ProQR Corporate Presentation · ProQR Therapeutics –Corporate Presentation 5 DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS LATE STAGE/ REGISTRATIONAL TRIALS Ophthalmology

CREATING MEDICINESfor patientsin need

Date:

June 2020

Nasdaq:

PRQR

Forward looking statements

ProQR Therapeutics – Corporate Presentation 2

This press release contains forward-looking statements. All statements other

than statements of historical fact are forward-looking statements, which are

often indicated by terms such as "anticipate," "believe," "could," "estimate,"

"expect," "goal," "intend," "look forward to", "may," "plan," "potential,"

"predict," "project," "should," "will," "would" and similar expressions. Such

forward-looking statements include, but are not limited to, statements

regarding QR-421a, and the clinical development and the therapeutic

potential thereof, our other programs and business operations, including

timing of commencing clinical trials and enrollment of patients therein, the

expected impact of the COVID-19 on our business operations, including our

research and development plans and timelines and the supply chain for our

clinical and development programs, and our financial position and cash

runway. Forward-looking statements are based on management's beliefs

and assumptions and on information available to management only as of

the date of this press release. 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.

ProQR at a glance


Patient-centric RNA THERAPEUTICS platform company, developing drugs for RARE DISEASES with a focus on 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

• Pivotal 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)

• Preclinical activities and natural history study completed by Ionis

• 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

Cash runway expected to fund operations into H2 2022

RNA therapies for inherited retinal diseases


Reverse blindness with 1 - 2 routine injections per year

RNA TherapyIntravitreal administration

RNA Therapy characteristics

• 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

Opportunity to treat unmet medical need

• >300 genes identified that cause inherited retinal disease with a combined total of >15,000 mutations.

• ProQR’s platform can target 25% of those mutations, currently pursuing a tangible list of >100 targets

ProQR RNA therapy development pipeline


DISCOVERY PRECLINICAL DEVELOPMENTPROOF OF

CONCEPT TRIALS

LATE STAGE/REGISTRATIONAL

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 (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

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

efficacy and favorable benefit/risk

√ Orphan drug designation & Rare pediatric

disease designation

√ FDA Fast track designation and access to

EMA PRIME program

• Pivotal Phase 2/3 Illuminate trial ongoing

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 (TE) Untreated (CE)

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


-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

Treated Eye Contralateral Eye

Improved

Acuity

Impaired

Acuity

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

Ch

an

ge

in F

ST (

cd/m

2)

FST

Treated eye blue light Contralateral eye blue light

Treated eye red light Contralateral eye red light

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

Treated Eye Contralateral Eye

More

Impairment

Less

Impairment

Key outcome measures change month 12 Target registration dose level: 160µg/80µg (n=6) Every six-month dosing interval-maintained benefit


Sepofarsen 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

• 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 first eye = Dose second eye

Ophthalmology pipeline

• Acceptable benefit/risk 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

10


CONCEPT TRIALS


TRIALS

OphthalmologySepofarsen (QR-110) for LCA10 p.Cys998X



QR-504a for FECD3





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

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

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

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

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

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

16ProQR Therapeutics – Corporate Presentation

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

• Phase 2/3 pivotal Illuminate trial ongoing

• 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


CONCEPT TRIALS


TRIALS

OphthalmologySepofarsen (QR-110) for LCA10 p.Cys998X



QR-504a for FECD3





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

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

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 expected

in H2 2020, including data on contralateral

eye treatment


√ 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

• 160 employees (35 nationalities)

• 2014 IPO NASDAQ: PRQR

• FD Shares outstanding: ~57 million (post October 2019 financing)

• Cash position (Q1 2020) €98.1 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 H2 2022

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


Facts and figures

IT’S INOUR RNA

RNA therapies for genetic disease

26

Taking away the underlying cause of disease in the RNA

An RNA therapy repairs the RNA,

without changing the patient’s DNA.

The cell can now perform its

function like a normal cell

In genetic disease a mistake in a

gene, called a mutation, is copied

into the RNA thereby causing

disease

In healthy cells parts of the DNA,

called genes, are copied into RNAs

so the cell can perform its function

Nucleus DNA

RNA

RNA Therapy

Normal cell

(retina)

Diseased cell

(retina)

Treated cell

(retina)

ProQR Therapeutics – Corporate Presentation

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

Adult 320/160µg dose

Adult 160/80µg dose

Pediatric 160/80µg dose

Pediatric 320/160µg dose

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

Disposition>4000 subject treatment-days at two dose levels

12 screened

1 screen fail

11 enrolled

6 treated 160µg/80µg

5 treated 320µg/160µg

6 completed

5 completed

roll-over to extension


Top-line safety summary


Positive benefit/risk in 160µg/80µg cohort with 50% incidence of lens opacitySubclinical 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

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

Mean ΔBCVALogMAR

Treated eye (SEM) Contralateral 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 (%)

Treated eye Contralateral eye

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 (%)

Treated eye Contralateral eye





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


Sustained improvement in BCVA for at least 1 yearAll responses (7/7) were maintained for a minimum of 6 months after a maintenance dose

Minimal Clinically

Important Difference

(MCID) (-0.3 LogMAR)

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

All treated (n=11)

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0.2

160μg/80μg Cohort (n=6)

TE CETreated eye Contralateral eye

Ch

an

ge

fro

m b

ase

line

in B

CV

A (

log

MA

R)

Improved

Acuity

Impaired

Acuity


Example of a 160µg/80µg responder7/7 trial subjects with BCVA improvement sustained that benefit during ≥6-month dosing interval


-2.4

-2.2

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

FST (cd/m2)

TE blue light TE red light

0

0.5

1

1.5

2

2.5

3

BCVA (LogMAR)

Improved

Acuity

Impaired

Acuity

More

Sensitive

Less

Sensitive

More

Impairment

Less

Impairment

Dose Dose Dose

6m interval*

*7/7 trial subjects with BCVA improvement sustained that benefit during ≥6-month dosing interval

0

2

4

6

8

10

12

14

16

18

20

Mobility (Levels)

TE

Example of homozygous subject13-letter improvement in BCVA with robust improvement in mobility and FST


-2.4

-2.2

-2

-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

FST (cd/m2)

TE blue light TE red light

0.3

0.35

0.4

0.45

0.5

0.55

0.6

0.65

0.7

BCVA (LogMAR)

0

2

4

6

8

10

12

14

16

18

20

Mobility (Levels)

Improved

Acuity

Impaired

Acuity

More

Sensitive

Less

Sensitive

More

Impairment

Less

Impairment

Dose

12m interval

Top-line efficacy dataTarget registration dose level: 160µg/80µg (n=6)

Group mean Treated eye Contralateral eye

BCVA (LogMAR) -0.93P<0.01 vs. baseline

-0.22P=N.S. vs. baseline

FST Red (Log) -0.66P<0.01 vs. baseline

0.05P=N.S. vs. baseline

FST Blue (Log) -0.63P<0.01 vs. baseline

0.12P=N.S. vs. baseline

Mobility (levels) +4.0P<0.01 vs. baseline

+2.7P<0.05 vs. baseline


Significance assessed by mixed effects repeated measures model

Summary 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


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 Exit

at 1, 50, 400 lux

(Ora, Inc. HCRE™)

Backlit Room Exit at 10%

and 100% backlighting

intensity (Ora, Inc. BRE™)

Grading scores:

QR-421a reference slides


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

∆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


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


World-class Scientific Advisory Committee

69ProQR Therapeutics – Corporate Presentation

Phillip D. Zamore

PhD

Peter A. Beal

PhD

Thaddeus Dryja

MD

Cy Stein

MDNUCLEIC ACID THERAPEUTICS

Yi-Tao Yu

PhD

Art Levin

PhD

Annemieke Aartsma Rus

PhD

Peter Adamson

PhD

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 · ProQR Therapeutics –Corporate Presentation 5 DISCOVERY PRECLINICAL DEVELOPMENT PROOF OF CONCEPT TRIALS LATE STAGE/ REGISTRATIONAL TRIALS Ophthalmology