension study, including

data on second eye treatment

QR-421a for Usher syndrome 2A exon 13

√ Stellar Phase 1/2 trial reported interim data

• Dose expansion and dose escalation cohorts

underway


√ Aurora Phase 1/2 trial underway Q4 2019

• Initial data expected 2021

QR-504a for Fuchs endothelial corneal

dystrophy

• Proof of mechanism study planned

Ophthalmology Pipeline

• Rapidly advancing several discovery

and nonclinical stage ophthalmology

programs to mature into development

and clinical trials


ProQR since 2012

• Based in Leiden, the Netherlands with an office in Cambridge, MA

• 160 employees (35 nationalities)

• 2014 IPO NASDAQ: PRQR

• FD Shares outstanding: ~62 million

• Cash position (Q2 2020) €87.1 million

• $7.5M grant funding awarded by Foundation Fighting Blindness

• €4.8M Innovation Credit from Dutch government for sepofarsen program

• Strategic convertible debt financing agreements with Pontifax and Kreos (Q3 2020)

• Projected cash runway into 2023

• Robust IP estate consisting of 26 fully owned patent families and 8 licenses


Facts and figures

Strong team with proven track record


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 of

Research & Development

Antoine Papiernik

Henri Termeer

James Shannon

Alison Lawton

Dinko ValerioChairman

Tiffany BurtVP Commercial

Leadership team

Aniz GirachChief Medical Officer

Bart Filius

Theresa Heggie

Scientific Advisory Board

28ProQR Therapeutics - Corporate Presentation

Phillip D. Zamore

PhD

Thaddeus Dryja

MD

Art Levin

PhD

James ShannonMD (Chair)

Donald S. Fong

MD

Mike Cheetham

PhD

J. Timothy Stout

MD, PhD, MBA

Martin Maier

PhD

IT’S INOUR RNA

Sepofarsen reference slides


Sepofarsen for LCA10


Splice correction for p.Cys998X CEP290 mRNA

In wild-type cells

CEP290 maintains cilium

structure and enables

normal protein transport

In p.Cys998X-LCA10 cells

protein transport

is hampered and the

outer segment degenerates

Exclusion of the cryptic

exon from the mutated

mRNA leads to

wild-type CEP290 protein

Exon 27Exon 26 XExon 27Exon 26

Exon 26 Exon 27

Outersegment

Innersegment

Nucleus

Connectingcilium

pre-mRNA

DNA

mRNA

sepofarsen

mRNA

pre-mRNA Exon 26 Exon 27X

Exon 27Exon 26

sepofarsen

Exon 26 Exon 27X

Phase 1/2 – trial design


Open label, multiple dose, dose escalation study

• Enrolled 11 LCA10 patients (age range 8-44) with

1 or 2 copies of the p.Cys998X mutation

• Intravitreal injections in one eye

• Participating sites: major sites in EU (UGhent) and

US (UPenn, UIowa)

Objectives:

• Base case: Safety/tolerability & Mechanistic

proof-of-concept (full-field stimulation)

• Up-side: Clinical proof-of-concept (best corrected

visual acuity), Identify target dose, Mobility course

feasibility in LCA10

• Explore: Additional secondary outcome measures

Top-line data, reported in October 2019:

• Validated efficacy of sepofarsen with statistically significant

increase in vision in target registration dose group,

• Established efficacious dose regimen with acceptable

benefit/risk and provides strong guidance for population

enrichment for the pivotal trial.

• Eligible patients will be rolled over into an extension trial

where they will be offered to also get their second eye treated

= DSMC review





12 months treatment in worse eyeScreeningbaseline

Roll-over to extension+ 2nd eye treatment

DSMC

DSMC

DSMC

DSMC

DSMC

Phase 1/2 – Baseline Demographics


160µg/80µg cohort, n=6; 2 LP only, 3 BRVT, 1 ETDRS320µg/160µg cohort, n=5; 3 LP only, 1 BRVT, 1 ETDRS

Gender 2nd CEP290 Allele Age/GroupBaseline BCVA

[LogMAR] Treated Eye Dose [µg]

M c.2503_2504delAC 19 / Adult LP / LP Right 160/80

M c.4723A>T 41 / Adult LP / LP Right 160/80

M c.5668G>T 44 / Adult 2.4 / 2.3 Left 160/80

F c.4438‐3delC 16 / Pediatric 2.5 / 2.5 Right 160/80

M c.6277delG 8 / Pediatric 1.9 / 2.1 Left 160/80

F c.2991+1655A>G 14 / Pediatric 0.6 / 0.6 Left 160/80

F c.3167_3168insA 21 / Adult LP / LP Right 320/160

F c.4723A>T 27 / Adult 1.1 / 0.7 Right 320/160

F c.4393C>T 24 / Adult LP / LP Right 320/160

M c.6277delG 10 / Pediatric 1.9 / 1.4 Right 320/160

F c.547_550delTACC 15 / Pediatric LP / LP Right 320/160

BRVT = Berkley Rudimentary Vision Test (1.7-4.0 LogMAR) | ETDRS = Standard Eye Chart (0.0-1.6 LogMAR)

4.0 LogMAR = Light perception (LP) only | 3.0 LogMAR = Hand motion | 2.0 LogMAR = Finger counting | 1.0 LogMAR = 20/200 | 0.0 LogMAR 20/20

Top-line safety summary


Phase 1/2 (001) study: Positive benefit/risk in 160µg/80µg cohort with 50% incidence of lens opacity; Subclinical retinal findings in 320µg/160µg cohort

CataractsCystoid Macular

EdemaRetinal thinning

SAE/AE 6 SAE (surgery)/2 AE 0 SAE / 2 AE 0 SAE / 2 AE

Dose-dependent incidence Yes Yes Yes

Timing (160μg/80μg cohort) 8-12 months No cases No cases

Timing (320μg/160μg cohort) 3-9 months 3-4 months 3-10 months

Treatment-responsive Yes Yes Stabilized

Example of mobility course


Before and after treatment

Link:https://youtu.be/YqVN3A7I1_4

https://youtu.be/YqVN3A7I1_4

https://youtu.be/YqVN3A7I1_4

Phase 1/2 top-line efficacy resultsPrimary and key secondary outcome measures pooled analysis n=11

Objective AssessmentDirection of

improvement

Responder

threshold

Mean change from

baseline at month 12 (SEM)

Treated eye Untreated eye

Mechanistic

proof-of-

concept

Full field stimulus (FST)

red – log cd/m2 (n=10)↓= improved -0.5

-0.92 (0.18)

p<0.01 vs. CE-0.16 (0.16)

Full field stimulus (FST)

blue – log cd/m2 (n=10)↓= improved -0.5

-0.79 (0.23)

p<0.02 vs. CE0.02 (0.11)

Clinical

proof-of-

concept

Best corrected visual acuity

(BCVA) – LogMAR (n=11)↓= improved -0.3

-0.55 (0.26)

p<0.05 vs. CE-0.11 (0.07)

Secondary

outcome*

Mobility course – composite

score (n=10)↑ = improved 2

2.5 (0.99)

p=0.1 vs. CE1.75 (0.75)

*Additional exploratory outcome measures, including OCI, PLR, OCT, PROs being analyzed


BCVA stratified by dose cohortPrimary outcome measure – mean change in BCVABenefit maintained from month 3 to month 12

Mean ΔBCVALogMAR

Treated eye (SEM) Untreated eye (SEM)

month 3 month 12 month 3 month 12

Pooled analysis

(n=11)-0.50(0.24)

-0.55(0.26)

0.0(0.04)

-0.11(0.07)

160μg/80μg (n=6) -0.81(0.41)

-0.93(0.43)

0.01(0.08)

-0.22(0.11)

320μg/160μg (n=5) -0.13(0.1)

-0.11(0.07)

0.0 (0.0)

0.01(0.04)

Phase

2/3 trial

target

dose


160µg/80µg cohortConsistent improvement with favorable benefit/risk

Responder (%)


US responder threshold

EU responder threshold



160μg/80μg (n=6) 67% 83% 33% 33%

* = homozygous subject

Responder Rate

Safety Findings

-2.66

-1.7

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0*

US

4.0 4.02.4 2.1 2.45 0.63

BCVA baseline (LogMAR)

Ch

an

ge

fro

m b

ase

line

(Lo

gM

AR

)

EU

160μg/80μg (n=6)

Tolerability No issues

Systemic safety No issues

Lens opacity 3 findings

Cataract surgery outcome2 surgeries. Complete recovery of pre-cataract benefit 2/2 subjects

Retinal findings No issues

Safety Findings


-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

320µg/160µg cohortLess improvement with dose-limiting safety findings

BCVA baseline (LogMAR)

Ch

an

ge

fro

m b

ase

line

(Lo

gM

AR

)

4.01.05 4.0

US

EU

4.01.9

Responder (%)






320μg/160μg (n=5) 20% 20% 0% 0%

320µg/160µg (n=5)

Tolerability No issues

Systemic safety No issues

Lens opacity 5 findings

Cataract surgery outcome4 surgeries. Complete recovery ofpre-cataract benefit 4/4 subjects

Retinal findings 4 findings in 3 individuals

Responder Rate

Safety Findings

CME treated topically with improvement. Retinal thinning stabilized 2-3 months


Phase 1/2 showed rapid and sustained benefitTreated Subjects (n=11) across 2 cohorts

40

EyeBCVA – LogMAR

(n=11)Red FST – log cd/m2

(n=10)Blue FST – log cd/m2

(n=10)Mobility course – composite

score (n=10)

Treated (TE)

-0.55 (0.26) p<0.05 vs. CE

-0.91 (0.18)p<0.01 vs. CE

-0.79 (0.23)p<0.02 vs. CE

2.5 (0.99) p=0.1 vs. CE

Untreated (CE) -0.12 (0.07) -0.16 (0.16) 0.02 (0.11) 1.75 (0.75)

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

Ch

an

ge

in B

CV

A (

Lo

gM

AR

)BCVA

1st eye 2nd eye

Improved

Acuity

Impaired

Acuity

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Ch

an

ge

in F

ST (

log c

d/m

2)

FST

More

Sensitive

Less

Sensitive

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

Ch

an

ge

in M

ob

ility

(le

vels

)

Mobility

More

Impairment

Less

Impairment

* Visual acuity and FST peaks associated with cataract occurrence. These subjects regained their pre-cataract visual acuity after surgery.

*


1st eye red light 2nd eye red light

1st eye blue light 2nd eye blue light

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

Subject P2

41

Baseline characteristics

• 41yrs, Male, Heterozygous

• Light Perception, both eyes

Treatment response

• First eye

• Significant and sustained benefit

• Lost benefit after not being redosed in

first eye for 15 months, as expected

• Scheduled to be redosed in first eye

after COVID-19

• Second eye

• Responded the same way as first eye

• Maximum treatment response -2.74 LogMAR

BCVAChange from

baseline

FST redChange from

baseline

FST blueChange from

baseline

160 μg 80 μg 80 μg

-2.66

-2.5

IVT injection1st eye

2nd eye

-1.5

-1

-0.5

0

0.5

1

1.5

2

-2

-1.5

-1

-0.5

0

0.5

1

1.5

Onset of

lens opacity

Lens

replacement

BC

VA

(Lo

gM

AR

)

Dir

ect

ion

of

imp

rove

me

nt

Dir

ect

ion

of

imp

rove

me

nt

FS

T (

log

cd

/m2)

FS

T (

log

cd

/m2)

Dir

ect

ion

of

imp

rove

me

nt


80 μg 80 μg 80 μg

Subject P3

42



• 1st eye: 2.4 LogMAR(HM); 2nd eye: 1.66

LogMAR(CF)

Treatment response

• First eye

• Significant and sustained benefit

• Developed a cataract in first eye at month

20 leading to reduction in BCVA

• Lens replacement completed, follow-up

measurement pending COVID-19

measures to lift

• Second eye


• Maximum treatment response -1.82 LogMAR

160 μg


2nd eye

Onset of

lens opacity

Lens

replacement

-2

-1.5

-1

-0.5

0

0.5

-1.5

-1

-0.5

0

0.5

-2.5

-2

-1.5

-1

-0.5

0

0.5BCVAChange from

baseline

FST redChange from

baseline

FST blueChange from

baseline

BC

VA

(Lo

gM

AR

)

Dir

ect

ion

of

imp

rove

me

nt

Dir

ect

ion

of

imp

rove

me

nt

FS

T (

log

cd

/m2)

FS

T (

log

cd

/m2)

Dir

ect

ion

of

imp

rove

me

nt


-1.28

-0.8

Subject P11

43


2nd eye

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

-0.35

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

-0.25

-0.06

BCVAChange from

baseline

FST redChange from

baseline

FST blueChange from

baseline

BC

VA

(Lo

gM

AR

)

Dir

ect

ion

of

imp

rove

me

nt

Dir

ect

ion

of

imp

rove

me

nt

FS

T (

log

cd

/m2)

FS

T (

log

cd

/m2)

Dir

ect

ion

of

imp

rove

me

nt

160 μg


• 14yrs, Female, Homozygous

• 1st eye: 0.63 LogMAR(20/80); 2nd eye: 0.48

LogMAR(20/50)

Treatment response

• First eye

• Benefit sustained for 15+ months, likely due to

homozygous genotype

• Subject will likely get redosed in first eye

• Second eye



-2.5

-2

-1.5

-1

-0.5

0

0.5

Subject P1

44



• Light Perception, both eyes

Treatment response

• First eye

• No response on BCVA as started trial at

Light perception only

• Meaningful response on FST

• Subject perceives meaningful benefit

• Second eye


160/80 μg 80 μg 80 μg


2nd eye

Onset of

lens opacity

-2.5

-2

-1.5

-1

-0.5

0

0.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

80 μg 80 μg 80 μg

BCVAChange from

baseline

FST redChange from

baseline

FST blueChange from

baseline

BC

VA

(Lo

gM

AR

)

Dir

ect

ion

of

imp

rove

me

nt

Dir

ect

ion

of

imp

rove

me

nt

FS

T (

log

cd

/m2)

FS

T (

log

cd

/m2)

Dir

ect

ion

of

imp

rove

me

nt


Mobility Course for LCA10


Optimized for Phase 2/3 study based on Phase 1/2 trial results

• 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.

• Validation study ongoing

Course Light level Score

Fail all courses

High contrast 400 lux 1







Low contrast 400 lux 8







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™)

Grading scores:

QR-421a reference slides


Disease progression and endpoints


100° 20° 10° 0°

Visual Acuityin Snellen

Visual field in degrees vision

20/20 20/20 No Light Perception

OutcomeMeasures

Disease Progressionwith Patient Age Hearing

impairment

Night blindness(start rod degeneration)

Loss of visual field (rod degeneration)

Loss of central vision(cone degeneration)

Mild to Moderate disease Severe disease

600

Complete blindness(rods and cones degenerated)

Dark-Adapted

Chromatic

PerimetryStatic Perimetry Micro-Perimetry

OCT – EZ area

Best Corrected Visual Acuity

Full-field Stimulation Test

Ranges are illustrative, not exact

20/32

Interim analysis - trial population baseline characteristics

Cohort Genotype PhenotypeVisual

impairment severity

Months of follow-up

50µg (n=4)

3 homozygous1 heterozygous

2 Usher2 nsRP

2 mild-moderate2 severe

6-11

100µg (n=4)


2 Usher2 nsRP


3-4

Sham (n=6)


2 Usher4 nsRP


3-9


Safety and tolerability

• No serious ocular or non-ocular Adverse Events.

• No evidence of inflammation.

• No treatment-associated cataracts.

• No cases of cystoid macular edema or retinal thinning.


A total of more than 1350 subject-treatment days at time of Interim Analysis

-1

0

1

2

3

4

5

6

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

0 4 8 12 16 20 24 28 32 36

-3

-2

-1

0

1

2

3

0 4 8 12 16 20 24 28 32 36

-10

-5

0

5

10

15

20

0 4 8 12 16 20 24 28 32 36

Responder 1 Concordant benefit in FST, EZ area and DAC relative to untreated eye (change from baseline)


Waning response at later time

points informs dosing interval

Direction of

Improvement

Direction of

ImprovementDirection of

Improvement

White FST, CFB

(log cd/m2 left and dB right)

DAC Cyan HoV total V, CFB

(dB.steradian)

EZ area, CFB (%)

Weeks Weeks Weeks

Baseline demographics

• Age/Gender: 30 yo/Female

• Genetic background: Homozygous

• Visual impairment: Moderate

• Visual acuity (BCVA):

• Left eye – 74 letters (Snellen 20/32)

• Right eye (treated) – 70 letters (Snellen 20/40)

• Received a single 50µg dose

Untreated EyeTreated Eye50µg dose x 1

Responder 2Concordant improvement in FST, BCVA and DAC relative to untreated eye (change from baseline)

100µg dose x 1


-14

-12

-10

-8

-6

-4

-2

0

2

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

0 4 8 12

-3-2-1012345678

0 4 8 12 16 20

-10

-5

0

5

10

15

0 4 8 12 16

Direction of

Improvement

Direction of

Improvement

BCVA, CFB (ETDRS letters)

Direction of

Improvement

Untreated EyeTreated Eye

White FST, CFB

(log cd/m2 left and dB right)

DAC Cyan HoV total V, CFB

(dB.steradian)

Baseline demographics

• Age/Gender: 60 yo/Male

• Genetic background: Heterozygous

• Visual impairment: Severe

• Visual acuity (BCVA):

• Left eye (treated) – 33 letters (Snellen 20/250)

• Right eye – 35 letters (Snellen 20/200)

• Received a single 100µg dose

Weeks Weeks Weeks

Progress against trial goals√ Establish early safety and tolerability

• Thus far, generally well tolerated with no serious adverse events

√ Characterize early examples of functional target engagement and if present,

duration of benefit to inform dosing interval

• 2 of 8 QR-421a-treated subjects demonstrated treatment benefit

• 0 of 6 sham-treated subjects met the responder definition

√ Assess utility of various outcome measures in moderate versus advanced disease

√ Inform further dose-ranging and the subject enrichment strategy for next

steps in development

• Enrichment for homozygous exon 13 mutation subjects in the 100µg dose cohort

• Dose escalation to a 200µg dose cohort

Characterize the contributions of drug dose and gene dose

Follow treatment-responsive subjects to characterize the duration

of response and estimate the dosing interval

52ProQR Therapeutics - Corporate Presentation

∆Exon13 Usherin protein is functional


Time (ms)

Wild-type range

Am

plit

ud

e

Treated exon 13 mutant zebrafish

Exon 13 mutant zebrafish without treatment

Erwin van Wijk, Radboudumc, Nijmegen, the Netherlands

ERG with light stimulus in zebrafishUsherin protein (in red) in zebrafish retina

Treated with oligo

With usherinprotein

Without usherin protein

Visual fields:


Quantifying visual field defects

Usher syndrome Earlier stage disease

Later stage disease

Potentially viable

photoreceptors

as shown by OCT.

Indicates potential

area of visual

functional

restoration by

QR-421a

Dark-adaptedchromatic (DAC)perimetry (Medmont)

Microperimetry (MAIA)

Automated perimetry (Octopus)

Visual field measurement


Se

nsi

tivi

ty (

dB

)

Isopter plot(Definition isopter: a line of equal

retinal sensitivity in the visual field)

Positive outcome:

Evidence of visual field

expansion at few points of

the isopter

Profile plot

Eccentricity (degrees of visual field)



Increased visual field

Se

nsi

tivi

ty (

dB

)

Profile plot

Isopter plot

Se

nsi

tivi

ty (

dB

)




Se

nsi

tivi

ty (

dB

)


Isopter plot

Profile plot

Increased visual field

Se

nsi

tivi

ty (

dB

)

Full Field Stimulus Test (FST)

• Test of most sensitive part of the retina

• White light for total retina

• Blue light for rods (mostly peripheral)

• Red light for cones (mostly central macula)


All study subjects

Goal

Directional improvement in treatment group

Visual Acuity

• Snellen VA chart used in

Clinical Practice

Snellen Visual Acuity ETDRS/LogMAR Visual Acuity

• ETDRS Chart used as Gold Standard

for assessing VA in Clinical Trials

• Alternative VA scales used for VA

with low vision patients

Only applicable in severe patients

Goals (in severe

patients only)

• In responder analysis an

improvement of -0.2

LogMAR (2 lines, or

10-letters) is considered

meaningful by EMA

• In responder analysis an

improvement of -0.3

LogMAR (3 lines, or

15-letters) is considered

meaningful by FDA

• Noise of assay is likely 0.1

LogMAR (1 line, or

5-letters)


Visual Field (VF)

• Dark Adapted Chromatic Perimetry (Medmont)

• Measure of visual field in peripheral vision

• Patients are dark adapted prior to measurement

• Measures visual field at different wavelengths (colors)

• Static visual field (Octopus)

• Measure of visual field in peripheral vision

• Gold standard in measuring VF

• Measures visual field with white light only


For moderate patients

Medmont device for DAC perimetry

Hill of Vision visualPerimetry data

Goals

Improvement above the noise of the assay and/or

improvement in hill of vision analysis

Visual Field (VF)

• Micro perimetry (Maia)

• Measures visual field in the macula (0-20°

visual field)

• Measures visual field with white light


For severe patients

Goals

Improvement above the noise of the assay

and/or improvement in hill of vision analysis

OCT – EZ-line

• Imaging of the retina through high

resolution OCT

• Visualizes anatomy of the central 6mm

of the retina

• Degeneration of photoreceptor cells in

the macula is visible at <20° visual field

as depicted by EZ-line


Only applicable in severe patients

Severe Usher Syndrome

Normal OCT

Goal

Restoration of the EZ line after treatment

compared to baseline

Patient Reported Outcomes

• Patient Global Impression of Severity (PGI-S)

Very brief questionnaire about the subject’s (eye) condition

in the past week

• Patient Global Impression of Change (PGI-C)

Very brief questionnaire about the change in the subject’s

condition since he/she started in the study

• Veteran Administration Low Vision Visual Acuity

Functioning Questionnaire (VFQ-20)

20 questions rating how difficult a certain functional task is


A range of PRO’s applicable to all subjects in the trial

QR-1123 reference slides



• 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

Am

plitu

de

(µ

V)

Am

plitu

de

(µ

V)

QR-1123 reduces retinal degeneration in humanized P23H mice


Optic Nerve Head (ONH)

Superior retina

Inferiorretina

Lens

Optic NerveHead

Superior Inferior

Additional Appendix


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

QR-411 for Usher syndrome


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

RNA therapy: QR-411

For Usher PE40no therapy available

Strong preclinical PoC in patient retinal model. Development candidate selected

Strong PoC

Next steps

• IND-enabling studies expected to start

in 2020

• Clinical development similar to QR-421a

QR-1011 for Stargardt’s disease


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 patient retinal

organoid model

RNA therapy: QR-1011

For Stargardt’s c.5461-10T>C in ABCA4 no therapy available

Preclinical PoC and efficacy in human mini-gene models

Strong PoC

ProQR spun-off non-core activities

Wings Therapeutics

Clinical stage company focussed

on development of life changing

therapies for Dystrophic

Epidermolysis Bullosa

• Spun out of ProQR in March 2019 with QR-313 for

Exon 73 mutations and all other DEB activities

• Wings led by CEO Deborah Ramsdall, Executive

Chairman Mark de Souza, PhD, and Chief Medical

Officer Hal Landy, MD

• ProQR has a minority stake and will be eligible for

milestone and royalty rights to commercial products

Amylon Therapeutics

Company focussed on the

development of CNS products with

initial focus on HCHWA-D

• ProQR incubated the activities of Amylon since 2015

and spun the company out in 2017

• The initial focus of Amylon is on its development

program AT-010 for HCHWA-D, a brain disease

caused by a mutation in beta-amyloid leading to

stroke in mid-adulthood

• ProQR retained a majority stake in the company and

will be eligible for milestone and royalty rights to

commercial


Broad IP estate

• ProQR built a broad IP estate consisting of:

• 26 fully owned patent families

• 8 external licenses (Radboud University, Leiden University, INSERM, Ionis Pharmaceuticals,

Rochester)

• Patent terms (excluding possible extension):

• 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


Documents

ProQR Corporate Presentation€¦ · AR) BCVA 1st eye 2nd eye Improved Acuity Impaired Acuity-1-0.8-0.6-0.4-0.2 0 m 2) FST More Sensitive Less Sensitive-0.5 0 0.5 1 1.5 2 2.5 3 3.5