Proqr Therapeutics N.v. · NASDAQ:PRQR
Proqr Therapeutics — Investor Day (November 2021)
96 slides from Proqr Therapeutics's investor day presentation, Nov 18, 2021
Slide 1: ProQR Analyst Event November 18, 2021
PROQR ANALYST EVENT November 18, 2021
Slide 2: Forward looking statements
Forward looking statements ProQR Therapeutics - Analyst Event 2021 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, statem
Slide 3: Agenda
Agenda 12:00 – 12:05pm Welcome Sarah Kiely Vice President Investor Relations and Corporate Communications 12:05 – 12:15pm ProQR’s Vision and Strategy Daniel A. de Boer Founder & CEO 12:15 – 12:55pm 12:55 – 1:15pm Sepofarsen QR-421a, QR-1123, QR-504a Aniz Girach, MD Chief Medical Officer 1:15 – 1:35p
Slide 4: ProQR's vision
ProQR’s vision is to become a biotech company that creates and provides multiple life-changing medicines to help create a world where millions of people living with rare genetic eye diseases no longer have to experience vision loss.
Slide 5: Two strategic pillars underpin our approach
Axiomer® A-to-I editing Trident® U-to-Ψ editing Two strategic pillars underpin our approach Operating at the intersection of RNA therapy and genetic eye diseases ProQR Therapeutics - Analyst Event 2021 5 Very few have a treatment Genetic eye diseases RNA editing technologies
Slide 6: >5,000,000 people living with inherited retinal disease
>5,000,000 people living with inherited retinal disease Very few have a treatment 6 ProQR Therapeutics - Analyst Event 2021
Slide 7: RNA therapies in pipeline for >100,000 IRD patients
RNA therapies in pipeline for >100,000 IRD patients 7 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 IRDs QR-1011 for Stargardt Disease QRX-136 for LCA10 5,000 10,000 15,000 20,000 25,000
Slide 8: ProQR pipeline
FULLY OWNED BY PROQR FULLY OWNED BY PROQR LICENSED FROM IONIS FULLY OWNED BY PROQR FULLY OWNED BY PROQR FULLY OWNED BY PROQR FULLY OWNED BY PROQR FULLY OWNED BY PROQR EXCLUSIVE GLOBAL LICENSE YARROW BIOTECHNOLOGY, EXCLUSIVE GLOBAL LICENSE ProQR Therapeutics - Analyst Event 2021 8 ProQR pipeline Sepo
Slide 9: Aniz Girach, MD, Chief Medical Officer
• Chief Medical Officer at Nightstar Therapeutics Overseeing development of gene therapies for IRD (most recently) • Academia and industry experience at Eli Lilly, Merck, Alcon and ThromboGenics (Oxurion) • Development and approval of Ocriplasmin (Jetrea) a first in class biologic therapy for retina
Slide 10: Ocular RNA therapy
Ocular Therapy • Eye is a small and enclosed organ • Cleaner safety profile • Deliver directly into the target organ • Effects of drugs are easily visible • Eye is a relatively immune-privileged site ProQR Therapeutics - Analyst Event 2021 10 Ocular RNA therapy The eye is exquisitely suited to ProQR
Slide 11: IVT administration is a routine procedure
ProQR Therapeutics - Analyst Event 2021 11 IVT administration is a routine procedure 4 3 2 Intravitreal administration A light and a needle are inserted into the eye to locate the place of injection The needle enters the retina, lifting off the retina until a bleb is formed, then depositing drug in
Slide 12: RNA IVT therapy enables broad distribution
ProQR Therapeutics - Analyst Event 2021 12 RNA IVT therapy enables broad distribution Targets central and peripheral diseases Intravitreal administration can target entire retina Sub-retinal procedure treats mainly central [6] mm of retina Treated area Treated area
Slide 13: Sepofarsen for Leber congenital amaurosis
Sepofarsen for Leber congenital amaurosis 10 ProQR Therapeutics - Analyst Event 2021 13
Slide 14: Sepofarsen for LCA10
Sepofarsen for LCA10 Splice correction for c.2991+1655A>G CEP290 mRNA ProQR Therapeutics - Analyst Event 2021 14 In wild-type cells CEP290 maintains cilium structure and enables normal protein transport In c.2991+1655A>G-LCA10 cells protein transport is hampered and the outer segment degenerates Exc
Slide 15: Sepofarsen (QR-110) for CEP290-mediated LCA10
Sepofarsen (QR-110) for CEP290-mediated LCA10 15 LCA10 Lose sight in first years of life No approved therapy currently available c.2991+1655A>G mutation (p.Cys998X) affects ~2,000 patients in the Western world RNA therapy: sepofarsen Goal: Restore vision/ prevent vision loss in patients with LCA10 L
Slide 16: Sepofarsen clinical trials for LCA10
Sepofarsen clinical trials for LCA10 Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Phase 1/2 patients, 2nd eye treatment Mobility (ongoing) Validate the mobility course as an endpoint in clinical trials Pediatric (ongoi
Slide 17: Sepofarsen clinical trials for LCA10
Sepofarsen clinical trials for LCA10 ProQR Therapeutics - Analyst Event 2021 17 Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Phase 1/2 patients, 2nd eye treatment Mobility (ongoing) Validate the mobility course as an e
Slide 18: Sepofarsen Phase 1/2 trial design
Sepofarsen Phase 1/2 trial design LCA10 patients with 1 or 2 copies of c.2991+1655A>G mutation ProQR Therapeutics - Analyst Event 2021 18 Adult 320/160 µg dose Adult 160/80 µg dose Pediatric 160/80 µg dose Pediatric 320/160 µg dose 12 months treatment in worse eye Screening baseline Phase 1/2 Study
Slide 19: Phase 1/2 study safety summary
Phase 1/2 study safety summary Positive benefit/risk in 160/80 µg cohort with 50% incidence of lens opacity; Subclinical retinal findings in 320/160 µg cohort ProQR Therapeutics - Analyst Event 2021 19 Cataracts Cystoid Macular Edema Retinal thinning SAE/AE 6 SAE (surgery)/2 AE 0 SAE / 2 AE 0 SAE /
Slide 20: Ph1/2 key outcomes in target registration dose
Ph1/2 key outcomes in target registration dose Onset of effect within 3 months, sustained out to month 12 in the 160/80 µg dose group (n=6) ProQR Therapeutics - Analyst Event 2021 20 Eye BCVA – logMAR (n=6) Red FST – log cd/m2 (n=6) Blue FST – log cd/m2 (n=6) Mobility course – composite score (n=6)
Slide 21: Sepofarsen clinical trials for LCA10
Sepofarsen clinical trials for LCA10 ProQR Therapeutics - Analyst Event 2021 21 Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Phase 1/2 patients, 2nd eye treatment Mobility (ongoing) Validate the mobility course as an e
Slide 22: Phase 1/2 + InSight extension trial design
Phase 1/2 + InSight extension trial design Open label, extension trial for Phase 1/2 participants ProQR Therapeutics - Analyst Event 2021 22 Adult 320/160 µg dose Adult 160/80 µg dose Pediatric 160/80 µg dose Pediatric 320/160 µg dose Screening baseline Extension trial 160/80 µg dose Phase 1/2 Study
Slide 23: InSight extension study responder overview
InSight extension study Responder overview and qualitative impact summary ProQR Therapeutics - Analyst Event 2021 23 Participant Treated eye Baseline vision BCVA FST Blue FST Red Mobility P1 1st Eye LP no √ √ no 2nd Eye LP no √ √ no P2 1st Eye LP √ √ √ √ 2nd Eye LP √ √ √ no P3 1st Eye HM √ √ √ √ 2nd
Slide 24: InSight extension study responder overview and qualitative impact
InSight extension study Responder overview and qualitative impact summary ProQR Therapeutics - Analyst Event 2021 24 Participant Treated eye Baseline vision BCVA FST Blue FST Red Mobility Qualitative/patient experience P1 1st Eye LP no √ √ no Treatment in both eyes, not missed injection in 4 yrs – S
Slide 25: Case study P11 – homozygous patient
Case study P11 – homozygous patient P11 would be expected to see smaller font and more words compared to baseline ProQR Therapeutics - Analyst Event 2021 25 Reading simulation 14mm’2◇ Before treatment (Baseline) 14 point font, one word After treatment (Month 4) 8 point font, more words Cideciyan, A.
Slide 26: Case study P2 – from LP to being on chart
• Went from “LP” to “on chart” in first eye. Untreated eye stayed at LP for 21 months. Second eye was treated on after 21 months with same response • Called his doctor to say that he could read signs at the airport • As a passenger in the car, started noticing headlights and streetlights • See the n
Slide 27: Case study P3 – from HM to being on eye chart
Participant P3 • Baseline: 2.4 logMAR (20/5000) • 9 months: 0.58 logMAR (20/63) • Improvement: 1.82 logMAR* * From being worse than legally blind to navigating freely, watching TV and being able to see family faces. ProQR Therapeutics - Analyst Event 2021 27 Case study P3 – from HM to being on eye c
Slide 28: Sepofarsen clinical trials for LCA10
Sepofarsen clinical trials for LCA10 Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Phase 1/2 patients, 2nd eye treatment Mobility (ongoing) Validate the mobility course as an endpoint in clinical trials Pediatric (ongoi
Slide 29: Mobility course clinical trial update
ProQR Therapeutics - Analyst Event 2021 29 Mobility course clinical trial update Objective • Study to Evaluate the Feasibility and Variability of Select Vision Assessments in Subjects with a Leber Congenital Amaurosis (LCA) Type Phenotype – validate as an endpoint for clinical trials Status • Trial
Slide 30: Sepofarsen clinical trials for LCA10
Sepofarsen clinical trials for LCA10 Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Phase 1/2 patients, 2nd eye treatment Mobility (ongoing) Validate the mobility course as an endpoint in clinical trials Pediatric (ongoi
Slide 31: Brighten pediatric clinical trial update
Objective • Safety and tolerability study in children under 8 years of age with Leber congenital amaurosis 10 (LCA10) due to the c.2991+1655A>G (p.Cys998X) mutation Design • Open-label dose escalation, followed by a double- masked randomized part • 10 sites in up to 7 countries • Subjects had to hav
Slide 32: Sepofarsen clinical trials for LCA10
Sepofarsen clinical trials for LCA10 Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Phase 1/2 patients, 2nd eye treatment Mobility (ongoing) Validate the mobility course as an endpoint in clinical trials Pediatric (ongoi
Slide 33: Sepofarsen pivotal Phase 2/3 trial
33 Sepofarsen pivotal Phase 2/3 trial Enrollment complete Jan. 2021; topline data expected late Q1/early Q2 ProQR Therapeutics - Analyst Event 2021 0 month 3 month 6 month 9 month 15 month 21 month 24 month 1st Eye 12 month Loading Dose Maintenance Dose Maintenance Dose Maintenance Dose Maintenance
Slide 34: Illuminate – statistical overview
Illuminate – statistical overview • Primary Endpoint: Change from baseline at Month 12 in BCVA (logMAR) in the treated eye compared to sham • Primary Analysis: ANCOVA, baseline BCVA as a covariate (to control baseline BCVA differences across subjects); adjusted for multiplicity • Sepofarsen 160/80 μ
Slide 35: Sepofarsen for CEP290-mediated LCA10
Sepofarsen for CEP290-mediated LCA10 • Robust development program ✓ Completed enrollment in pivotal Phase 2/3 Illuminate trial (January 2021) ✓ Started pediatric Brighten study (Q2 2021) ✓ InSight extension study ongoing • Top-line readout from pivotal Phase 2/3 Illuminate trial in late Q1 / early Q
Slide 36: QR-421a for retinitis pigmentosa and Usher syndrome
QR-421a for retinitis pigmentosa and Usher syndrome ProQR Therapeutics - Analyst Event 2021 36
Slide 37: QR-421a for RP and Usher syndrome
QR-421a for RP and Usher syndrome Skipping of exon 13 in USH2A RNA ProQR Therapeutics - Analyst Event 2021 37 In wild-type cells Ush2A protein enables protein transport through the connecting cilium In cells with the mutation Ush2A protein is not active hampering protein transport through the cilium
Slide 38: QR-421a for USH2A-mediated RP
QR-421a for USH2A-mediated RP Designed to treat genetic vision loss in Usher syndrome & retinitis pigmentosa ProQR Therapeutics - Analyst Event 2021 38 RNA therapy for Usher & nsRP Develop hearing and vision loss in childhood and are completely blind by mid adulthood USH2A exon 13 mutations affect ~
Slide 39: Clinical trials for QR-421a
ProQR Therapeutics - Analyst Event 2021 39 Clinical trials for QR-421a Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Stellar patients, multiple dose & 2nd eye treatment Phase 2/3 in advanced (planned) Potential pivotal
Slide 40: Clinical trials for QR-421a
ProQR Therapeutics - Analyst Event 2021 40 Clinical trials for QR-421a Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Stellar patients, multiple dose & 2nd eye treatment Phase 2/3 in advanced (planned) Potential pivotal
Slide 41: QR-421a Stellar Phase 1/2 safety summary
QR-421a Stellar Phase 1/2 safety summary • QR-421a was well tolerated in >3,700 subject follow up days • No SAEs, no inflammation • Cataracts occur in >30% patients in natural history of disease • 1 patient had worsening of pre-existing cataracts in both the treated and untreated eye with cataract e
Slide 42: Summary of Phase 1/2 Stellar trial results
Summary of Phase 1/2 Stellar trial results Redosing interval established at 6 month ProQR Therapeutics - Analyst Event 2021 42 QR-421a Treated eye Untreated eye BL 4 12 24 36 48 -2 0 2 4 6 8 10 12 14 BL 1 4 8 12 16 24 36 48 -10 -8 -6 -4 -2 0 2 4 6 Weeks Weeks Change in BCVA (ETDRS letters) # of loci
Slide 43: BCVA stabilization in all treated eyes
-10 -8 -6 -4 -2 0 2 4 6 BCVA stabilization in all treated eyes Mean change from baseline in BCVA after single injection ProQR Therapeutics - Analyst Event 2021 43 • Stabilization of vision observed in treated eye vs decline in untreated eye in all patients • Deterioration of untreated eye in line wi
Slide 44: BCVA stabilization driven by advanced population
BCVA stabilization driven by advanced population Mean change from baseline in BCVA after single injection ProQR Therapeutics - Analyst Event 2021 44 • BCVA response is driven by advanced disease population • Stabilization of vision in treated eye after single dose • Mean 9.3 letter benefit at week 4
Slide 45: Clinical trials for QR-421a
ProQR Therapeutics - Analyst Event 2021 45 Clinical trials for QR-421a Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Stellar patients, multiple dose & 2nd eye treatment Phase 2/3 in advanced (planned) Potential pivotal
Slide 46: Helia extension trial
Objectives • Generate further safety and efficacy data for Stellar patients • Repeat dose & 2nd eye treatment (180 μg loading dose followed by 60 μg every 6 months) for both eyes Status • Started to roll over Stellar participants into Helia study Next steps • Update from Helia extension trial by yea
Slide 47: Clinical trials for QR-421a
ProQR Therapeutics - Analyst Event 2021 47 Clinical trials for QR-421a Trial phase Trial objectives Phase 1/2 (completed) Safety & tolerability Phase 1/2 extension (ongoing) Continued treatment for Stellar patients, multiple dose & 2nd eye treatment Phase 2/3 in advanced (planned) Potential pivotal
Slide 48: QR-421 Phase 2/3 trial for Advanced Patients
48 • Double-masked, randomized, sham controlled, 24-month, multiple dose study • Population: • Approx. 80 patients (age ≥ 12 years) • Homozygous and heterozygous, Usher and RP • Baseline BCVA 30 - 68 ETDRS letters in study eye (< 20/40) • Primary endpoint: Change from baseline in BCVA at month 18, v
Slide 49: QR-421 Phase 2/3 trial for Early-Moderate Patients
49 • Double-masked, randomized, sham controlled, 24-month, multiple dose study • Population: • Approx. 120 patients (age ≥ 12 years) • Homozygous and heterozygous, Usher and RP • Baseline BCVA ≥ 69 ETDRS letters in study eye (≥ 20/40) • Primary endpoint: Change from baseline in mean sensitivity usin
Slide 50: QR-421a for Usher syndrome and RP
QR-421a for Usher syndrome and RP • Phase 1/2 Stellar study completed - participants rolled over into Helia extension study • On track to start pivotal Phase 2/3 Sirius and Celeste trials by year end • Update from Helia extension trial by year end 2022 ProQR Therapeutics - Analyst Event 2021 50
Slide 51: QR-1123 for autosomal dominant retinitis pigmentosa
QR-1123 for autosomal dominant retinitis pigmentosa ProQR Therapeutics - Analyst Event 2021 51
Slide 52: Visual acuity loss in selected IRDs
Visual acuity loss in selected IRDs Individuals with adRP will eventually go completely blind, though disease progression is slower than Usher/RP and LCA10 ProQR Therapeutics - Analyst Event 2021 52 Direction of decline BCVA ( logMAR ( snellen )) Illustrative only Normal 20/20 vision Age (years) 0 5
Slide 53: QR-1123 mechanism of action
Rhodopsin Rhodopsin QR-1123 Rhodopsin QR-1123 mechanism of action Blocks expression of toxic P23H mutant RHO protein ProQR Therapeutics - Analyst Event 2021 53 Healthy people inherit two wild type copies of the rhodopsin gene P23H mutant rhodopsin is misfolded and toxic, causing progressive loss of
Slide 54: QR-1123 for P23H adRP
QR-1123 for P23H adRP Gapmer targeting autosomal dominant RP due to the P23H mutation in RHO ProQR Therapeutics - Analyst Event 2021 54 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
Slide 55: QR-1123 Phase 1/2 trial in adRP patients
ProQR Therapeutics - Analyst Event 2021 55 QR-1123 Phase 1/2 trial in adRP patients Single ascending dose = 1st Eye Dose through intravitreal administration DS MC = DSMC review 1 month DS MC 75 µg n=1 0 month 150 µg n=1 12-month follow up 300 µg n=3 DS MC DS MC Single dose 450 µg n=3 DS MC 600 µg n=
Slide 56: QR-1123 Phase 1/2 safety summary
Objective of study was met • Manageable safety profile observed • QR-1123 is well tolerated • No SAEs observed • No cases of retinal thinning • Cataracts • 9 of 11 patients had cataracts in both eyes at baseline • 3 cases of cataract worsening were observed • Cystoid macular edema (CME) • 7 of 11 pa
Slide 57: QR-1123 Phase 1/2 efficacy summary
ProQR Therapeutics - Analyst Event 2021 57 QR-1123 Phase 1/2 efficacy summary Single dose Aurora study • Target engagement was established across majority of patients, across different endpoints • Half life of QR-1123 (gapmer) is 5 weeks • Maximum benefit in BCVA observed after 5 weeks of treatment
Slide 58: QR-1123 next steps
Key take-aways • QR-1123 is well tolerated • Consistent target engagement/efficacy signal with doses 75 μg through 300 μg Next steps • Based on the findings from Aurora, a repeated dosing Phase 2 study is planned with doses up to 300 μg • Endpoints will include BCVA and static perimetry • Study to s
Slide 59: QR-504a for Fuchs endothelial corneal dystrophy
QR-504a for Fuchs endothelial corneal dystrophy ProQR Therapeutics - Analyst Event 2021 59
Slide 60: QR-504a mode of action
QR-504a mode of action Targets TCF4 repeat expansions to normalize splicing processes ProQR Therapeutics - Analyst Event 2021 60 TNR expansions in TCF4 RNA form aggregates (foci) and sequester splice factors, disrupting splicing QR-504a targets the TCF4 RNA (foci) and releases splice factors to re-e
Slide 61: QR-504a for FECD3
ProQR Therapeutics - Analyst Event 2021 61 QR-504a for FECD3 Fuchs Endothelial Corneal Dystrophy Type 3 • Corneal disease leading to blindness in mid-adulthood • Only treatment is corneal transplant • Genetic disease caused by Trinucleotide Repeat (TNR) expansion (>50 repeats) in TCF4 >250,000 patie
Slide 62: Corneal endothelial cell loss causes FECD
Corneal endothelial cell loss causes FECD Underlying molecular mechanism is based on accumulation of abnormally-spliced RNA ProQR Therapeutics - Analyst Event 2021 62 Clinical edema - reduced visual acuity Advanced loss of normal endothelium Subclinical edema -light scatter Fluid accumulation Guttae
Slide 63: MBNL1 example for aberrant splicing in FECD3
• Muscleblind Like Splicing Regulator 1 (MBNL1) has 2 isoforms, termed Long (L) and Short (S) • In patients with FECD3 the ratio of between Long & Short Isoforms is altered • Quantifying splice ratio of MBNL1 transcripts serves as Biomarker for FECD3 ProQR Therapeutics - Analyst Event 2021 63 MBNL1
Slide 64: QR-504a treatment to normalize splicing
• QR-504a is complementary to TNR expansions in TCF4 • Binding of QR-504a to TNRs results in release of the splicing factors (e.g. MBNL1) • Reduction in aberrant splicing should prevent RNA mediated toxicity & cell death in FECD3 ProQR Therapeutics - Analyst Event 2021 64 QR-504a treatment to normal
Slide 65: IVT administered QR-504a shows robust delivery to the corneal endothelium
ProQR Therapeutics - Analyst Event 2021 65 IVT administered QR-504a shows robust delivery to the corneal endothelium • C57BL/6 mice, m/f (12-14 w) • Single IVT injection QR-504a (50 µg) • Detection by Cy5-labeled FISH probe, after 2 days and 14 days post injection, resp. Blue Nuclear stain (DAPI) Re
Slide 66: QR-504a Phase 1b trial in FECD
Fuchs Focus Phase 1b trial • Open-label, single-dose, dose escalation, exploratory study • Goals include safety, tolerability and molecular proof of concept • Approximately 6 adults • Trial open, initial data expected 2022 QR-504a Phase 1b trial in FECD Molecular proof of concept (PoC) to lead to cl
Slide 67: Gerard Platenburg, Chief Innovation Officer
• Co-founded ProQR and has served as our Chief Innovation Officer since 2014 • Extensive background in RNA modulation, orphan drug discovery & development • 25 years of senior managerial experience in growing biotech companies • Previously served as Chief Executive Officer at Isa Pharmaceuticals • C
Slide 68: RNA toolbox – editing platform technologies
Axiomer® and Trident® invented by ProQR ProQR Therapeutics - Analyst Event 2021 68 RNA toolbox – editing platform technologies Axiomer® A-to-I editing • Exploiting endogenous ADAR • Recruited by synthetic Editing Oligonucleotide (EON) • I is translated as a G, allowing to target G-to-A mutations • S
Slide 69: A-to-I RNA Editing platform Axiomer®
A-to-I RNA Editing platform Axiomer® ProQR Therapeutics - Analyst Event 2021 69
Slide 70: ADAR is the body's own system to edit RNA
ProQR Therapeutics - Analyst Event 2021 70 ADAR is the body’s own system to edit RNA EON Target adenosine ADAR deaminase domain Target RNA • ADAR = Adenosine Deaminase Acting on RNA • ADAR is an RNA editing system that is present in all human cells • In the human body, ADAR is responsible for editin
Slide 71: EONs designed to recruit endogenous ADAR
EONs designed to recruit endogenous ADAR ADAR deaminates target A in EON-target RNA complex ProQR Therapeutics - Analyst Event 2021 71 Endogenous editing Editing OligoNucleotide (EON)-directed therapeutic editing RNA EON I RNA I A ADAR dsRBDs ADAR deaminase domain RNA RNA EON A
Slide 72: EONs designed for targeted RNA editing
EONs designed for targeted RNA editing Functionality defined by sequence and chemistry ProQR Therapeutics - Analyst Event 2021 72 Editing Enabling Region (EER) Backbone modifications enable ADAR binding, and disable off-target editing; Provides Stability Sequence defines target RNA binding EON chemi
Slide 73: Optimizing EONs for therapeutic use
Optimizing EONs for therapeutic use Separate screening for potency, stability and bioavailability ProQR Therapeutics - Analyst Event 2021 73 Challenge: Replace defined regions in EONs with new chemical modifications, without compromising ADAR binding and activity. Efficacy optimization: Biochemical
Slide 74: Single nucleotide modification within EER increases EON efficacy
Single nucleotide modification Within EER increases EON efficacy ProQR Therapeutics - Analyst Event 2021 74
Slide 75: Modification improving EON efficacy identified
Modification improving EON efficacy identified Mimicking E488Q mutation in ADAR2 causing hyperactivity ProQR Therapeutics - Analyst Event 2021 75 Metthews 2016, Nature Structural & Molecular Biology ADAR2 DD EON Target RNA Protonation dependent hydrogen bond – pH dependency Protonation independent h
Slide 76: dZ base modification of the EER
dZ base (dZ) modification of the EER dZ improves editing in human retinal pigment epithelial cells ProQR Therapeutics - Analyst Event 2021 76 Editing of adenosine target in human ARPE-19 dZ in EER (EER) 0 40 0 20 10 0 h PP d h PP d cr oc diting ddP R
Slide 77: New chemical optimization for EON ABR region
New chemical optimization For EON ABR region ProQR Therapeutics - Analyst Event 2021 77
Slide 78: New chemical modification of the ABR
New chemical modification of the ABR ABR modification greatly enhances editing ProQR Therapeutics - Analyst Event 2021 78 Backbone modifications enable ADAR binding, and improve stability ADAR-binding region (ABR) • Chemical optimization greatly increases EON editing in positions within ABR region •
Slide 79: Development of Axiomer® for IRD indications
Development of Axiomer® For IRD indications ProQR Therapeutics - Analyst Event 2021 79
Slide 80: ProQR inherited blindness platform
ProQR Therapeutics - Analyst Event 2021 80 ProQR inherited blindness platform Intravitreal delivery is routine procedure • Long half-life in the eye allows for dosing once or twice yearly • Chemical modification enables naked delivery Predictive optic cup model • Sophisticated organoid model for ret
Slide 81: Human retinal organoids
Human retinal organoids Differentiation from induced pluripotent stem cells (iPSC) ProQR Therapeutics - Analyst Event 2021 81 2 days 30 days 45 days 90 days 17 days Photoreceptors 150 days RPE Neural Retina 225 days Photoreceptors, elongated and thickened brush border • Takes 150 days to generate or
Slide 82: Human iPSC-derived retinal organoids
Human iPSC-derived retinal organoids Brief introduction to the model ProQR Therapeutics - Analyst Event 2021 82 Ganglion Cells RPE 0.5 mm Photoreceptors TuJ1 Ganglion Cells Opsin red/green Cones Rhodopsin Rods GC INL ONL
Slide 83: Substantial A-to-I editing in retinal organoids
Substantial A-to-I editing in retinal organoids >40% editing was achieved in IPSC derived organoids ProQR Therapeutics - Analyst Event 2021 83 225 days Retinal organoid • Each chemical modification improves EON editing efficacy • The highest editing efficacy increase is obtained for EONs with all mo
Slide 84: Axiomer® is uniquely positioned in genetic medicines
Axiomer® is uniquely positioned in genetic medicines • Axiomer® edits RNA using the body’s own A-to-I editing machinery – no external enzymes have to be inserted into the cells • Optimizing the EON designs and have shown excellent editing levels in retinal organoid models • ProQR is developing Axiom
Slide 85: An emerging RNA Editing platform Trident®
An emerging RNA Editing platform Trident® ProQR Therapeutics - Analyst Event 2021 85
Slide 86: Trident® RNA editing technology
Trident® RNA editing technology Based on RNA-guided pseudouridylation of selected uridines in RNA ProQR Therapeutics - Analyst Event 2021 86 ψ Translational read through and NMD inhibition Use of endogenously expressed RNA editing machinery Site-specific PTC repair at the RNA level Delivery modality
Slide 87: Targeted pseudouridylation of PTC in RNA
Targeted pseudouridylation of PTC in RNA Translational read-through and nonsense mediated decay (NMD) inhibition ProQR Therapeutics - Analyst Event 2021 87 DNA mRNA UGC ψ AGACG Readthrough protein + Inhibition of mRNA degradation by NMD Translation TGCTAGACG Premature Termination Codon (PTC) UGCUAGA
Slide 88: Optimizing guide-RNA design for therapeutic use
Optimizing guide-RNA design for therapeutic use Computational modelling using Archaeal H/ACA box RNP ProQR Therapeutics - Analyst Event 2021 88 Archaeal H/ACA box RNP (Li et al. 2006 Nature) Single hairpin guide with stems and loops reduced in size In silico, Biophysical, biochemical methods
Slide 89: gRNAs are halved and chemically modified
gRNAs are halved and chemically modified In silico and biochemical screening used to improve design (SAR) ProQR Therapeutics - Analyst Event 2021 89 Natural gRNAs: 130nt ACA ACA H Single Hairpin Pseudouridylation biochemical assay + Different chemical modifications were tested ABCD Modified gRNA
Slide 90: Example in beta-globin
Example in beta-globin • Trident® inhibits NMD (increases PTC-containing mRNA levels), which affects the NMD-sensitive beta-globin gene • PTC insertion leads to decrease in beta-globin protein production • One of the most common nonsense mutations in this gene is Q39X, prevalent in Mediterranean cou
Slide 91: Trident® Pseudouridylation PoC in human cells
Trident® Pseudouridylation PoC in human cells ProQR Therapeutics - Analyst Event 2021 91 “ editerranean” mutation Sequence- and gRNA-specific readthrough and NMD-I effect Increase of beta-globin protein Control gRNA Q39X-specific gRNA 0 2 4 6 8 10 12 Relative % to WT (Globin/MUP) Control gRNA Q39X-s
Slide 92: Trident® scientific progress summary
Trident® scientific progress summary • The Trident® platform has numerous applications in mutation correction and protein modulation • 11% of genetic diseases are caused by premature termination codons (PTCs), in principle correctable with the technology • Specific amino acids can be altered to modu
Slide 93: Milestones
Milestones ProQR Therapeutics - Analyst Event 2021 93
Slide 94: Recent achievements & anticipated milestones
Recent achievements & anticipated milestones ProQR Therapeutics - Analyst Event 2021 94 Sepofarsen for CEP290-mediated LCA10 ✓ Complete enrollment in pivotal Phase 2/3 Illuminate trial (January 2021) ✓ Start pediatric Brighten study (Q2 2021) • Top-line readout from pivotal Phase 2/3 Illuminate tria
Slide 95: The ProQR value proposition
• Axiomer® and Trident® - Leading RNA base-editing platforms • Strong IP portfolio • Validating partnership in Axiomer® with Eli Lilly, deal value up to $1.3B • Large opportunity >20,000 targets for Axiomer® • ProQR ophthalmology targets • Partner other targets • Best in class / first in class • Cli
Slide 96: \ IT’S IN
\ IT’S IN ProQR) ouR RNA