Proqr Therapeutics N.v. · NASDAQ:PRQR
Proqr Therapeutics — Investor Day (December 2024)
78 slides from Proqr Therapeutics's investor day presentation, Dec 11, 2024
Slide 1: Investor & Analyst Event December 11, 2024
INVESTOR & ANALYST EVENT December 11, 2024
Slide 2: Agenda and Speakers
1. Welcome & Agenda Sarah Kiely 2. Strategy overview Daniel A. de Boer 3. Axiomer Platform Peter Beal, PhD 4. AX -0810 for Cholestatic Diseases Prof. Gideon Hirschfield, MA, MB Bchir, FRCP, PhD Gerard Platenburg 5. AX -2402 for Rett Syndrome Monica Coenraads, MBA Gerard Platenburg ProQR Therapeutics
Slide 3: Forward-looking statements
Forward-looking statements This presentation 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
Slide 4: Strategic Overview
Presenter: Daniel A. de Boer Strategic Overview ProQR Therapeutics – Investor and Analyst Event 2024 4
Slide 5: Peter Beal, PhD, ProQR Chief ADAR Scientist
ProQR Therapeutics – Investor and Analyst Event 2024 5 Peter Beal, PhD ProQR Chief ADAR Scientist & SAB member, Professor UC Davis • Professor in the Department of Chemistry at the University of California at Davis and Director of the NIH-funded UC Davis Chemical Biology Graduate Program • Advanced
Slide 6: Axiomer advancing to value inflection
Axiomer advancing to value inflection ProQR Therapeutics – Investor and Analyst Event 2024 6 Pipeline with transformative potential for diseases with high unmet medical needs work at root cause Innovative ADAR-enabled RNA editing science driving advancement of Axiomer supported by robust IP estate E
Slide 7: Axiomer Platform
Driving innovation in the ADAR RNA editing field Axiomer Platform ProQR Therapeutics – Investor and Analyst Event 2024 7 Presenter: Peter Beal, PhD
Slide 8: Axiomer RNA-editing platform technology
ProQR Therapeutics – Investor and Analyst Event 2024 8 Axiomer RNA-editing platform technology ADAR: Adenosine deaminase acting on RNA, mRNA: messenger RNA, miRNA: microRNA, lcRNA: long non-coding RNA Versatile • Ability to target multiple organs and a wide range of diseases with numerous applicatio
Slide 9: ProQR's Axiomer ADAR journey since 2014
9 ProQR’s Axiomer ADAR journey since 2014 ProQR Therapeutics – Investor and Analyst Event 2024 ADARs: Adenosine deaminases acting on RNA, EONs: Editing oligonucleotides ProQR and Eli Lilly enter into first 5 target partnership worth $1.25B 2021 ProQR demonstrates >50% editing in CNS and liver in NHP
Slide 10: What is ADAR editing?
ProQR Therapeutics – Investor and Analyst Event 2024 10 What is ADAR editing? Enzyme that performs specific form of natural RNA editing, called A-to-I editing. During A-to-I editing an A nucleotide (adenosine) is changed into an I nucleotide (inosine) ADAR (Adenosine Deaminase Acting on RNA) Inosine
Slide 11: Axiomer EONs attract ADARs for specific editing
By attracting ADARs and allowing highly specific editing ProQR Therapeutics – Investor and Analyst Event 2024 Axiomer EONs unlock cellular machinery potential to treat diseases Natural ADAR editing (A-to-I) ADARs: Adenosine deaminases acting on RNA. RNA Double stranded Adenosine RNA Double stranded
Slide 12: Oligonucleotide-directed RNA editing
Oligonucleotide-directed RNA editing Reference: Doherty EE, Beal PA. Mol Ther. 2022 Jun 1;30(6):2117-2119. ProQR Therapeutics – Investor and Analyst Event 2024 12 Genetics Phenotype Wild type MECP2 gene Functional MECP2 protein W104X mutation Truncated protein UGG UAG Mutation Guide Oligonucleotide
Slide 13: Driving innovation with Axiomer editing oligonucleotides
ProQR Therapeutics – Investor and Analyst Event 2024 13 Driving innovation in the RNA field with Axiomer editing oligonucleotides • A targeting portion for binding to a target RNA incl. target adenosine • A recruitment portion (hairpin structure) for recruiting endogenous ADAR to edit the target ade
Slide 14: Leading research to optimize editing oligonucleotides
No PMe PMe 0 1 2 3 4 Fold-change relative editing % (ddPCR) to no PMe ProQR Therapeutics – Investor and Analyst Event 2024 14 ProQR leading research to optimize editing oligonucleotides for therapeutic use RNA editing of SERPINA1 E366K in A1AD patient hepatocytes Transfection of 100nM EON, N=2, 48 h
Slide 15: Sequence optimization enables stable EONs with prolonged PK
Sequence optimization enables stable editing oligonucleotides with prolonged PK Learnings from advanced programs inform editing optimization ProQR Therapeutics – Investor and Analyst Event 2024 EON11 concentration in liver of mice disease model Hybridization-HPLC, n=6, 30mg/kg, EON11, SC, GalNAc con
Slide 16: Creating a new class of medicines
Mutations correction Thousands of G-to-A mutations, many of them described in literature Alter protein function or include protective variants Modified proteins achieving loss- or gain-of-functions that help addressing or preventing diseases Disrupt >400 different types of PTMs Regulate protein acti
Slide 17: Axiomer RNA editing science translating toward therapeutic applications
ProQR Therapeutics – Investor and Analyst Event 2024 17 Axiomer RNA editing science translating toward therapeutic applications Science • Harnessing advanced knowledge of ADAR and oligonucleotide science • Pioneering the optimization of editing oligonucleotides (EONs) to achieve best-in-class therap
Slide 18: AX-0810 Program: Targeting NTCP for cholestatic diseases
Targeting NTCP to address cholestatic diseases unmet medical need at the root cause AX-0810 Program ProQR Therapeutics – Investor and Analyst Event 2024 18 Presenters: Prof. Gideon Hirschfield, Gerard Platenburg
Slide 19: AX-0810 RNA editing therapy targeting NTCP
ProQR Therapeutics – Investor and Analyst Event 2024 19 AX-0810 RNA editing therapy targeting NTCP for cholestatic diseases Cholestatic diseases have high unmet medical need. Patients accumulate bile acids in liver leading to fibrosis and ultimately liver failure. Initial indications are Primary Scl
Slide 20: Prof. Gideon Hirschfield
Prof. Gideon Hirschfield MA (Oxon), MB BChir (Cantab), PhD, FRCP Professor of Gastroenterology and Hepatology, Toronto, Ontario, Canada ProQR Therapeutics – Investor and Analyst Event 2024 20 • Lily and Terry Horner Chair in Autoimmune Liver Disease Research • Director, The Autoimmune and Rare Liver
Slide 21: AX-0810 RNA editing therapy targeting NTCP
ProQR Therapeutics – Investor and Analyst Event 2024 42 AX-0810 RNA editing therapy targeting NTCP for cholestatic diseases Cholestatic diseases have high unmet medical need. Patients accumulate bile acids in liver leading to fibrosis and ultimately liver failure. Initial indications are Primary Scl
Slide 22: NTCP modulation effects on cholestasis mechanisms
ProQR Therapeutics – Investor and Analyst Event 2024 43 NTCP modulation leads to positive effect on different mechanism involved in cholestasis Zeng J, Fan J, Zhou H. Cell Biosci. 2023 Apr 29;13(1):77; Trauner M, Fuchs CD. Gut 2022;71:194–209; Halilbasic E, Claudel T, Trauner M. J Hepatol. 2013 Jan;
Slide 23: NTCP variants reduce bile acid uptake in healthy population
ProQR Therapeutics – Investor and Analyst Event 2024 44 NTCP variants reduced bile acids uptake into liver in health population research Healthy population discovered with NTCP variants that reduces bile acids uptake into liver1-4 1Salhab A, et al. Gut. 2022 Jul;71(7):1373-1385; 2Ho RH, et al. J Bio
Slide 24: NTCP modulation has hepato-protective effects in vivo
Bulevirtide Bulevirtide Bulevirtide ProQR Therapeutics – Investor and Analyst Event 2024 NTCP modulation has hepato-protective effects in vivo in disease models Bulevirtide (Hepcludex) is a daily SC injected NTCP inhibitor approved for Hepatitis D. Slijepcevic D, et al. Hepatology. 2018 Sep;68(3):10
Slide 25: NTCP modulation leads to clinically meaningful impact in patients
ProQR Therapeutics – Investor and Analyst Event 2024 46 NTCP modulation leads to clinically meaningful impact in patients *NTCP channel is a known transporter for bile acids and hepatitis virus from bloodstream to the liver. Bulevirtide (Hepcludex) is a daily SC injected NTCP inhibitor approved for
Slide 26: AX-0810 modifies the NTCP channel
High concentration of bile acids in hepatocytes AX-0810 modifies the NTCP channel to limit bile acids uptake while preserving all other functions of the channel ProQR Therapeutics – Investor and Analyst Event 2024 47 Human genetics validates NTCP modulation as strategy for cholestatic disease • The
Slide 27: Q68R NTCP variant modulates bile acid re-uptake
ProQR Therapeutics – Investor and Analyst Event 2024 48 Q68R NTCP variant leads to modulation of bile acids re-uptake Glutamine Arginine Hydrophobicity Electrostatic potential • The Q68R variant disrupts some hydrogen bonds and contacts in the Na+ binding pocket. • Clashes are inevitable since the A
Slide 28: Q68R NTCP variant solely affects bile acid re-uptake
ProQR Therapeutics – Investor and Analyst Event 2024 49 Q68R NTCP variant solely affects bile acids re-uptake function Western Blot Analysis Rabbit anti-mFlag Na/K-ATPase** GAPDH* *Loading control for intracellular proteins **Loading control for surface proteins EON: editing oligonucleotide, NTCP: N
Slide 29: EON editing leads to NTCP Q68R variant in hepatocytes
EON mediated RNA editing leads to NTCP Q68R variant in WT hepatocytes Editing of NTCP RNA modulates bile acids reuptake in a dose dependent fashion ProQR Therapeutics – Investor and Analyst Event 2024 50 NTCP: Na-taurocholate cotransporting polypeptide, BAs mentioned in this experiment are specifica
Slide 30: NTCP editing in NHP correlates with plasma bile acids
ProQR Therapeutics – Investor and Analyst Event 2024 51 EON mediated NTCP editing in NHP has linear correlation with bile acids plasma levels NTCP: Na-taurocholate cotransportingpolypeptide, BAs mentioned in this experiment are specifically Tauro-nor-THCA-24-DBD. SLC10A1 is the gene that encodes for
Slide 31: Consistent NTCP editing and biomarker impact in vivo
Plasma TBA in Humanized Mice (N=4, 20mg/kg, 6 doses, GalNac conjugation, SC, D25) Plasma TBA in NHP (N=1, 1-4mg/kg, 4 doses, LNP formulation IV, up to D39) PLASMA TOTAL BILE ACIDS Control EON A 0 2 4 6 Change from Baseline (Fold Change) ProQR Therapeutics – Investor and Analyst Event 2024 52 EON med
Slide 32: Favorable bile acid profile in NHP
NTCP editing demonstrates favorable composition of bile acids profile in NHP Increase in conjugated bile acids confirms NTCP engagement in vivo ProQR Therapeutics – Investor and Analyst Event 2024 53 • Conjugated bile acids are transported by NTCP back to the liver • The observed change in plasma BA
Slide 33: Reduced clearance in bile acids challenge assay in NHP
ProQR Therapeutics – Investor and Analyst Event 2024 54 EON mediated NTCP editing demonstrates reduced clearance in bile acids challenge assay in NHP • TUDCA is a Tauro-conjugated bile acids specifically transported by NTCP from the plasma to the liver • In an NHP experiment using administration of
Slide 34: AX-0810 clinical candidate has enhanced potency
AX-0810 clinical candidate has an enhanced potency profile over EON A in PHH Transfection, n=3, 72 hours, dPCR, mean±SEM AX-0810 clinical candidate selected with enhanced potency and stability profile ProQR Therapeutics – Investor and Analyst Event 2024 55 • AX-0810 clinical candidate is a GalNAc co
Slide 35: GLP tox and CTA enabling activities ongoing for AX-0810
GLP tox studies ProQR Therapeutics – Investor and Analyst Event 2024 56 CTA enabling activities ongoing for AX-0810 In vitro safety screening Delivery method Manufacturing Regulatory • AX-0810 clinical candidate passed in vitro screening for class toxicities • Chemical modifications and Z-base deris
Slide 36: First in human trial of AX-0810
First in human trial of AX-0810 to establish target engagement ProQR Therapeutics – Investor and Analyst Event 2024 57 Integrated single/multiple ascending dose study design Cohort 1 Cohort 2 Cohort 3 Cohort 4 Treatment AX-0810 GalNAc conjugated editing oligo-nucleotide Objectives • Confirm target e
Slide 37: Summary & next steps: AX-0810
Summary & next steps AX-0810 for cholestatic diseases ProQR Therapeutics – Investor and Analyst Event 2024 58 Modulating NTCP activity to reduce hepatic bile acids load is a promising target for hepatoprotection in cholestatic diseases Promising and consistent results reported to date in humanized m
Slide 38: NTCP and bile acids across therapeutic areas
NTCP and bile acids are involved in a variety of therapeutic areas Providing opportunity across multiple indications ProQR Therapeutics – Investor and Analyst Event 2024 59 Cholestatic diseases • Primary Sclerosing Cholangitis (PSC) • Biliary Atresia • Primary Biliary Cholangitis (PBC) • Alagille sy
Slide 39: AX-2402 Program: Targeting MECP2 in Rett Syndrome
Targeting MECP2 to restore protein functionality in Rett Syndrome, a severe neurodevelopmental disorder AX-2402 Program ProQR Therapeutics – Investor and Analyst Event 2024 60 Presenters: Monica Coenraads, MBA and Gerard Platenburg
Slide 40: CNS is a prime target organ for Axiomer
CNS is a prime target organ for Axiomer RNA editing technology • Numerous neurological disorders lack effective therapies, urge for new therapeutic approaches • ADAR enzymes are highly expressed in the brain with very active editing capacity • EONs have shown broad distribution, durability and were
Slide 41: Robust ADAR expression across mouse brain
Robust ADAR expression across cell type and regions in mouse brain Cell type specific expression of Adarb1 and Adarb2 genes ProQR Therapeutics – Investor and Analyst Event 2024 Cell type clusters ADAR1 Glut neurons Thalamus Glut neurons Cerebellum GABA neurons olfactory bulb GABA neurons cortex ADAR
Slide 42: Predictive CNS models for RNA editing
ProQR Therapeutics – Investor and Analyst Event 2024 63 Predictive CNS models to inform development of RNA editing Development of reproducible, region-specific neural stem cell (NSC)-derived spheroids addresses limitations of 3D iPSC-derived organoids, offering a robust and predictive tool for accel
Slide 43: Highly efficient RNA editing in brain organoid
Highly efficient RNA editing in brain organoid recapitulating human cortex Reaching 90% editing in neurospheroids ProQR Therapeutics – Investor and Analyst Event 2024 PFC-like spheroids are composed by 90% neurons and 10% astrocytes and exhibit a 70:30 ratio of excitatory (Glutamatergic) and inhibit
Slide 44: Consistent CNS editing across species
ProQR Therapeutics – Investor and Analyst Event 2024 65 Consistent CNS editing demonstrated across species • Up to 40% editing in vivo leading to 26-fold change in protein function recovery in brain tissues of interest at 4 weeks with a single dose in mice model • In rat, Axiomer EONs demonstrated u
Slide 45: Axiomer potential for CNS diseases
Axiomer holds strong potential to make a meaningful impact to CNS diseases ProQR Therapeutics – Investor and Analyst Event 2024 66 Strong RNA Editing Performance • Robust RNA editing in critical CNS regions validating the efficiency of Axiomer platform in CNS indications Broad Applicability Across C
Slide 46: AX-2402 RNA editing therapy targeting MECP2
ProQR Therapeutics – Investor and Analyst Event 2024 AX-2402 RNA editing therapy targeting MECP2 for Rett Syndrome 67 Rett Syndrome is a devastating and progressive neurodevelopmental disorder caused by variants in the transcription factor Methyl CpG binding protein 2 (MECP2). There is a high unmet
Slide 47: Monica Coenraads, Rett Syndrome Research Trust
• Monica Coenraads’ involvement with Rett syndrome began the day her then-two-year-old daughter was diagnosed with the disorder. A year later, in 1999, she co-founded the Rett Syndrome Research Foundation (RSRF) and held the position of scientific director during the eight years of the Foundation’s
Slide 48: AX-2402 RNA editing therapy targeting MECP2
ProQR Therapeutics – Investor and Analyst Event 2024 AX-2402 RNA editing therapy targeting MECP2 for Rett Syndrome 69 Rett Syndrome is a devastating and progressive neurodevelopmental disorder caused by variants in the transcription factor Methyl CpG binding protein 2 (MECP2). There is a high unmet
Slide 49: MECP2 gene is frequently mutated in Rett syndrome
• MECP2 gene, encoding methyl-CpG binding protein 2 (MeCP2): • Master epigenetic modulator of gene expression and plays a vital role in neuronal maturation and function • Mutations lead to misfolded, truncated or absent protein and loss of function • This loss of MECP2 regulating function leads to R
Slide 50: MECP2 expression level tightly regulated in neurons
MECP2 expression level tightly regulated in neurons Axiomer is a well-suited approach to restore physiological levels of MECP2 ProQR Therapeutics – Investor and Analyst Event 2024 71 • Axiomer approach makes use of ADAR endogenous system to restore physiological levels of functional MECP2 • Axiomer
Slide 51: Axiomer can restore physiological levels of functional MECP2
Axiomer has the potential to restore physiological levels of functional MECP2 AX-2402 correcting MECP2 R270X into WT-like R270W ProQR Therapeutics – Investor and Analyst Event 2024 72 • MeCP2 protein restoration/recovery • MeCP2 R270W (Arg > Trp) mouse model indistinguishable from wild type mice Pos
Slide 52: R270W variant demonstrates wild-type like profile
ProQR Therapeutics – Investor and Analyst Event 2024 73 R270W variant demonstrates wild-type like profile AX-2402 can restore physiological levels of functional MECP2 potentially reverting Rett syndrome into a WT like phenotype1 Severity score (0-12) Probability of survival Body weight (g) Brain wei
Slide 53: EON editing in patient cells restores protein expression
EON mediated editing in patient's cells increases mRNA levels and restores protein expression PTC recoding leading to absent NMD mediated RNA degradation ProQR Therapeutics – Investor and Analyst Event 2024 74 Up to 80 % editing of R270X MECP2 in patient fibroblasts Increased MECP2 RNA levels due to
Slide 54: Preliminary clinical trial design
ProQR Therapeutics – Investor and Analyst Event 2024 75 Preliminary clinical trial design Single dose Repeated dose • Preliminary Phase 1/2 SAD & MAD design • Up to 18 subjects with the R270X mutation • Primary objective: safety, tolerability and pharmacokinetics • Secondary objectives: target engag
Slide 55: AX-1412 Program: Targeting B4GALT1 for cardiovascular disease
Targeting B4GALT1 to reduce the risk of cardiovascular diseases AX-1412 Program ProQR Therapeutics – Investor and Analyst Event 2024 76 Presenter: Gerard Platenburg
Slide 56: AX-1412 RNA editing therapy targeting B4GALT1
ProQR Therapeutics – Investor and Analyst Event 2024 77 AX-1412 RNA editing therapy targeting B4GALT1 for cardiovascular diseases Leading causes of death in the world ~18 million people die from CVDs every year (32% of all global deaths) Despite therapies, the unmet medical need remains. AX-1412 is
Slide 57: B4GALT1 p.Asn352Ser variant reduces CVD risk
ProQR Therapeutics – Investor and Analyst Event 2024 78 B4GALT1 p.Asn352Ser variant reduces CVD risk • It is described that people who carry missense variants like the p.Ans352Ser in B4GALT1, have 36% lower chance of the development of coronary artery disease.1 This variant is known as the “old Amis
Slide 58: Glycosylation is a key process in lipid metabolism
ProQR Therapeutics – Investor and Analyst Event 2024 79 Glycosylation is a key process in lipid metabolism • Glycosylation stabilizes the folding and conformation of apolipoproteins (e.g., ApoB, ApoE), ensuring proper assembly and secretion of lipoproteins such as LDL and HDL. • Glycosylation of rec
Slide 59: B4GALT1 variant reduces galactosylation of CVD risk factors
B4GALT1 p.Asn352Ser variant to reduce galactosylation of CVD risk factors ProQR Therapeutics – Investor and Analyst Event 2024 80 Fibrinogen ApoB EON ADAR Fibrinogen ApoB B4GALT1 mRNA B4GALT1 mRNA B4GALT1 protein B4GALT1-p.Ans352Ser protein Reduction in galactosylation INTRODUCTION OF PROTECTIVE VAR
Slide 60: EON editing of B4GALT1 reduces glycosylation activity
EON-mediated editing of B4GALT1 leads to reduced glycosylation activity In line with natural population ProQR Therapeutics – Investor and Analyst Event 2024 81 1Montasser ME, et al. Science. 2021 Dec 3;374(6572):1221-1227. Percentage of 352Asn B4GALT1 galactosylation activity of 352Asn B4GALT1 and 3
Slide 61: E3L.CETP mice disease model
ProQR Therapeutics – Investor and Analyst Event 2024 82 E3L.CETP mice disease model is industry standard for assessing CVD therapeutics • CETP facilitates the transfer of cholesteryl esters from HDL to VLDL and LDL, a key process in human lipid metabolism that is absent in most rodent models. • Thes
Slide 62: B4GALT1 editing impacts proteins in lipid metabolism
B4GALT1 editing impacts activity of key proteins involved in lipid metabolism Minimal changes in transcript and protein levels associated with decrease in CETP activity in vivo ProQR Therapeutics – Investor and Analyst Event 2024 83 Control EON 1 0 5 10 15 20 Log2 (read_counts) CETP RNA Control EON
Slide 63: B4GALT1 editing affects key biomarkers in E3L.CETP mice
D1 D19 D33 D46 3 4 5 6 7 8 Plasma LDL-c (mM) - 30% ProQR Therapeutics – Investor and Analyst Event 2024 84 EON-mediated editing of B4GALT1 leads to meaningful effect on key biomakers in E3L.CETP Mice Following treatment with EON B, a marked reduction in total cholesterol, ApoB, and LDL-c by observed
Slide 64: B4GALT1 EON shifts lipoprotein profiles
• Treatment with EON B significantly decreases VLDL and LDL cholesterol compared to control • These lipoproteins are associated with increased cardiovascular risk due to their role in atherosclerotic plaque formation • HDL cholesterol which supports reverse cholesterol transport and is associated wi
Slide 65: Summary & next steps: AX-1412
Summary & next steps AX-1412 for CVD ProQR Therapeutics – Investor and Analyst Event 2024 86 EON-mediated RNA editing of B4GALT1 leads to the required reduction in galactosylation reflecting the human genetics observed effect LNP-delivered EON editing B4GALT1 leads to editing and meaningful changes
Slide 66: AX-2911 Program: Targeting PNPLA3 in MASH
Targeting PNPLA3 to address unmet medical needs in MASH AX-2911 Program ProQR Therapeutics – Investor and Analyst Event 2024 87 Presenter: Gerard Platenburg
Slide 67: AX-2911 RNA-editing therapy for MASH
MASH and subsequent stages of liver disease are very prevalent and still on the rise worldwide. MASH individuals have a high unmet medical needs due to the progressive nature of the disease (cirrhosis and hepatocellular carcinoma) and limited therapeutic options available1 PNPLA3 (patatin-like phosp
Slide 68: Axiomer creates PNPLA3 protein with WT-like functionality
PNPLA3 148I (WT) Isoleucine (ATC) PNPLA3 148M (Mutant) Methionine (ATG) PNPLA3 148V (Axiomer de-novo variant) Valine (GTG) ProQR Therapeutics – Investor and Analyst Event 2024 89 Axiomer creates a PNPLA3 protein with WT-like functionality Electrostatic potential Hydrophobicity In silico analysis of
Slide 69: PNPLA3 148V variant has WT-like lipid metabolizing properties
PNPLA3 148V variant has WT-like lipid metabolizing properties 148I and 148V reports equivalence in lipid droplet sizes ProQR Therapeutics – Investor and Analyst Event 2024 90 148I (WT) 148M (mut) 148V (de-novo) Treatment conditions: HeLa cells, plasmid, transfection, 250uM linoleic acids, 24h, cell
Slide 70: EON PNPLA3 editing and lipid droplet change
ProQR Therapeutics – Investor and Analyst Event 2024 91 EON mediated PNPLA3 editing leads to over 50% RNA editing and change in lipid droplet Editing of PNPLA3 in PHH 100nM EON, transfection, 72h, dPCR, mean, SEM, n=3 Change in intracellular lipid droplets post PNPLA3 148V EON treatment in HepG2 Bod
Slide 71: Summary & next steps: AX-2911
Summary & next steps AX-2911 for MASH ProQR Therapeutics – Investor and Analyst Event 2024 92 Final optimization of AX-2911 EONs ongoing for clinical candidate selection in 2025 Development activities to start in 2025 Expected 3-6 monthly dosing interval subcutaneous GalNAc-delivered Start clinical
Slide 72: Closing summary
Daniel A. de Boer Closing summary ProQR Therapeutics – Investor and Analyst Event 2024 93
Slide 73: ProQR development pipeline
DEVELOPMENT PIPELINE AX-0810 for Cholestatic diseases NTCP CTA filing in Q2 2025 ~100K patients AX-2402 for Rett syndrome MECP2 R270X Candidate selection in 2025 ~5K patients AX-1412 for Cardiovascular disease B4GALT1 Scientific update in mid 2025 ~200M patients AX-2911 for MASH PNPLA3 Candidate sel
Slide 74: Catalyst overview
AX-0810 for Cholestatic disease • CTA submission Q2 2025 • Top-line data Q4 2025 AX-2402 for Rett Syndrome • Clinical candidate selection in 2025 • Anticipated trial start and top-line data in 2026 AX-1412 for Cardiovascular disease • Non-clinical data update in mid 2025 AX-2911 for MASH • Clinical
Slide 75: Well positioned to advance Axiomer
Well positioned to advance Axiomer ProQR Therapeutics – Investor and Analyst Event 2024 96 € Clinical trial results across 4 trials in 2025 and 2026 expected • Clinical PoC data of NTCP trial in 2025 • Up to 4 clinical trials with data readouts in 2025/2026 Rich discovery pipeline with potential for
Slide 76: Q&A
Q&A
Slide 77: Q&A
Daniel de Boer Founder and Chief Executive Officer Gerard Platenburg Chief Scientific Officer René Beukema Chief Corporate Development Officer Q&A
Slide 78: ProQR) Win
ProQR) Win OUR RNA