CREATING MEDICINES for patients in need · • Strong patent portfolio, with protection out to 2033 for QR-010, 2036 for QR-110 and QR-313 and 2037 for QR-421a and QR-411 • Majority

CREATING MEDICINESfor patientsin need

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 pre-clinical 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, 2016 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.

Company overview

RNA platform technology company focused

on developing therapies to treat rare

diseases with well understood causality

with high unmet patient need


• QR-110 for the treatment of Leber's

congenital amaurosis type 10 due to the

p.Cys998X mutation

• Open label phase 1/2 trial ongoing,

• 6 month treatment interim data in

2018; full 12 month treatment results

in 2019

• QR-313 for DEB due to exon 73 mutations

• IND enabling studies completed

• Start phase 1/2 clinical trial names

“WINGS” in H1 2018

• Initial PoC data in 2018

• Full results in early 2019

• QR-421a for the treatment of Usher

syndrome 2A due to exon 13 mutations

• In partnership with Foundation

Fighting Blindness, co-funding $7.5M

• IND enabling work ongoing

• Clinical trial to start around YE 2018

with

• Interim data in H1 2019

• Full data in H2 2019

• QR-010, for the treatment of cystic

fibrosis due to F508del mutation

• Completed 2 clinical trials

• QR-010 was demonstrated safe and

well tolerated

• QR-010 restored CFTR function in NPD

trial and improved respiratory

symptoms

• End of Phase 1 meetings with FDA and

EMA defined path forward for 12 week

Phase 2 trial – pending partnership

• Broad pipeline in genetic eye diseases

and dystrophic epidermolysis bullosa

("DEB") and other CF mutations

• Novel RNA editing platform technology

Axiomer®, recruiting endogenous

system to edit A to I in RNA, potentially

applicable to >20,000 disease causing

mutations

• Partnership with Galapagos NV

(GLPG) on use of Axiomer RNA editing

technology for Fibrosis targets

• Strong patent portfolio, with

protection out to 2033 for QR-010,

2036 for QR-110 and QR-313 and 2037

for QR-421a and QR-411

• Majority shareholder of Amylon

Therapeutics BV, a CNS focused

company

Strong team with proven track record


Management team Supervisory board

Daniel de Boer*Chief Executive Officer

Former supervisory board member

Gerard Platenburg*Chief Innovation Officer

Smital ShahChief Financial Officer

René BeukemaChief Corp. Development

Officer & General Counsel

Robert CornelisseChief People & Organization

David RodmanExecutive Vice President of

Research & Development

Dinko Valerio*Chairman

Alison Lawton

Paul Baart

Antoine Papiernik

Henri Termeer*

James Shannon

* Founding team

Therapeutic Strategy


Well understood causalitySingle gene defect leading to

disease manifestation

Local deliveryFeasible delivery route

to target organ

RNA therapyHighly specific approach for a

wide range of mutations

Expedited developmentExpedited development strategies

to treat patients faster

Patient centricBest-in-class potential high impact

products for patients in need

Genetic rare diseasesLimited treatment options,viable commercial strategy

RNA technology platform

ProQR Therapeutics 6

One therapeutic modality using different MoA’s

Deletion mutation

Splice correction

Exon skippingRepeat

targetingExon

inclusionProtein

modulationAxiomer®

QR-010 for F508del cystic fibrosis

QR-110for LCA10 and QR-411 for Usher syndrome

QR-421afor Usher syndromeand QR-313for DEB andother DEB programs

QRX-504for FuchsEndothelial Corneal Dystrophy

QRX-1011 for Stargardt’sdisease

Ability to use ‘RNA toolbox’ to change the RNA to create modified proteins

Undisclosedtargets

Technology for novel drug development targeting G>A mutations

CF stop codonmutations

Hurlerdisease

PNAS, Zamecnicket al MGH,2004

MTNA, Collin et al, Radboud, 2012

Ritsema et al, ProQR, 2015

Adamson et al., ProQR 2014

Adamson et al., ProQR 2014

Yilmaz Elis et al. 2013

Klein et al, 2014, ProQR

Single stranded RNA oligonucleotides, chemically modified to enhance uptake and increase stabilityOne modality

Variety of mechanisms

ProQR development pipeline


DISCOVERY PRE-CLINICAL DEVELOPMENTPROOF OF

CONCEPT TRIALS

LATE STAGE/REGISTRATIONAL

TRIALS

Cystic FibrosisQR-010 for F508del

QRX-042 for W1282X

QRX-036 for G542X

QRX-052 for R553X

QRX-065 for 621+1G->T

QRX-075 for 1717-1G->A

Ophthalmology

QR-110 for LCA 10

QR-421a for Usher Exon 13

QRX-504 for FECD3

QR-411 for Usher c.7595-2144A>G

QRX-1011 for Stargardt’s

Dystrophic Epidermolysis Bullosa

QR-313 for DEB exon 73

QRX-323 for DEB exon 80

QRX-333 for DEB exon 3

FibrosisPartnered with Galapagos NV

Undisclosed Targets

Central Nervous System

Amylon Therapeutics

AT-010 for HCHWA-D

PARTNERED PROGRAMS

Several Milestones in Next 18 months


Rapid value creation in key therapeutic areas

QR-110 for LCA 10

• Ongoing clinical trial

• 6 month treatment safety and

efficacy data in 2018, 12 month

treatment results in 2019

QR-313 for Dystrophic EB Exon 73


• Phase 1/2 clinical trial to start in 2018,

Initial data expected in 2018

QR-421a for Usher Syndrome Exon 13


• Scheduled to deliver safety and

efficacy data expected in H1 2019

• QR-411 is ready to follow QR-421a

rapidly into the clinic

QR-010 for cystic fibrosis F508del

• Phase 1b and NPD trials

demonstrated safety and efficacy

• Phase 2 program pending partnership

discussions

Axiomer® RNA editing platform

technology

• In vivo PoC achieved

• Strong potential for product dev and

BD

Spin-off of Amylon Therapeutics

• Majority ownership in CNS focused

company with initial focus on

HCHWA-D and then advance to CAA

ProQR inherited blindness platform


Intravitreal delivery targets all cellular layers in retina

• Efficient delivery of oligos

• IVT is a standard

procedure

Chemical modification allows for “naked” delivery

• Long half-life allows for

infrequent dosing

• Enhances cellular uptake

• Reduces immunogenicity

Accelerated Clinical Development

• Genetic eye diseases

provide an opportunity

for accelerated

clinical development and

significant

Translatable optic models

• Sophisticated organoid

model for retinal

dystrophies

QR-110 for LCA 10


LCA 10

Lose sight in first years of life

No therapy available

~2,000 patients with LCA 10 in western world

QR-110

Restore vision/prevent vision loss in patients with LCA 10

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 pre-clinical proof of

concept in human retina in

pre-clinical models

√ Orphan drug designation

√ Fast track designation

Next steps

• Cilinical trial in 6 adult and 6

pediatric patients ongoing,

6 month treatment data

expected in 2018, 12 month

treatment data in mid 2019

ProQR Therapeutics – Corporate Presentation

QR-110 corrects CEP290 mRNA in LCA patient Eye cups

Key takeaways:

• QR-110 shows strong pre-clinical PoC in eye cup retinal organoid model

• Restoration of WT protein in dose dependent way was observed

• QR-110 restored QT mRNA in dose dependent way

• Optic cup model is sophisticated in vitro retinal structure

• PoC established in both homozygous and compound heterozygous models

11

QR-110 treatment in optic cups shows increase in incidence and length of cilia


Untreated

10µM QR-110

PCNArl13

Percentage of Ciliated cells Length of Cilia

Clinical study design – PQ-110-001


Open label, multiple dose, dose escalation study, Phase 1/2

• Twelve p.Cys998X LCA10 patients; adults and

children (≥6yrs)

• 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:

• Pharmacokinetics, FST, mobility testing, visual

acuity, OCT, PRO, ERG, nystagmus tracking,

pupilometry)

• IND and CTA (BE) open

• Orphan drug designation in EU and US

• FDA Fast-track designation

• 6 month treatment data in 2018, 12 month

treatment data in 2019

1 loading dose & 3 maintenance doses over 1 year:

• 160 µg loading dose / 80 µg maintenance dose



= DSMC review

Adult Mid dose

Adult Low dose

Adult High dose

Pediatric Low dose

Pediatric Mid dose

Pediatric High dose

QR-411 and QR-421a for Usher syndrome


Designed to treat genetic eye disease in Usher syndrome

Ushers

Develop hearing loss and blindness in childhood and turn completely blind by mid adulthood

Exon 13 mutations affect ~16,000 patients in western world.PE-40 mutation affects ~1,000 patients in western world

√ RNA is established modality in eye

√ Strong pre-clinical proof of

concept in patient retina

√ Orphan drug designation

Next steps

• Preclinical development initiated,

start clinical trails around YE 2018

with part A data in H1 2019 and part

B data in H2 2019

QR-411

For Usher PE-40No therapy available

For Usher Exon 13No therapy available

QR-421a

In vivo restoration of ERG to wild-type level following Exon-13 deletion


Exon 13 deleted mutant zebrafish

Bands have been Sanger sequenced and confirmed to be Ex13-skipped

Exon 13 skip in zebrafish model AON treated zebrafish shows b-wave ERG amplitude restoration

Exon 12 Exon 14Exon 13

Ush2A Ex13m WT

Ctrl. AON Untreated

Exon 12 Exon 14 Time (ms)

Wild-type range

Am

plitu

de

AON treated Exon 13 mutant

Erwin van Wijk, Radboudumc, Nijmegen, the Netherlands

15

QR-421a Phase 1/2 trial in Usher 2a patients

Dose 2N=1

Dose 3N=1

Part ASingle Dose

Part B6-month Adaptive Multiple Dose

Multiple dose adaptive (n=~13)

Post dose Follow-up

Single dose (n=~3)

DosingintervalInforms MAD

Business update Board meeting February 13th 2018 16

• IND enabling studies are ongoing


• Open Label Phase 1/2 trial

• ~16 Ush2a patients with a mutation in Exon 13

• up to 4 sites in US and select EU countries

• Independent DSMC

• Single high dose in Part A

• 2 doses in Part B

• Primary endpoints

• Safety, tolerability and pharmacokinetics

• Efficacy and pharmcaodynamic endpoints:

• OCT, Visual Acuity, Visual Field, Full field ERG

• Clinical trial start around YE 2018:

• Part A data readout in H1 2019

• Part B data readout in H2 2019

Open label extension

Pivotal

QR-313 for dystrophic epidermolysis bullosa


DEB

Limited life expectancy

Blistering from birth

First product tar-gets most common mutation affecting ~2,000 patients

QR-313

Molecular targeting with potential disease-modification due to long protein half-life

√ Strong pre-clinical proof

of concept

√ Topical formulation based

on existing hydrogel

√ FDA & EMA granted

Orphan drug designation

Next steps

• Start clinical trial in DEB

patients in 2018

• Report interim data from

trial in 2018

• Expedited path to market

projected

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

Restoring the intact skin in DEB


Exon skipping by QR-313 leads to restoration of anchoring fibrils

Pre-mRNA

mRNA

Protein

Anchoringfibrils

Interstitialcollagen fibers

Exon 72 Exon 73 Exon 74


Blister



Exon 72 Exon 74


In healthy skin anchoring fibrils bind dermis to epidermis

In patients the anchoring fibrils are missing leading to disease

After skipping the mutated exon a truncated protein forms functional anchoring fibrils

QR-313 PoC


Collagen 7 in green in dermal fibroblasts

WT Patient Patient treated with QR-313

Delivery of QR-313 (red) in human skin equivalents

epidermis

dermis dermis

epidermis

dermis

Intact skin “Blister” edge “Blister" bed

QR-313 nuclei

C7 protein

2d penetration in dermis 7d penetration in dermis

Delivery of QR-313 (red) in pig – wounded skin

0 scr 25 50 100 200

48 hrs

Full length COL7A1

Exon skip

QR-313 in µM

Exon skip in patient cells

Untreated QR-313

Full length

Exon skip

Exon skip in human skin model

QR-313 phase 1/2 trial in DEB patients


• Placebo controlled, double-blinded phase 1/2 trial

• 8 RDEB exon 73 patients, >2yo (possibility of expansion

to 15 patients for adaptive repowering)

• 10 sites in US and select EU countries

• Independent DSMC

• Dosing 4 weeks, follow-up 8 weeks

• 2 or 3 doses per week depending on bandage change

frequency, 5gram gel (50mg QR-313) per 100cm2 area

• Endpoints

• Primary: Safety, tolerability and exon skip

• Secondary: C7 protein detection (IF), anchoring fibrils (TEM),

wound healing (imaging), skin strength, time to re-blistering


• Readouts:

• Exon skip in 8 patients in Q4 2018

• Wound healing, re-blistering, IF, TEM in mid 2019

ProQR Therapeutics – Board February 13th 2018 20

4 weeks treatment 8 weeks follow up

Start of treatment

Biopsy for exon skip

End of treatment

Biopsy for C7 protein and anchoring fibrils

Monitor wound healing and re-blistering

QR-010 for F508del Cystic fibrosis


QR-010

Aims to stop progression of disease or prevent symptoms and improve quality of life

Inhaled drug for lung delivery and systemic uptake

Single agent for F508del to treat underlying cause of disease

√ 2 positive clinical trials

demonstrating safety and

efficacy in homozygous

F508del patients

√ CFTR function increased in

NPD trial

√ Phase 1b trial demonstrated

efficacy (CFQ-R)

√ QR-010 was safe and well

tolerated

√ Drug activity as

monotherapy

√ Rapid progression from pre-

clinical to clinical stage

(3 years)

√ Fast track designation &

Orphan drug designation

Beyond QR-010 for F508del,

Class 1 stop-codon mutations

• QRX-036 for G542X

• QRX-052 for R553X

• QRX-042 for W1282X

• QRX-065 for 621+1G->T

• QRX-075 for 1717-1G->A

Convenient at home dosing of 3 times a week or less in under 15 minutes

~77,000 CF patients worldwide of which 40% F508del heterozygous and 45% F508del homozygous

QR-010 for cystic fibrosis


Robust functional PoC in every step of development

In Vitro PoC in

3 separate

F508del CF

assays

In Vivo PoC in 2

separate

mouse assays,

including NPD

Pre-clinical In Vitro

and In Vivo PoC

for delivery to CF

diseased lung

Proof on

concept in

Nasal potential

Difference clinical

trial: QR-010

improves CFTR

function in

homozygous

F508del patients

Several single

ascending dose

arms of phase 1b

clinical trial show

that QR-010 is

detected in blood

after inhaled

administration

Promising

safety and

efficacy (CFQ-R)

results in Phase

1b trial in 70

CF patients

Invented by

Paul Zamecnick

at Mass General

Hospital

QR-010 improves CFTR function


Results of “NPD” Study in homozygous F508del patients

Key takeaways:

• QR-010 increased CFTR mediated

total chloride transport response

• Statistically significant response

on Day 26 in per protocol subjects

• Basal PD measurements support

CFTR mediated total chloride

transport data

• Basal PD is direct measurement

of ENaC activity

• Improvement observed across

multiple measures

Different methods to analyze chloride responsePer protocol population (N=7)

Different methods to analyze sodium response per protocol population (N=7)

CFTR mediated total chloride transportper protocol population (N=7)

Sodium transport: average basal potential difference per protocol population (N=7)

*+9.4 mVP = 0.04

*-4.1 mV P = 0.04

Phase 1b Goals and design

• Phase 1b trial in 64 homozygous F508del CF

patients in North America and Europe

• Study included mild CF patients (69.2-115.6%

ppFEV1 baseline) to assess safety in mild

background disease

• Goals: establish safety and tolerability and get

steer on active dose for further development

• Primary endpoints: Safety and tolerability

• Secondary endpoints: PK and exploratory efficacy

endpoints: FEV1, CFQ-R, weight, sweat


Cohort 16.25 mg

DMC review

Cohort 212.5 mg

Cohort 325 mg

Cohort 450 mg

Single Ascending Dose1 dose

8 patients per cohort,

randomized 3:1, double blind,

placebo-controlled

DMC review

DMC review

DMC review

Cohort 56.25 mg

Cohort 612.5 mg

Cohort 725 mg

Cohort 850 mg

Multiple Ascending Dose3 dosings/week x 4 weeks

DMC review

DMC review

DMC review

DMC review

24

Positive efficacy results after 28 day treatment


QR-010 was observed to be safe and well tolerated to date

CFQ-R Respiratory Symptom Score

• Data from multiple dose cohorts

• 3/4 cohorts or 65% of patients improved above the MCID of

4.0 points as described in literature (2009, A. Quittner et al.)

• Promising signal of clinical benefit in CF patients, as

measured by CFQ-R RSS

MCID (4.0)

Pre-specified 70-90%ppFEV1 subgroup (n=20) Pre-specified 70-90%ppFEV1 subgroup (n=20)

FEV1

• Data from multiple dose cohorts

• Patients in per protocol population had high ppFEV1

baseline and therefore limited room for improvement

• A pre-specified subgroup of patients with a lower baseline

showed a trend supporting the findings in CFQ-R RSS

Axiomer® Editing Oligonucleotides (EONs)


Oligonucleotide mediated targeted RNA editing

In-vitro PoC establishedin multiple disease models

Potentially applicable to >20,000 disease-causing

mutations

IP fully owned ProQR far ahead of competition

Capabilities similar toCRISPR, without the key risks

Brings clinical applicabilityof “editing” in reach

Unique RNA editing technology

26

Endogenous editing

EONs designed to recruit natural ADARs

ProQR Therapeutics - Confidential 27

RNA

I

A

ADAR dsRBDs

ADARdeaminase

domain

RNA

Endogenous editing

EONs designed to recruit natural ADARs

ProQR Therapeutics - Confidential 28

Axiomer EON-directed therapeutic editing

RNAEON

I

RNAEON

A

RNA

I

A

ADAR dsRBDs

ADARdeaminase

domain

RNA

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 %

PoC in Hurler mouse model 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® next steps and strategy

Current status

• Axiomer achieved in vitro and in vivo Proof

of concept in hurler model as measured by

RNA sequencing, enzyme and enzymatic

activity

• In vitro PoC in many other models, including

CFTR class I mutations

• In vivo PoC in Hurler animal model

Strategy

• >20,000 disease causing mutations are G>A

mutations

• Axiomer® platform technology can yield

large number of new medicines for

currently untreatable diseases

• ProQR will pursue an active business

development strategy to develop the

platform to its full potential and generate

non-dilutive funding


Broad IP estate

• ProQR built a broad IP estate consisting of

• 18 fully owned patent families

• 6 licenses from academia (MGH, Radboud University and Leiden University)

• Protecting our programs (excluding possible extension):

• QR-010 for F508del through 2033

• QR-110 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

• Freedom to operate searches conducted for all programs


Several Milestones in Next 18 months


Rapid value creation in key therapeutic areas

QR-110 for LCA 10

• Ongoing clinical trial

• 6 month treatment safety and

efficacy data in 2018, 12 month

treatment results in 2019

QR-313 for Dystrophic EB Exon 73


• Phase 1/2 clinical trial to start in 2018,

Initial data expected in 2018

QR-421a for Usher Syndrome Exon 13


• Scheduled to deliver safety and

efficacy data expected in H1 2019

• QR-411 is ready to follow QR-421a

rapidly into the clinic

QR-010 for cystic fibrosis F508del

• Phase 1b and NPD trials

demonstrated safety and efficacy

• Phase 2 program pending partnership

discussions

Axiomer® RNA editing platform

technology

• In vivo PoC achieved

• Strong potential for product dev and

BD

Spin-off of Amylon Therapeutics

• Majority ownership in CNS focused

company with initial focus on

HCHWA-D and then advance to CAA

Amylon Therapeutics


CNS focused spin-off company

• In September 2017 ProQR spun out Amylon Therapeutics BV with

a financing round funded by a group of external investors

• ProQR incubated the activities of Amylon since 2015

• Amylon aims to develop RNA therapeutics for CNS indications

• 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

• Ultra-genetics approach for small genetic disorders with global potential

and expansion possibility to CAA

• ProQR retained a majority shareholding in the company after spin-off

ProQR since 2012

• Based in Leiden, the Netherlands

• 140 employees (30 nationalities)

• 18 fully owned patent families and 6 licenses from academia

• 2014 IPO NASDAQ: PRQR

• Shares outstanding (end Q3 2017): ~25 million

• Cash position (end Q3 2017): € 39.7M

• Raised approximately $20 million in Q4

• Projected cash runway: H2 2019

Facts and figures


IT’S INOUR RNA

Documents

CREATING MEDICINES for patients in need · • Strong patent portfolio, with protection out to 2033 for QR-010, 2036 for QR-110 and QR-313 and 2037 for QR-421a and QR-411 • Majority