6-K
ProQR Therapeutics N.V. (PRQR)
6-K
2024-12-11
For: 2024-12-11
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April 06, 2026
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 6-K
Report of Foreign Private Issuer
Pursuant to Rule 13a-16 or 15d-16 of
the Securities Exchange Act of 1934
For the month of December 2024
Commission File Number: 001-36622
PROQR THERAPEUTICS N.V.
Zernikedreef 9
2333 CK Leiden
The Netherlands
Tel: +31 88 166 7000
(Address, Including Zip Code, and Telephone Number,
Including Area Code, of Registrant’s Principal Executive Offices)
Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F.
Form 20-F x Form 40-F ¨
Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(1): ¨
Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(7): ¨
On December 11, 2024, ProQR Therapeutics N.V. (“ProQR”) hosted a virtual analyst and investor event to discuss its proprietary Axiomer™ ADAR-mediated RNA editing platform, along with updates on its pipeline of development candidates including data updates and next steps on its programs for NTCP and B4GALT1, AX-0810 and AX-1412. A copy of the presentation is attached hereto as Exhibit 99.1 and is incorporated herein by reference.
ProQR hereby incorporates by reference the information contained herein into ProQR’s registration statements on Form F-3 (File No. 333-282419, File No. 333-270943, and File No. 333-263166).
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.
| PROQR THERAPEUTICS N.V. | ||
|---|---|---|
| Date: December 11, 2024 | By: | /s/ René Beukema |
| René Beukema | ||
| Chief Corporate Development Officer and General Counsel |
INDEX TO EXHIBITS
| Number | Description |
|---|---|
| 99.1 | Presentation of ProQR Therapeutics N.V. for December 11, 2024 Analyst and Investor Event. |
Exhibit 99.1
| INVESTOR<br> & ANALYST<br>EVENT<br>December 11, 2024 | |
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| 1. Welcome & Agenda<br>Sarah Kiely<br>2. Strategy overview<br>Daniel A. de Boer<br>3. Axiomer Platform<br>Peter Beal, PhD<br>4. AX<br>-0810 for<br>Cholestatic Diseases<br>Prof. Gideon Hirschfield, MA,<br>MB Bchir, FRCP, PhD<br>Gerard Platenburg<br>5. AX<br>-2402 for Rett<br>Syndrome<br>Monica Coenraads, MBA<br>Gerard Platenburg<br>ProQR Therapeutics<br> – Investor and Analyst Event 2024<br>2<br>Agenda<br>Speakers<br>6. AX<br>-1412 for CVD<br>Gerard Platenburg<br>7. AX<br>-2911 for MASH<br>Gerard Platenburg<br>8. Summary &<br>Milestones<br>Daniel A. de Boer<br>9. Q&A<br>Daniel A. de Boer<br>Gerard Platenburg<br>René Beukema<br>10. Closing<br>Daniel A. de Boer<br>Monica Coenraads,<br>MBA<br>Founder, CEO at Rett<br>Syndrome Research<br>Trust<br>Prof. Gideon<br>Hirschfield, MA<br>(Oxon) MB BChir<br>(Cantab) FRCP PhD<br>Professor of<br>Gastroenterology and<br>Hepatology, Toronto<br>Centre for Liver<br>Disease<br>Sarah Kiely<br>VP Investor<br>Relations &<br>Corporate Affairs<br>Daniel A.<br>de Boer<br>Founder & CEO<br>Gerard<br>Platenburg<br>Chief Scientific<br>Officer<br>René Beukema<br>Chief Corporate<br>Development<br>Officer<br>Peter Beal, PhD<br>Professor, UC Davis;<br>ProQR Chief ADAR<br>Scientist; SAB member | |
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| Forward-looking statements<br>This presentation contains forward-looking statements. All statements<br>other than statements of historical fact are forward-looking statements,<br>which are often indicated by terms such as "anticipate," "believe,"<br>"could," "estimate," "expect," "goal," "intend," "look forward to", "may,"<br>"plan," "potential," "predict," "project," "should," "will," "would" and<br>similar expressions. Such forward-looking statements include, but are<br>not limited to, statements regarding our strategy and future operations,<br>statements regarding the potential of and our plans with respect to our<br>technologies and platforms (including Axiomer ), our preclinical model<br>data, our pipeline targets, our other programs and business operations,<br>our current and planned partnerships and collaborators and the<br>intended benefits thereof, including the collaboration with Lilly and the<br>intended benefits thereof, including the upfront payment, equity<br>investment, and milestone and royalty payments from commercial<br>product sales, if any, from the products covered by the collaboration, as<br>well as the potential of our technologies and product candidates; our<br>updated strategic plans and the intended benefits thereof, our plans to<br>seek strategic partnerships for our ophthalmology assets, and our<br>financial position and cash runway. Forward-looking statements are<br>based on management's beliefs and assumptions and on information<br>available to management only as of the date of this presentation. Our<br>actual results could differ materially from those anticipated in these<br>forward-looking statements for many reasons, including, without<br>limitation, the risks, uncertainties and other factors in our filings made<br>with the Securities and Exchange Commission, including certain<br>sections of our annual report filed on Form 20-F. These risks and<br>uncertainties include, among others, the cost, timing and results of<br>preclinical studies and other development activities by us and our<br>collaborative partners whose operations and activities may be slowed<br>or halted due to shortage and pressure on supply and logistics on the<br>global market; our reliance on contract manufacturers to supply<br>materials for research and development and the risk of supply<br>interruption from a contract manufacturer; the ability to secure,<br>maintain and realize the intended benefits of collaborations with<br>partners, including the collaboration with Lilly; the possible impairment<br>of, inability to obtain, and costs to obtain intellectual property rights;<br>possible safety or efficacy concerns that could emerge as new data are<br>generated in research and development; general business, operational,<br>financial and accounting risks; and risks related to litigation and<br>disputes with third parties. Given these risks, uncertainties and other<br>factors, you should not place undue reliance on these forward-looking<br>statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the<br>future, except as required by law.<br>ProQR Therapeutics – Investor and Analyst Event 2024 3 | |
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| Presenter: Daniel A. de Boer<br>Strategic Overview<br>ProQR Therapeutics – Investor and Analyst Event 2024 4 | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 5<br>Peter Beal, PhD<br>ProQR Chief ADAR Scientist & SAB member, Professor UC Davis<br> • Professor in the Department of Chemistry at the University of California at Davis and<br>Director of the NIH-funded UC Davis Chemical Biology Graduate Program<br> • Advanced understanding of the structures and mechanism of action for the ADAR<br>enzymes responsible for adenosine to inosine RNA editing in humans<br> • Led in the development of structure-guided methods for optimizing chemically<br>modified oligonucleotides for recruitment of RNA-binding proteins including ADARs<br> • Teaches organic chemistry at the undergraduate level and several classes in nucleic<br>acids chemistry and chemical biology at the graduate level<br> • Over 100 peer-reviewed publications in the field of RNA chemical biology and<br>mentored over 50 Ph.D. and M.S. degree students<br> • ProQR Chief ADAR Scientist, Scientific Advisory Board | |
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| Axiomer advancing<br>to value inflection<br>ProQR Therapeutics – Investor and Analyst Event 2024 6<br>Pipeline with<br>transformative<br>potential for<br>diseases with high<br>unmet medical<br>needs<br>work at root cause<br>Innovative ADAR-enabled RNA editing<br>science driving<br>advancement of<br>Axiomer<br>supported by robust<br>IP estate<br>Experienced team<br>driving execution<br>High impact strategic<br>partnerships<br>Eli Lilly, Rett Syndrome<br>Research Trust<br>Runway into mid 2027<br> €89.4 million cash and<br>cash equivalents as of<br>end of Q3, plus $82.1<br>million gross proceeds<br>from October financing<br>providing runway into<br>mid-2027<br> € | |
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| Driving innovation in the ADAR RNA editing field<br>Axiomer Platform<br>ProQR Therapeutics – Investor and Analyst Event 2024 7<br>Presenter: Peter Beal, PhD | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 8<br>Axiomer RNA-editing platform technology<br>ADAR: Adenosine deaminase acting on RNA, mRNA: messenger RNA, miRNA: microRNA, lcRNA: long non-coding RNA<br>Versatile<br> • Ability to target multiple organs and a wide<br>range of diseases with numerous applications<br> • Potential to include protective variants<br> • Designed to target a variety of RNA species<br>(mRNA, miRNA, lncRNA)<br>Safety<br> • No permanent changes<br> • No irreversible DNA damages and less risk of<br>permanent side effects<br>High specificity<br> • Highly targeted therapeutic with potential to<br>minimize off-target effects and reduce the risk<br>of adverse reactions<br>Transient<br> • Provide a long-lasting therapeutic effect that<br>does not require frequent dosing<br> • Potential to target diseases for which<br>permanent changes would be deleterious<br>No viral vector<br> • No risk of immunogenicity or capacity limitation<br>due to the vector<br> • Efficient development and faster production<br>increase the chance to reach market<br>Endogenous ADARs<br> • Leverage body’s potential to treat disease<br> • Less risk of off-target effect vs. exogenous<br>ADARs | |
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| 9<br>ProQR’s Axiomer ADAR journey since 2014<br>ProQR Therapeutics – Investor and Analyst Event 2024<br>ADARs: Adenosine deaminases acting on RNA, EONs: Editing oligonucleotides<br>ProQR and Eli Lilly<br>enter into first 5<br>target partnership<br>worth $1.25B<br>2021<br>ProQR<br>demonstrates >50%<br>editing in CNS and<br>liver in NHP and<br>announces pipeline<br>2023<br>ProQR files key patents<br>that protect ADAR<br>mediated RNA editing<br>broadly<br>2014-2018+<br>ProQR optimizes<br>the ADAR<br>platform in<br>stealth<br>2015-2021<br>ProQR and Eli Lilly<br>expand<br>partnership to 10<br>targets worth<br>~$3.9B<br>2022<br>2022<br>ProQR pivots to<br>solely focus on<br>ADAR editing<br>2014 2023-2024<br>Key ADAR patents<br>get granted in EU<br>and US<br>2020-2023<br>ProQR’s ADAR<br>patents win<br>opposition cases filed<br>by strawmen across<br>the world<br>ProQR invents oligo<br>mediated RNA<br>Editing recruiting<br>endogenous ADAR<br>2024<br> • ProQR first in the field to<br>report a disease relevant<br>biomarker effect using<br>Axiomer in NHP. Initial<br>indication of good safety<br>profile.<br> • Initial clinical validation of<br>ADAR editing | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 10<br>What is ADAR editing?<br>Enzyme that performs specific form of natural<br>RNA editing, called A-to-I editing. During A-to-I<br>editing an A nucleotide (adenosine) is changed<br>into an I nucleotide (inosine)<br>ADAR (Adenosine Deaminase Acting on RNA)<br>Inosine<br>Adenosine<br>Natural ADAR editing (A-to-I)<br>RNA<br>Double<br>stranded<br>RNA<br>Double<br>stranded<br>ADAR Inosine<br>Adenosine | |
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| By attracting ADARs and allowing highly specific editing<br>ProQR Therapeutics – Investor and Analyst Event 2024<br>Axiomer EONs unlock cellular machinery<br>potential to treat diseases<br>Natural ADAR editing (A-to-I)<br>ADARs: Adenosine deaminases acting on RNA.<br>RNA<br>Double<br>stranded<br>Adenosine<br>RNA<br>Double<br>stranded<br>ADAR Inosine<br>Editing Oligonucleotide (EON)-directed<br>therapeutic editing (A-to-I)<br>RNA+EON<br>Double<br>stranded<br>EON<br>ADAR Inosine<br>RNA<br>Single<br>stranded<br>Adenosine<br>11 | |
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| Oligonucleotide-directed RNA editing<br>Reference: Doherty EE, Beal PA. Mol Ther. 2022 Jun 1;30(6):2117-2119.<br>ProQR Therapeutics – Investor and Analyst Event 2024 12<br>Genetics Phenotype<br>Wild type<br>MECP2 gene<br>Functional<br>MECP2 protein<br>W104X<br>mutation<br>Truncated<br>protein<br>UGG UAG<br>Mutation<br>Guide Oligonucleotide<br>Target transcript with corrective edit<br>Target transcript<br>+<br>5’- -3’<br>5’- -3’<br>5’- -3’<br>3’- -5’<br>ADAR | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 13<br>Driving innovation in the RNA field with<br>Axiomer editing oligonucleotides<br> • A targeting portion for binding to a target RNA incl. target<br>adenosine<br> • A recruitment portion (hairpin structure) for recruiting<br>endogenous ADAR to edit the target adenosine<br>EON<br>ADAR<br>Targeting<br>portion<br>Recruitment<br>portion<br>A-to-I edit<br>Target RNA<br>EON<br>Target RNA<br>ADAR<br>A-to-I edit<br>Patents: Granted appeal pending EP 3 234 134 B1; Granted US 10,676,737; Granted US 11,781,134 Patents: Granted US 10,941,402; Granted US 11,851,656; Allowed US 18/296,912<br><br>1st Axiomer EONs generation<br>relate to (chemically modified) oligonucleotides that comprise<br>2ndAxiomer EONs generation<br>relate to oligonucleotides that comprise<br> • No hairpin structure<br> • One or more wobbles and/or mismatches, and chemical<br>modifications in the base, ribose sugar and/or linkage to<br>increase activity as well as stability and are still able to<br>recruit endogenous ADAR to edit the target adenosine. | |
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| No PMe PMe<br>0<br>1<br>2<br>3<br>4<br>Fold-change relative editing %<br>(ddPCR) to no PMe<br>ProQR Therapeutics – Investor and Analyst Event 2024 14<br>ProQR leading research to optimize editing<br>oligonucleotides for therapeutic use<br>RNA editing of SERPINA1 E366K in<br>A1AD patient hepatocytes<br>Transfection of 100nM EON, N=2, 48 hours<br>hA1AD dC hA1AD dZ<br>0<br>2<br>4<br>6<br>8<br>10<br>Fold change editing % (ddPCR)<br>relative to dC<br>Adapted from Doherty EE, et al. Nucleic Acids Res. 2022;50(19):10857-10868. Statistical significance between groups was determined using one-way<br>ANOVA with Tukey’s multiple comparisons test or an unpaired t-test with Welch’s correction; **P < 0.01; ***P < 0.001; ****P < 0.0001.<br>dZ in EER to increase ADAR activity PN and PMe linkages in the ABR to increase stability,<br>EON liver concentration and target engagement<br>Modification of the orphan base<br>In vitro deamination kinetics for ADAR2 and<br>duplex RNAs derived from hMECP2 R255X<br>100nM ADAR2, 3 technical replicates, mean, SD<br>3-deaza-dA in EER to increase editing activity<br>in 5’G unfavorable context<br>Modification of the base opposite to 5’g Linkage modifications in the ABR<br>14<br>Phosphoroamidate linkage<br>RNA editing of ActB in liver<br>C57Bl/6J mice, 7d, 3x10mg/kg, SC,<br>N=4, dPCR, mean, SEM<br>Methylphosphonate linkage<br>RNA editing of APP<br>in HepG2 cells<br>Gymnosis, 5d, 5µM single dose,<br>N=2, dPCR, mean, SEM<br>O<br>P<br>O<br>HN O<br>S<br>O<br>O<br>R<br>R = Me: Mesyl-PN<br>PN PMe<br>O<br>P<br>O<br>O<br>Low<br>-<br>Low<br>-<br>High<br>+<br>0<br>10<br>20<br>30<br>40<br>50<br>Editing (%)<br> ✱<br> ✱✱✱✱<br>#PN<br>GalNac | |
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| Sequence optimization enables stable<br>editing oligonucleotides with prolonged PK<br>Learnings from advanced programs inform editing optimization<br>ProQR Therapeutics – Investor and Analyst Event 2024<br>EON11 concentration in liver of mice disease model<br>Hybridization-HPLC, n=6, 30mg/kg, EON11, SC, GalNAc conjugation,<br>up to 4 weeks<br>15<br>0 168 336 504 672<br>0.01<br>0.1<br>1<br>10<br>100<br>1000<br>Time (hr)<br>Peak Area Ratio<br>Unconjugated EON<br>Metabolite 1<br>Metabolite 2<br>Metabolite 3<br>Metabolite 4<br>Metabolite 5<br>Metabolite 6<br>Sum Total<br>Analytes PAR<br> • Rapid absorption in the liver and long half-life of<br>EON11 in liver measured – around 80 days<br> • EON show high stability with no metabolites<br>observed for oligonucleotide itself<br> • Up to six metabolite were identified and all were the metabolite of the GalNAc entity<br> • Most represented is linker between EON and GalNAc moiety<br> • Others were a combination of different cleavages of different GalNAc arms or<br>within the linker<br>EON11 metabolites in liver of mice disease model<br>LC-MS, n=6, 30mg/kg, EON11, SC, GalNAc conjugation, up to 4 weeks<br>Perkins E. 726. Complex Metabolism and Prolonged PK/PD of a GalNAc-Conjugated Editing Oligonucleotide (EON) in Mice. ASGCT 27th Annual Meeting Abstracts; Molecular Therapy, Volume 32, Issue 4, 1 - 889 | |
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| Mutations correction<br>Thousands of G-to-A<br>mutations, many of them<br>described in literature<br>Alter protein function or<br>include protective variants<br>Modified proteins achieving<br>loss- or gain-of-functions that<br>help addressing or<br>preventing diseases<br>Disrupt >400 different types<br>of PTMs<br>Regulate protein activity,<br>change localization, folding,<br>preventing immune escape<br>or slowing down degradation<br>Change protein<br>interactions<br>Changes localization, folding,<br>protein function or prevents<br>immune escape of<br>glycosylated tumor antigens<br>Mutation correction leading<br>to protein recovery<br>Variant resulting in a<br>dominant negative effect<br>Reduction of protein<br>phosphorylation altering<br>protein function<br>Variant impacting protein<br>interaction with sugar<br>ProQR Therapeutics – Investor and Analyst Event 2024 16<br>Creating a new class of medicines with<br>broad therapeutic potential<br>Correction Protein modulation | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 17<br>Axiomer RNA editing science translating<br>toward therapeutic applications<br>Science<br> • Harnessing advanced knowledge of ADAR and oligonucleotide science<br> • Pioneering the optimization of editing oligonucleotides (EONs) to achieve best-in-class<br>therapeutic solutions<br>Versatile applicability<br> • Demonstrating proven success in correcting genetic mutations and enabling diverse<br>protein modulation strategies<br> • Platform with potential to address diverse conditions rooted in human genetics<br>Leadership position<br> • Driving innovation in the ADAR RNA editing science with Axiomer EONs since 2014<br> • Dominant IP position to drive ADAR-mediated RNA editing platform innovation | |
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| Targeting NTCP to address cholestatic diseases unmet<br>medical need at the root cause<br>AX-0810 Program<br>ProQR Therapeutics – Investor and Analyst Event 2024 18<br>Presenters: Prof. Gideon Hirschfield, Gerard Platenburg | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 19<br>AX-0810 RNA editing therapy targeting<br>NTCP for cholestatic diseases<br>Cholestatic diseases have high unmet medical need. Patients accumulate<br>bile acids in liver leading to fibrosis and ultimately liver failure.<br>Initial indications are Primary Sclerosing Cholangitis affecting adults<br>and Congenital Biliary Atresia affecting pediatrics early in life. Both<br>conditions have no approved therapies and may require liver<br>transplantation.1,2<br> • Biliary Atresia is projected to affect ~20,000 pediatric individuals in<br>US and EU.<br> • Primary Sclerosing Cholangitis is projected to affect more than<br>80,000 individuals in US and EU.<br>AX-0810 is a unique therapeutic approach leading to a potentially<br>disease modifying therapy by targeting the NTCP channel which is<br>responsible for majority of bile acid re-uptake in liver cells.<br>1Trivedi PJ, et al. Clin Gastroenterol Hepatol. 2022 Aug;20(8):1687-1700.e4; 2Schreiber RA, et al. J Clin Med. 2022 Feb 14;11(4):999 | |
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| Prof. Gideon Hirschfield MA (Oxon), MB<br>BChir (Cantab), PhD, FRCP<br>Professor of Gastroenterology and Hepatology, Toronto, Ontario, Canada<br>ProQR Therapeutics – Investor and Analyst Event 2024 20<br> • Lily and Terry Horner Chair in Autoimmune Liver<br>Disease Research<br> • Director, The Autoimmune and Rare Liver Disease<br>Programme, Toronto General Hospital<br> • Professor, Division of Gastroenterology and<br>Hepatology, University of Toronto<br> • Prof. Gideon M. Hirschfield is an experienced and<br>highly focused clinician-scientist specialising in<br>autoimmune and cholestatic liver diseases. He<br>holds the Lily and Terry Horner Chair in<br>Autoimmune Liver Disease Research at the<br>Toronto Centre for Liver Disease, Toronto General<br>Hospital, and serves as a Professor of Medicine in<br>the Division of Gastroenterology and Hepatology<br>at the University of Toronto.<br> • Prof. Hirschfield completed undergraduate<br>studies in Medicine from the Universities of<br>Oxford and Cambridge and subsequently was<br>awarded a PhD from the University of London in<br>2006. He completed specialist training in Internal<br>Medicine, Gastroenterology and Hepatology in<br>London, Cambridge and Toronto.<br> • An internationally recognised expert, Prof.<br>Hirschfield has published over 350 peer-reviewed<br>articles, including lead authorship in high-impact<br>journals such as the New England Journal of<br>Medicine, The Lancet, and Nature Genetics.<br> • His research focuses on advancing therapies for<br>autoimmune and cholestatic liver diseases with<br>the clear goal of preventing the need for<br>transplantation alongside improving patient<br>quality of life | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 42<br>AX-0810 RNA editing therapy targeting<br>NTCP for cholestatic diseases<br>Cholestatic diseases have high unmet medical need. Patients accumulate<br>bile acids in liver leading to fibrosis and ultimately liver failure.<br>Initial indications are Primary Sclerosing Cholangitis affecting adults<br>and Congenital Biliary Atresia affecting pediatrics early in life. Both<br>conditions have no approved therapies and may require liver<br>transplantation.1,2<br> • Biliary Atresia is projected to affect ~20,000 pediatric individuals in<br>US and EU.<br> • Primary Sclerosing Cholangitis is projected to affect more than<br>80,000 individuals in US and EU.<br>AX-0810 is a unique therapeutic approach leading to a potentially<br>disease modifying therapy by targeting the NTCP channel which is<br>responsible for majority of bile acid re-uptake in liver cells.<br>1Trivedi PJ, et al. Clin Gastroenterol Hepatol. 2022 Aug;20(8):1687-1700.e4; 2Schreiber RA, et al. J Clin Med. 2022 Feb 14;11(4):999 | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 43<br>NTCP modulation leads to positive effect on<br>different mechanism involved in cholestasis<br>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;58(1):155-68.<br>Restores Bile Acids Balance<br>Protect hepatocytes by<br>lowering bile acid levels and<br>decrease hepatic bile<br>production through<br>downregulating effects<br> ↑ Liver<br>bile acids<br>Reduces Inflammation<br>Prevents bile leakage and<br>infiltration, limiting liver cell<br>damage and release of<br>proinflammatory mediators<br>Slows Fibrosis Progression<br>Stops cholangiocyte<br>senescence and<br>proliferation, reducing fibro-inflammatory responses<br>Genetic<br>predisposition<br>environmental insults<br>Failed metabolic<br>homeostasis<br>Cell stress and<br>cell death<br>Inflammation Cholestasis Fibrosis<br>NTCP MODULATION | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 44<br>NTCP variants reduced bile acids uptake<br>into liver in health population research<br>Healthy population<br>discovered with NTCP<br>variants that reduces<br>bile acids uptake into<br>liver1-4<br>1Salhab A, et al. Gut. 2022 Jul;71(7):1373-1385; 2Ho RH, et al. J Biol Chem. 2004 Feb 20;279(8):7213-22; 3Vaz FM, et al. Hepatology. 2015 Jan;61(1):260-7; 4Schneider AL, et al. Clin Res Hepatol Gastroenterol. 2022 Mar;46(3):101824; 5Slijepcevic D, et al.<br>Hepatology. 2018 Sep;68(3):1057-1069; 6Cai SY, et al. JCI Insight. 2017 Mar 9;2(5):e90780. | |
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| Bulevirtide Bulevirtide<br>Bulevirtide<br>ProQR Therapeutics – Investor and Analyst Event 2024<br>NTCP modulation has hepato-protective<br>effects in vivo in disease models<br>Bulevirtide (Hepcludex) is a daily SC injected NTCP inhibitor approved for Hepatitis D. Slijepcevic D, et al. Hepatology. 2018 Sep;68(3):1057-1069.<br>NTCP inhibition increases plasma bile<br>acids concentrations<br>(2- to 3-fold in mouse models)<br>Reduced bile acid production during<br>cholestasis (expected to decrease<br>intrahepatic bile acids load)<br>Reduced cholestatic liver injury via<br>improvement in liver enzymes<br>45<br>3-fold increase in<br>conjugated BA<br>2-fold increase in<br>conjugated BA<br>Bulevirtide<br>Bulevirtide<br>Bulevirtide | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 46<br>NTCP modulation leads to clinically<br>meaningful impact in patients<br>*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 Hepatitis D. Wedemeyer H, et al. N Engl J Med. 2023 Jul 6;389(1):22-32; Wedemeyer H, J Hepatol. 2024<br>Oct;81(4):621-629.; Dietz-Fricke C, JHEP Rep. 2023 Mar 15;5(4):100686.<br>NTCP inhibition increases plasma bile<br>acids concentrations in humans<br>(2- to 4-fold)<br>Treatment with NTCP inhibitor led to<br>improvement in liver fibrosis<br>(stiffness and histology)<br>Liver enzyme improvement occur in<br>patients, even without virologic<br>response*<br>0 1 2 3 4<br>Bulevirtide<br>Phase 3<br>10mg W48<br>Bulevirtide<br>Phase 3<br>2mg W48<br>Fold change plasma bile acids vs. control<br>VR: viral responders<br>PR: Partial responders<br>NR: Non responders<br>Bulevirtide 2 mg<br>ALT Normal values<br>7-56 U/L<br>Bulevirtide 10 mg<br>-5 -4 -3 -2 -1 0 1 2<br>Bulevirtide<br>10mg<br>Bulevirtide<br>2 mg<br>50 60 70<br>Histological activity<br>index improvement (N)<br>Liver stiffness<br>CFB W48 (kPa)<br>Improvement direction<br>Reducing liver bile acids toxic overload via NTCP modulation is a key driver for hepatoprotective effects | |
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| High concentration of bile acids<br>in hepatocytes<br>AX-0810 modifies the NTCP channel to<br>limit bile acids uptake while preserving all<br>other functions of the channel<br>ProQR Therapeutics – Investor and Analyst Event 2024 47<br>Human genetics validates NTCP modulation<br>as strategy for cholestatic disease<br> • The AX-0810 program introduces a<br>variant in individuals with<br>cholestatic disease to lower bile<br>acids concentration in hepatocytes<br>by a single A-to-I change<br> • The AX-0810 program is designed to<br>be a disease modifying treatment<br> • To alleviate symptoms in PSC<br>and BA<br> • To limit inflammation and<br>fibrosis linked to bile acid toxicity<br> • To prevent or delay the<br>development of cirrhosis, organ<br>failure and need for transplant<br>NTCP WT NTCP Q68R<br>EON<br>ADAR Inosine<br>BA, Biliary atresia; PSC, Primary Sclerosing Cholangitis<br>Liver with cholestatic disease AX-0810 strategy for diseased liver | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 48<br>Q68R NTCP variant leads to modulation of<br>bile acids re-uptake<br>Glutamine Arginine<br>Hydrophobicity<br>Electrostatic potential<br> • The Q68R variant disrupts some hydrogen bonds and contacts<br>in the Na+ binding pocket.<br> • Clashes are inevitable since the Arg side chain is buried and<br>likely to be found in one or another unfavorable rotamer state.<br> • Further assessment of Q68R variant in a bile acids uptake assay<br>showed a near complete inhibition of BAs (specifically<br>Taurocholic Acid or TCA) uptake in vitro, confirming findings<br>from the 3D modeling<br>BAs uptake (TCA) in vitro*<br>n=3, mean±SEM<br>3D Model of Q68R variant<br>impact on Na+ binding pocket of NTCP<br>NTCP: Na-taurocholate cotransporting polypeptide, *Transiently transfected U2OS cells. Control is WT without TCA.<br>Q68R WT Control<br>NTCP Variants<br>0<br>2<br>4<br>6<br>8<br>10<br>pmol TCA uptake<br>TCA 10 μM | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 49<br>Q68R NTCP variant solely affects bile acids<br>re-uptake function<br>Western Blot Analysis<br>Rabbit<br>anti-mFlag<br>Na/K-ATPase**<br>GAPDH*<br>*Loading control<br>for intracellular<br>proteins<br>**Loading control<br>for surface<br>proteins<br>EON: editing oligonucleotide, NTCP: Na-taurocholate cotransporting polypeptide, *transiently transfected U2OS cells. SLC10A1 is the gene that encodes for NTCP protein<br> • No significant differences in NTCP RNA and protein levels were<br>detected. The plasma membrane location of the Q68R variant<br>was also unaffected.<br> • The Q68R variant solely affects NTCP bile acids reuptake<br>function making it an approach of interest for Axiomer EON<br>therapeutic application.<br>NTCP protein expression was detected on western blot<br>using the anti-FLAG antibody for all constructs<br> ▮ Nuclei<br> ▮ Anti-FLAG<br>Parental<br>Q68R WT<br>Empty vector<br>NTCP protein localization in vitro* | |
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| EON mediated RNA editing leads to NTCP<br>Q68R variant in WT hepatocytes<br>Editing of NTCP RNA modulates bile acids reuptake in a dose dependent fashion<br>ProQR Therapeutics – Investor and Analyst Event 2024 50<br>NTCP: Na-taurocholate cotransporting polypeptide, BAs mentioned in this experiment are specifically Tauro-nor-THCA-24-DBD. SLC10A1 is the gene that encodes for NTCP protein<br>NTCP-mediated BAs uptake in HepaRG cells<br>with Axiomer EON treatment<br>n=3, 50-100nM, 72 hours, mean±SEM<br>Early generation of EONs induces a dose-response inhibition of bile acids in vitro confirming its modulation by NTCP<br>Early generation of EONs targeting<br>NTCP RNA in PHH<br>Transfection, n=3, 72 hours, mean±SEM, dPCR<br>0 20 40 60 80 100<br>0<br>20<br>40<br>60<br>Concentration (nM)<br>Editing (%)<br>EON A<br>Vehicle 50nM EON A 100nM EON A<br>0.0<br>0.1<br>0.2<br>0.3<br>Fluorescence (AU)/protein (mg/mL) | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 51<br>EON mediated NTCP editing in NHP has linear<br>correlation with bile acids plasma levels<br>NTCP: Na-taurocholate cotransportingpolypeptide, BAs mentioned in this experiment are specifically Tauro-nor-THCA-24-DBD. SLC10A1 is the gene that encodes for NTCP protein<br>Correlation between change in plasma BAs<br>and editing of NTCP RNA in NHPs in vivo<br>n=6, Early generation EONs, IV, LNP formulation, 72 hours, dPCR<br>0 5 10 15 20 25 30<br>0<br>2<br>4<br>6<br>8<br>10<br>Editing of NTCP RNA (%)<br>Plasma Bile Acids<br>(fold increase from baseline)<br>R2<br> = 0.51<br> • NTCP target engagement with<br>Axiomer EONs leads to the<br>desired changes in biomarkers<br> • Correlation between plasma bile<br>acids and early-generation EONs<br>editing level in NHPs in vivo (linear<br>regression R2 = 0.51) | |
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| Plasma TBA in Humanized Mice<br>(N=4, 20mg/kg, 6 doses, GalNac conjugation,<br>SC, D25)<br>Plasma TBA in NHP<br>(N=1, 1-4mg/kg, 4 doses, LNP formulation<br>IV, up to D39)<br>PLASMA TOTAL BILE ACIDS<br>Control EON A<br>0<br>2<br>4<br>6<br>Change from Baseline<br>(Fold Change)<br>ProQR Therapeutics – Investor and Analyst Event 2024 52<br>EON mediated editing demonstrates consistent<br>editing of NTCP and impact on biomarker in vivo<br> • EON A results in consistent<br>editing data in humanized<br>mouse model and NHP in<br>vivo with approx. 15%<br>editing reaching expected<br>NTCP modulation<br> • Reaching >2-fold changes in<br>biomarkers - expected<br>impact on plasma bile acids<br>levels following NTCP EON<br>treatment<br>MICE in vivo NHP in vivo<br>EON A<br>0<br>5<br>10<br>15<br>20<br>25<br>Editing (%)<br>NTCP RNA Editing in NHP<br>(N=1, 1-4mg/kg, 4 doses, LNP formulation,<br>IV, up to D46, ddPCR)<br>NTCP RNA Editing in Humanized Mice<br>(N=4, 20mg/kg, 6 doses, GalNAc conjugation,<br>SC, D25, ddPCR)<br>EDITING EFFICIENCY<br>Control EON A<br>0<br>2<br>4<br>6<br>Change from Baseline<br>(Fold Change)<br>EON A<br>0<br>10<br>20<br>Editing (%) | |
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| NTCP editing demonstrates favorable<br>composition of bile acids profile in NHP<br>Increase in conjugated bile acids confirms NTCP engagement in vivo<br>ProQR Therapeutics – Investor and Analyst Event 2024 53<br> • Conjugated bile acids are<br>transported by NTCP back to<br>the liver<br> • The observed change in plasma<br>BA profile confirms NTCP<br>specific modulation<br> • In view of the preclinical data,<br>high confidence on NTCP EON<br>treatment to positively impact<br>BA toxic load in the liver<br>Conditions in humanized mice: N=4, 20mg/kg, 6 doses, GalNAc conjugation, SC, D25, ddPCR; Conditions in the NHP experiment N=1, 1-4mg/kg, 4 doses, LNP formulation, IV, up to D42, ddPCR. Mao F, et al. J Biol Chem. 2019 Aug 2;294(31):11853-11862; Haag M, et al. Anal<br>BioanalChem. 2015 Sep;407(22):6815-25.; Wedemeyer H, et al. N Engl J Med. 2023 Jul 6;389(1):22-32.<br>Change in Plasma BA Profile<br>NHP<br>Baseline<br>EON A<br>NHP<br>Unconjugated Bile Acids<br>Conjugated Bile Acids<br>Human<br>Normal values<br>Human<br>NTCP variant<br>Bulevirtide<br>post treatment<br>0<br>50<br>100<br>Bile acids %<br>Unconjugated Bile Acids<br>Conjugated Bile Acids | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 54<br>EON mediated NTCP editing demonstrates<br>reduced clearance in bile acids challenge<br>assay in NHP<br> • TUDCA is a Tauro-conjugated bile<br>acids specifically transported by<br>NTCP from the plasma to the liver<br> • In an NHP experiment using<br>administration of TUDCA following<br>NTCP EON treatment, TUDCA<br>plasma clearance into the liver was<br>assessed<br> • Decrease in plasma clearance<br>kinetics further confirm NTCP target<br>engagement for EON treated NHP<br>TUDCA elimination rate from plasma in NHP<br>(Exploratory study, early generation EON, n=5-7,<br>10mg/kg, 4 doses, SC, D51)<br>Control EON treated<br>0.04<br>0.06<br>0.08<br>0.10<br>kel (min-1)<br>P=0.047<br> ✱ | |
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| AX-0810 clinical candidate has an enhanced<br>potency profile over EON A in PHH<br>Transfection, n=3, 72 hours, dPCR, mean±SEM<br>AX-0810 clinical candidate selected with<br>enhanced potency and stability profile<br>ProQR Therapeutics – Investor and Analyst Event 2024 55<br> • AX-0810 clinical candidate is a<br>GalNAc conjugated EON<br> • 5.5-fold increase in potency over<br>early generation NTCP editing<br>oligonucleotide<br> • Improved stability profile in vitro<br> • Confirmed class safety, with no<br>hepatotoxicity or<br>immunostimulatory score<br>0 20 40 60 80 100<br>0<br>20<br>40<br>60<br>Concentration (nM)<br>Editing (%)<br>AX-0810 EON A<br>5.5-fold<br>increase | |
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| GLP tox studies<br>ProQR Therapeutics – Investor and Analyst Event 2024 56<br>CTA enabling activities ongoing for AX-0810<br>In vitro safety<br>screening Delivery method Manufacturing Regulatory<br> • AX-0810 clinical<br>candidate passed<br>in vitro screening<br>for class toxicities<br> • Chemical<br>modifications and<br>Z-base derisked in<br>genotoxicity tests<br>Preferential<br>distribution of<br>GalNAc conjugated<br>EONs confirmed<br> • Dose ranges and<br>margins<br>established for GLP<br>toxicity studies,<br>ongoing studies in<br>two species<br> • Bioanalytical<br>methods to<br>measure clinical<br>candidates in<br>plasma and tissue<br>established<br>Scale-up of EON<br>manufacturing<br>process successfully<br>completed, stability<br>of formulated EON<br>confirmed, and<br>favorable shelf life<br>achieved<br>Interactions with<br>regulatory<br>authorities ongoing | |
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| First in human trial of AX-0810 to establish<br>target engagement<br>ProQR Therapeutics – Investor and Analyst Event 2024 57<br>Integrated single/multiple ascending dose study design<br>Cohort 1<br>Cohort 2<br>Cohort 3<br>Cohort 4<br>Treatment<br>AX-0810 GalNAc conjugated<br>editing oligo-nucleotide<br>Objectives<br> • Confirm target engagement as<br>measured by biomarkers<br> • Assess safety, tolerability, and<br>PK of AX-0810<br>Trial design<br> • Combined single and multiple ascending dose<br> • ≥60 heathy volunteers, 4 weeks dosing phase<br>followed by 12 safety weeks follow-up<br> • 5 weekly subcutaneous injections<br> • Baseline and placebo-controlled design<br> • Standardized conditions for assessment of bile<br>acids at multiple timepoints<br> • DMC safety reviews before proceeding to next<br>dose and dose escalation<br>Key endpoints<br> • Change in bile acids levels and profile in plasma<br>and urine, liver biomarkers<br> • Circulating RNA as exploratory endpoint<br>Top-line data in Q4 2025<br>Follow-up<br>Weekly dose A<br>Weekly dose B<br>Weekly dose C<br>Weekly dose D<br>Follow-up<br>Follow-up<br>Follow-up | |
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| Summary & next steps<br>AX-0810 for cholestatic diseases<br>ProQR Therapeutics – Investor and Analyst Event 2024 58<br>Modulating NTCP activity to reduce<br>hepatic bile acids load is a promising<br>target for hepatoprotection in<br>cholestatic diseases<br>Promising and consistent results reported<br>to date in humanized mice and NHPs<br>Meaningful impact on bile acid plasma level and bile<br>acids profile build confidence for data readout in FIH<br>clinical trial<br>Axiomer NTCP EON impact on biomarkers in line with<br>preclinical disease model and clinical data reported<br>with NTCP inhibition<br>Favorable safety profile observed<br>AX-0810 GalNAc candidate with optimized<br>potency and stability to enter clinic<br>CTA submission in Q2 2025<br>Top-line data from FIH<br>expected in Q4 2025 | |
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| NTCP and bile acids are involved in a variety<br>of therapeutic areas<br>Providing opportunity across multiple indications<br>ProQR Therapeutics – Investor and Analyst Event 2024 59<br>Cholestatic diseases<br> • Primary Sclerosing Cholangitis (PSC)<br> • Biliary Atresia<br> • Primary Biliary Cholangitis (PBC)<br> • Alagille syndrome<br> • Dubin-Johnson Syndrome<br> • Progressive Familial Intrahepatic<br>Cholestasis (PFIC)<br> • Drug-Induced Cholestasis<br> • Alcoholic Liver Disease<br> • Secondary Biliary Cirrhosis<br> • Rotor syndrome<br> • Neonatal cholestasis<br>Neurological diseases<br> • Multiple Sclerosis<br> • Amyotrophic Lateral Sclerosis<br> • Neurological diseases<br> • Epilepsy<br> • Parkinson’s Disease<br>Infectious disease<br> • Parasitic Infections<br> • Sepsis-Associated Cholestasis<br> • Viral Hepatitis: Hepatitis A, B, C, D, E<br>Metabolic diseases<br> • Hyperlipidemia<br> • Hypertension<br> • MASH<br> • Obesity<br> • Diabetes<br> • Lysosomal<br>storage diseases<br> • Hyper-cholesterolemia<br> • ASCVD | |
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| Targeting MECP2 to restore protein functionality in Rett<br>Syndrome, a severe neurodevelopmental disorder<br>AX-2402 Program<br>ProQR Therapeutics – Investor and Analyst Event 2024 60<br>Presenters: Monica Coenraads, MBA and Gerard Platenburg | |
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| CNS is a prime target organ for Axiomer<br>RNA editing technology<br> • Numerous neurological disorders lack<br>effective therapies, urge for new<br>therapeutic approaches<br> • ADAR enzymes are highly expressed<br>in the brain with very active editing<br>capacity<br> • EONs have shown broad distribution,<br>durability and were observed to have<br>a favorable safety profile making<br>them a well-suited approach for CNS<br>indications<br>ProQR Therapeutics – Investor and Analyst Event 2024 61<br>ADAR mediated A-to-I editing in human tissues1<br>Editing level<br>1Figure adapted from Tan et al. Nature. 2017 Oct 11;550(7675):249-254 | |
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| Robust ADAR expression across cell type<br>and regions in mouse brain<br>Cell type specific expression of Adarb1 and Adarb2 genes<br>ProQR Therapeutics – Investor and Analyst Event 2024<br>Cell type clusters ADAR1<br>Glut neurons<br>Thalamus<br>Glut neurons<br>Cerebellum<br>GABA neurons<br>olfactory bulb<br>GABA<br>neurons<br>cortex<br>ADARB1 ADARB2<br>High expression of Adar genes in different cell type and regions in the mouse brain<br>Whole Mouse Brain Transcriptomic Cell Type Atlas – Allen brain atlas<br>62 | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 63<br>Predictive CNS models to inform<br>development of RNA editing<br>Development of reproducible, region-specific neural stem cell<br>(NSC)-derived spheroids addresses limitations of 3D iPSC-derived organoids, offering a robust and predictive tool for<br>accelerating drug discovery in neurodegenerative diseases,<br>substance abuse, and pain management.<br> • Spheroids are 3D cultures<br>that model specific brain<br>regions depending on the mix<br>of hIPSC-derived neuronal<br>subpopulations used<br> • They can give rise to pre-frontal cortex-like (PFC`) or<br>ventral tegmental area (VTA)-<br>like 3D structures<br> • Uniformly-shaped PFC, form<br>within 24-48 hours with size<br>yield of ~400 μm<br>iPSC-derived mature neuronal<br>subtypes and astrocytes<br>Thaw and mix of select<br>neuronal subtypes/astrocytes<br>at desired ratios in 384w,<br>round bottom plates<br>Culture 3 weeks for<br>matured region-specific neuronal<br>spheroids | |
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| Highly efficient RNA editing in brain<br>organoid recapitulating human cortex<br>Reaching 90% editing in neurospheroids<br>ProQR Therapeutics – Investor and Analyst Event 2024<br>PFC-like spheroids are composed by 90% neurons and 10% astrocytes and<br>exhibit a 70:30 ratio of excitatory (Glutamatergic) and inhibitory (GABAergic)<br>neurons recapitulating the cellular composition of the human cortex<br>RNA editing of APP in<br>human PFC-like spheroids<br>Transfection, 5 µM, single dose, n=3, 7 days,<br>mean, SD, ddPCR<br>Control EON<br>0<br>20<br>40<br>60<br>80<br>100<br>Editing (%)<br>Merge vGlut Merge BIII Tub<br>vGAT Hoechst GFAP Hoechst<br>64 | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 65<br>Consistent CNS editing demonstrated<br>across species<br> • Up to 40% editing in vivo leading to 26-fold change in protein<br>function recovery in brain tissues of interest at 4 weeks with a<br>single dose in mice model<br> • In rat, Axiomer EONs demonstrated up to 50% editing in vivo<br>with sustained editing between W2 and W4 after single dose<br> • Up to 30% RNA editing reported in brain and approx. 50% in<br>spinal cord in NHP in vivo<br>ICV, 250μg, undisclosed target, single dose,<br>n=6, 4 weeks, ddPCR, mean, SD<br>ICV, 500μg, APP, single dose,<br>n=5, 2 weeks, ddPCR, mean, SD<br>Control<br>Spinal cord<br>Lombar W2<br>Cerebellum W2<br>Medulla W2<br>Spinal cord<br>Thoracic W2<br>Spinal cord<br>Cervical W2<br>Cortex W2<br>Pons W2<br>Midbrain W2<br>Hippocampus W2<br>0<br>10<br>20<br>30<br>40<br>50<br>Editing %<br>Cerebellum<br>Parietal<br>cortex<br>Frontal<br>cortex<br>Pons<br>Medulla<br>Spinal cord<br>Cervical<br>Temporal<br>cortex<br>Spinal cord<br>Thoracic<br>Spinal cord<br>Lumbar<br>0<br>10<br>20<br>30<br>40<br>50<br>Editing (%)<br>IT administration, undisclosed target 12mg,<br>single dose, n=3*, 7 days, ddPCR<br>MICE in vivo NHP in vivo<br>Cortex Hippocampus Cerebellum Midbrain<br>0<br>10<br>20<br>30<br>40<br>50<br>Editing (%)<br>Control EON<br>RAT in vivo<br>* Data of 2 NHPs not analyzable due to human error during injection procedure. | |
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| Axiomer holds strong potential to make a<br>meaningful impact to CNS diseases<br>ProQR Therapeutics – Investor and Analyst Event 2024 66<br>Strong RNA Editing Performance<br> • Robust RNA editing in critical CNS regions validating the efficiency of Axiomer<br>platform in CNS indications<br>Broad Applicability Across CNS Regions<br> • RNA editing was successfully achieved in multiple regions of the nervous<br>system, indicating the platform’s broad applicability across different CNS<br>regions<br>Consistent and Durable Results with Well Understood Safety Profile<br> • Consistent RNA editing across species, with durable effects observed<br> • EONs have been observed to have a favorable safety profile in CNS | |
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| ProQR Therapeutics – Investor and Analyst Event 2024<br>AX-2402 RNA editing therapy targeting<br>MECP2 for Rett Syndrome<br>67<br>Rett Syndrome is a devastating and progressive neurodevelopmental<br>disorder caused by variants in the transcription factor Methyl CpG<br>binding protein 2 (MECP2). There is a high unmet need for a disease<br>modifying therapy.<br>Nonsense variants lead to severe phenotypes. They represent more<br>than one third of Rett Syndrome cases and are projected to affect<br>20,000 individuals in US and EU.1,2<br>Rett Syndrome is not a neurodegenerative disorder and restoring<br>levels of the MECP2 protein has shown to reverse symptoms in mice.3<br>Axiomer has the potential to restore the precise level of MECP2<br>protein regulatory function, which is lacking in Rett Syndrome, and<br>become a disease modifying therapy.<br>Rett Syndrome Research Trust partnership includes $9.1 M in funding;<br>collaboration established in January 2024, expanded in December 2024<br>1Krishnaraj R, et al. Hum Mutat. 2017 Aug;38(8):922-93; 2RSRT 2023 conference; 3Guy J, et al. Science. 2007 Feb 23;315(5815):1143-7. | |
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| • Monica Coenraads’ involvement with Rett syndrome began the day her then-two-year-old<br>daughter was diagnosed with the disorder. A year later, in 1999, she co-founded the Rett<br>Syndrome Research Foundation (RSRF) and held the position of scientific director during<br>the eight years of the Foundation’s drive to stimulate scientific interest and research in Rett<br>syndrome, culminating with the groundbreaking work in 2007 which demonstrated the first<br>global reversal of symptoms in preclinical models of the disorder. Monica launched the Rett<br>Syndrome Research Trust in late 2008 to pursue the next steps from that milestone.<br> • As chief executive officer she oversees all aspects of the organization, including day-to-day<br>operations, strategic direction, fundraising, and communications. Together with her<br>colleagues and with input from advisors and the scientific community at large, Monica sets<br>and executes RSRT's research agenda.<br> • Under Monica’s leadership at RSRF and RSRT, $117 million has been raised for<br>Rett syndrome.<br>ProQR Therapeutics – Investor and Analyst Event 2024 68<br>Monica Coenraads, MBA<br>Founder, Chief Executive Officer at Rett Syndrome Research Trust | |
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| ProQR Therapeutics – Investor and Analyst Event 2024<br>AX-2402 RNA editing therapy targeting<br>MECP2 for Rett Syndrome<br>69<br>Rett Syndrome is a devastating and progressive neurodevelopmental<br>disorder caused by variants in the transcription factor Methyl CpG<br>binding protein 2 (MECP2). There is a high unmet need for a disease<br>modifying therapy.<br>Nonsense variants lead to severe phenotypes. They represent more<br>than one third of Rett Syndrome cases and are projected to affect<br>20,000 individuals in US and EU.1,2<br>Rett Syndrome is not a neurodegenerative disorder and restoring<br>levels of the MECP2 protein has shown to reverse symptoms in mice.3<br>Axiomer has the potential to restore the precise level of MECP2<br>protein regulatory function, which is lacking in Rett Syndrome, and<br>become a disease modifying therapy.<br>Rett Syndrome Research Trust partnership includes $9.1 M in funding;<br>collaboration established in January 2024, expanded in December 2024<br>1Krishnaraj R, et al. Hum Mutat. 2017 Aug;38(8):922-93; 2RSRT 2023 conference; 3Guy J, et al. Science. 2007 Feb 23;315(5815):1143-7. | |
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| • MECP2 gene, encoding methyl-CpG binding<br>protein 2 (MeCP2):<br> • Master epigenetic modulator of gene<br>expression and plays a vital role in neuronal<br>maturation and function<br> • Mutations lead to misfolded, truncated or<br>absent protein and loss of function<br> • This loss of MECP2 regulating function leads<br>to Rett syndrome and 35% of point mutations<br>cause a premature termination codon (PTC)<br> • In 2007, Adrian Bird's lab demonstrated that<br>Rett syndrome symptoms are reversible in mice1<br>ProQR Therapeutics – Investor and Analyst Event 2024 70<br>MECP2 gene is frequently mutated in Rett<br>syndrome (RTT)<br>WT mice<br>Mecp2 mutant mice<br>Mecp2 mutant treated mice<br>Direction of improvement<br>1Guy J, et al. Science. 2007 Feb 23;315(5815):1143-7. Figure adapted from Guy J, et al. Science. 2007 Feb 23;315(5815):1143-7. | |
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| MECP2 expression level tightly regulated<br>in neurons<br>Axiomer is a well-suited approach to restore physiological levels of MECP2<br>ProQR Therapeutics – Investor and Analyst Event 2024 71<br> • Axiomer approach makes<br>use of ADAR endogenous<br>system to restore<br>physiological levels of<br>functional MECP2<br> • Axiomer avoid the risk of<br>expressing unsafe levels<br>of MECP2, potentially<br>leading to MECP2<br>duplication syndrome<br>Overexpression leads to toxicity<br>(1.5-fold increase)<br>Deficit due to lack of MECP2<br>MECP2 expression level<br>Physiological MECP2 level<br>MECP2 duplication syndrome<br>RETT syndrome | |
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| Axiomer has the potential to restore<br>physiological levels of functional MECP2<br>AX-2402 correcting MECP2 R270X into WT-like R270W<br>ProQR Therapeutics – Investor and Analyst Event 2024 72<br> • MeCP2 protein restoration/recovery<br> • MeCP2 R270W (Arg > Trp) mouse model<br>indistinguishable from wild type mice<br>Postnatal microcephaly, stereotypic hand<br>movements, ataxia, abnormal breathing, and<br>growth retardation, social withdrawal, loss of<br>speech, seizures<br>GGGGCUGA>GAAGCCG<br>EXON 3 EXON 4 EXON 3 EXON 4 EXON 5<br>GGGGCC>UGAAAGCCG<br>RETT syndrome WT like phenotype | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 73<br>R270W variant demonstrates wild-type like profile<br>AX-2402 can restore physiological levels of functional<br>MECP2 potentially reverting Rett syndrome into a WT like phenotype1<br>Severity score (0-12) Probability of survival Body weight (g) Brain weight (mg)<br>v<br>1Colvin, S. (2023) thesis. Massachusetts Institute of Technology. Figures adapted from: Colvin, S. (2023) thesis. Massachusetts Institute of Technology | |
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| EON mediated editing in patient's cells increases<br>mRNA levels and restores protein expression<br>PTC recoding leading to absent NMD mediated RNA degradation<br>ProQR Therapeutics – Investor and Analyst Event 2024 74<br>Up to 80 % editing of R270X<br>MECP2 in patient fibroblasts<br>Increased MECP2 RNA levels<br>due to PTC recoding and<br>NMD inhibition<br>Increased R270W MECP2<br>protein levels<br>Control EON A EON B<br>0<br>20<br>40<br>60<br>80<br>100<br> Editing (%)<br>Control EON A EON B<br>0<br>2<br>4<br>6<br>Fold change (vs. control)<br>MeCP2-R270X EON A<br>0<br>2<br>4<br>6<br>8<br>10<br>Fold increase from MeCP2-R270X Non treated<br>EON, Editing oligonucleotide; NT, Non-treated; TF, transfection, Conditions panel on the left and middle: 100 nM EON, transfection, 48h, N=2, mean±SEM. Conditions panel on the right: MeCP2-R270X-NanoLuc activity; 100 nM EON, transfection, 48h, N=8, mean±SEM. | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 75<br>Preliminary clinical trial design<br>Single dose Repeated dose<br> • Preliminary Phase 1/2 SAD & MAD design<br> • Up to 18 subjects with the R270X mutation<br> • Primary objective: safety, tolerability and<br>pharmacokinetics<br> • Secondary objectives: target engagement and<br>biomarkers<br> • Financially supported by $8.1M funding<br>provided by Rett syndrome Research Trust<br> • Clinical candidate selection in 2025<br> • Top-line data expected in 2026<br>Dose 1, N=3, IT<br>Dose 2, N=3, IT<br>Dose 3, N=3, IT<br>Dose 1, N=3, IT, Q3-6M<br>Dose 2, N=3, IT, Q3-6M<br>Dose 3, N=3, IT, Q3-6M | |
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| Targeting B4GALT1 to reduce the risk of cardiovascular<br>diseases<br>AX-1412 Program<br>ProQR Therapeutics – Investor and Analyst Event 2024 76<br>Presenter: Gerard Platenburg | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 77<br>AX-1412 RNA editing therapy targeting<br>B4GALT1 for cardiovascular diseases<br>Leading causes of death in the world<br>~18 million people die from CVDs every year (32% of all<br>global deaths) Despite therapies, the unmet medical<br>need remains.<br>AX-1412 is designed to provide people with a protective<br>genetic variant of B4GALT1 that is associated with 36%1<br>reduction in the risk of cardiovascular disease.<br>AX-1412 may become a stand-alone cardiovascular<br>therapy that may also work synergistically with<br>standard of care to further reduce risk of CVDs.<br>1Montasser ME, et al. Science. 2021 Dec 3;374(6572):1221-1227 | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 78<br>B4GALT1 p.Asn352Ser variant reduces CVD risk<br> • It is described that people who carry missense<br>variants like the p.Ans352Ser in B4GALT1, have<br>36% lower chance of the development of<br>coronary artery disease.1 This variant is known as<br>the “old Amish order variant”<br> • This variant reduces CVD risk through 2<br>independent risk factors, fibrinogen and LDL-C,<br>through independent pathways from PCSK9<br> • This protective variant is a A-to-G variant, on that<br>can be introduced by Axiomer mediated ADAR<br>editing<br> • B4GALT1 is not suitable for knockdown<br>technologies, as leads to semi-lethality and severe<br>development abnormalities in mouse studies<br>1Montasser ME, et al. Science. 2021 Dec 3;374(6572):1221-1227 | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 79<br>Glycosylation is a key process in lipid<br>metabolism<br> • Glycosylation stabilizes the folding and<br>conformation of apolipoproteins (e.g.,<br>ApoB, ApoE), ensuring proper assembly<br>and secretion of lipoproteins such as LDL<br>and HDL.<br> • Glycosylation of receptors like LDLR is<br>critical for their membrane localization<br>and ligand binding, enabling efficient<br>lipoprotein clearance from the<br>bloodstream.<br> • Aberrant glycosylation can lead to<br>dysfunctional lipoproteins, a key driver of<br>atherosclerosis.<br>1Pirillo A, et al. Cardiovasc Res. 2021 Mar 21;117(4):1033-1045.<br>Physiological lipoprotein glycosylation1 | |
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| B4GALT1 p.Asn352Ser variant to reduce<br>galactosylation of CVD risk factors<br>ProQR Therapeutics – Investor and Analyst Event 2024 80<br>Fibrinogen<br>ApoB<br>EON<br>ADAR<br>Fibrinogen<br>ApoB<br>B4GALT1 mRNA<br>B4GALT1 mRNA<br>B4GALT1 protein<br>B4GALT1-p.Ans352Ser<br>protein Reduction in<br>galactosylation<br>INTRODUCTION OF<br>PROTECTIVE VARIANT WT SITUATIONS | |
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| EON-mediated editing of B4GALT1 leads to<br>reduced glycosylation activity<br>In line with natural population<br>ProQR Therapeutics – Investor and Analyst Event 2024 81<br>1Montasser ME, et al. Science. 2021 Dec 3;374(6572):1221-1227. Percentage of 352Asn B4GALT1 galactosylation activity of 352Asn B4GALT1 and 352Ser B4GALT1 immunoprecipitated proteins<br>B4GALT1 activity reported in<br>Montasser et al.1<br>COS-7 cells, cell lysate, transfection, n=4, mean, SEM<br>EON mediated editing of<br>B4GALT1 in PHH<br>5µM transfection, dPCR, mean, SD, n=3<br>B4GALT1 activity following editing<br>PMH, cell lysate, transfection 5µM, 4 days,<br>mean, SD, ANOVA<br>Control EON A EON B<br>0<br>10<br>20<br>30<br>40<br>Editing (%)<br>Control EON A EON B<br>0<br>50<br>100<br>B4GALT1 activity per<br>total protein (mU/µg)<br>0.0224<br>352Asn 352Ser<br>0<br>50<br>100<br>B4GALT1 activity (%)<br>P=0.027 | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 82<br>E3L.CETP mice disease model is industry<br>standard for assessing CVD therapeutics<br> • CETP facilitates the transfer of cholesteryl esters<br>from HDL to VLDL and LDL, a key process in<br>human lipid metabolism that is absent in most<br>rodent models.<br> • These mice, fed a high-fat high-cholesterol diet<br>(HFCD), exhibit a biphasic dyslipidemic response,<br>closely mimicking plasma lipid changes in humans<br> • The presence of CETP in this model makes it<br>uniquely suited to study dyslipidemia and<br>cholesterol metabolism, especially in relation to<br>B4GALT1, which is involved in glycosylation<br>processes affecting lipid metabolism.<br> • In humans, most circulating lipids<br>are confined to VLDL/LDL particles<br>..<br>Human E3L.CETP mice disease model<br>Wildtype healthy mice | |
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| B4GALT1 editing impacts activity of key<br>proteins involved in lipid metabolism<br>Minimal changes in transcript and protein levels associated with decrease in<br>CETP activity in vivo<br>ProQR Therapeutics – Investor and Analyst Event 2024 83<br>Control EON 1<br>0<br>5<br>10<br>15<br>20<br>Log2 (read_counts)<br>CETP RNA<br>Control EON 1<br>0<br>5<br>10<br>15<br>20<br>Log2 (Intensity)<br>CETP PROTEIN<br>Control EON 1<br>0<br>20<br>40<br>60<br>80<br>nmol/hr/mL<br> ✱ ✱<br>-34%<br>CETP activity<br>CETP RNA, protein and activity following EON B treatment<br>E3L.CETP mice, LNP formulation, 2mg/kg, Q1W, D31, RNAseq, Roar, mean, max-min n=3, T-test Reduced CETP activity<br>in the absence of<br>changes at the<br>transcriptomic or<br>proteomic levels<br>highlights the<br>impact of EON on<br>glycosylation rather<br>than on expression<br>levels | |
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| D1 D19 D33 D46<br>3<br>4<br>5<br>6<br>7<br>8<br>Plasma LDL-c (mM)<br>- 30%<br>ProQR Therapeutics – Investor and Analyst Event 2024 84<br>EON-mediated editing of B4GALT1 leads to<br>meaningful effect on key biomakers in E3L.CETP Mice<br>Following treatment<br>with EON B, a marked<br>reduction in total<br>cholesterol, ApoB, and<br>LDL-c by observed<br>already at Day 19<br>confirms our<br>approach to address<br>cardiovascular<br>diseases<br>D1 D19 D33 D46<br>0<br>10<br>20<br>30<br>CETP activity (nmol/mL/h)<br>Control<br>EON B<br>- 39%<br>CETP activity<br>D1 D19 D33 D46<br>0.0<br>0.5<br>1.0<br>1.5<br>ApoB (mg/mL)<br>- 72%<br>ApoB<br>D1 D19 D33 D46<br>0<br>1<br>2<br>3<br>4<br>5<br>Fibrinogen (mg/mL)<br>- 55%<br>Fibrinogen<br>Plasma LDL-c<br>B4GALT1 editing and biomarkers<br>in E3L.CETP mice (N=10, 2mg/kg, LNP<br>formulation, IV Q1W, D46, ddPCR)<br>D1 D19 D33 D46<br>0<br>5<br>10<br>15<br>20<br>25<br>Total cholesterol (mmol/L)<br>- 61%<br>Total Cholesterol<br>Control EON B<br>0<br>5<br>10<br>Editing (%) (G/G+A)<br>Control<br>EON B | |
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| • Treatment with EON B significantly<br>decreases VLDL and LDL cholesterol<br>compared to control<br> • These lipoproteins are associated with<br>increased cardiovascular risk due to<br>their role in atherosclerotic plaque<br>formation<br> • HDL cholesterol which supports reverse<br>cholesterol transport and is associated<br>with reduced cardiovascular risk,<br>remains unchanged<br>B4GALT1 EON leads to a positive shift in<br>lipoprotein profiles<br>Specifically targeting atherogenic lipoproteins<br>ProQR Therapeutics – Investor and Analyst Event 2024 85<br>Impact on lipoprotein profile following<br>editing of B4GALT1 in E3L.CETP mice<br>(N=10, 2mg/kg, LNP formulation, IV Q1W, D46)<br>0 10 20<br>0<br>2<br>4<br>Fraction<br>Cholesterol (mmol/L)<br>Control EON B<br>VLDL LDL HDL<br>Direction of improvement<br>Control<br>EON B | |
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| Summary & next steps<br>AX-1412 for CVD<br>ProQR Therapeutics – Investor and Analyst Event 2024 86<br>EON-mediated RNA editing of<br>B4GALT1 leads to the required<br>reduction in galactosylation<br>reflecting the human genetics<br>observed effect<br>LNP-delivered EON editing<br>B4GALT1 leads to editing and<br>meaningful changes<br>in biomarker effect on LDLC, CEPT, cholesterol<br>and fibrinogen in an industry-standard in vivo<br>disease model<br>Further optimization of a<br>GalNAc delivered EON<br>ongoing<br>to achieve a TPP desirable for CVD<br>Expected to provide an<br>update on the optimization<br>efforts in mid 2025 | |
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| Targeting PNPLA3 to address unmet medical needs in MASH<br>AX-2911 Program<br>ProQR Therapeutics – Investor and Analyst Event 2024 87<br>Presenter: Gerard Platenburg | |
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| MASH and subsequent stages of liver disease are very<br>prevalent and still on the rise worldwide. MASH individuals<br>have a high unmet medical needs due to the progressive<br>nature of the disease (cirrhosis and hepatocellular carcinoma)<br>and limited therapeutic options available1<br>PNPLA3 (patatin-like phospholipase domain-containing 3) I148M<br>is a variant commonly reported in the MASH population<br>worldwide (20-60% of the patients) and is known as associated<br>risk factor.<br>2,3 Approximately 8 million individuals in US and EU<br>are homozygous for the 148M variant.<br>Axiomer EONs have the potential to change the Methionine into<br>a Valine bringing the PNPLA3 protein back to a WT-like<br>functional conformation.<br>AX-2911 RNA-editing therapy to address<br>Metabolic dysfunction associated<br>steatohepatitis (MASH)<br>ProQR Therapeutics – Investor and Analyst Event 2024 88<br>1Sandireddy R, et al. Front Cell Dev Biol. 2024 Jul 16;12:1433857; 2Romeo S, et al. Nat Genet. 2008 Dec;40(12):1461-5; 3Salari N, et al. BMC Endocr Disord. 2021 Jun 19;21(1):125. | |
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| PNPLA3 148I (WT)<br>Isoleucine (ATC)<br>PNPLA3 148M (Mutant)<br>Methionine (ATG)<br>PNPLA3 148V<br>(Axiomer de-novo variant)<br>Valine (GTG)<br>ProQR Therapeutics – Investor and Analyst Event 2024 89<br>Axiomer creates a PNPLA3 protein with<br>WT-like functionality<br>Electrostatic potential Hydrophobicity<br>In silico analysis of variants<br> • 148M shows a non-conservative substitution<br>with predicted functional<br>consequences, with change<br>in binding cavity volume<br>limiting access of substrate<br>to the active site<br> • Equivalent potential between<br>Isoleucine (WT) or Valine<br>(Axiomer correction) at<br>location 148 in 3D models<br> • 148I and 148V predict no<br>functional consequences<br>for PNPLA3, with valine<br>expected to behave like<br>isoleucine<br>F226 not included here | |
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| PNPLA3 148V variant has WT-like lipid<br>metabolizing properties<br>148I and 148V reports equivalence in lipid droplet sizes<br>ProQR Therapeutics – Investor and Analyst Event 2024 90<br>148I (WT) 148M (mut) 148V (de-novo)<br>Treatment conditions: HeLa cells, plasmid, transfection, 250uM linoleic acids, 24h, cell lipase activity by IF One-way ANOVA, ****, P<0.0001; Mean, SEM.<br>148I<br>Mean area of Bodipy per cell (µm2)<br>148M 148V<br>Hoechst (nuclei), Bodipy (Lipids) and M2 anti-flag (PNPLA3)<br> • The wild-type 148I shows<br>smaller lipid droplets,<br>reflecting normal lipid<br>metabolism<br> • The 148M variant induces<br>significantly larger lipid<br>droplets, consistent with its<br>pathogenic role in lipid<br>metabolism disorders<br> • The corrected variant 148V<br>results in wild-type like<br>droplet sizes, suggesting a<br>corrective effect on lipid<br>accumulation, similar<br>to 148I | |
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| ProQR Therapeutics – Investor and Analyst Event 2024 91<br>EON mediated PNPLA3 editing leads to over<br>50% RNA editing and change in lipid droplet<br>Editing of PNPLA3 in PHH<br>100nM EON, transfection, 72h, dPCR, mean,<br>SEM, n=3<br>Change in intracellular lipid droplets post<br>PNPLA3 148V EON treatment in HepG2<br>Bodipy/DAPI stainings, 5µM EON, transfection, exposure to<br>linoleic acid, mean, SEM, n=2<br>Control EON A EON B EON C<br>0<br>20<br>40<br>60<br>Editing (%)<br>24 hours 48 hours 120 hours<br>-40<br>-30<br>-20<br>-10<br>0<br>% Change compared to Mock | |
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| Summary & next steps<br>AX-2911 for MASH<br>ProQR Therapeutics – Investor and Analyst Event 2024 92<br>Final optimization of<br>AX-2911 EONs ongoing for<br>clinical candidate selection<br>in 2025<br>Development activities to<br>start in 2025<br>Expected 3-6 monthly<br>dosing interval<br>subcutaneous<br>GalNAc-delivered<br>Start clinical trial in 2026 | |
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| Daniel A. de Boer<br>Closing summary<br>ProQR Therapeutics – Investor and Analyst Event 2024 93 | |
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| DEVELOPMENT PIPELINE<br>AX-0810 for Cholestatic diseases NTCP CTA filing in Q2 2025 ~100K patients<br>AX-2402 for Rett syndrome MECP2 R270X Candidate selection in 2025 ~5K patients<br>AX-1412 for Cardiovascular disease B4GALT1 Scientific update in mid 2025 ~200M patients<br>AX-2911 for MASH PNPLA3 Candidate selection in 2025 ~8M patients<br>DISCOVERY PIPELINE<br>AX-1005 for CVD Undisclosed ~200M patients<br>AX-0601 for obesity and T2D Undisclosed ~650M patients<br>AX-9115 for rare metabolic condition Undisclosed<br>AX-2403 for Rett syndrome MECP2 R168X ~6K patients<br>AX-2404 for Rett syndrome MECP2 R255X ~5K patients<br>AX-2405 for Rett syndrome MECP2 R294X ~6K patients<br>AX-2406 for Rett syndrome MECP2 R133H<br>AX-3875 for rare metabolic & CNS disorder Undisclosed<br>AX-4070 for rare CNS disorder Undisclosed<br>PARTNERED PIPELINE<br>10 targets (option to expand to 15) Undisclosed<br>ProQR Therapeutics – Investor and Analyst Event 2024<br>ProQR development pipeline<br>1Approximately 100K people affected with Primary Sclerosing Cholangitis and Biliary Atresia in US and EU5. 2Approximately 200 million people suffer from too high a level of cholesterol in US and EU5. SLC10A1 is the gene that encodes for NTCP protein.<br>CVD: Cardiovascular Diseases, NASH: Nonalcoholic steatohepatitis, T2D: Type 2 Diabetes. | References: Trivedi PJ, et al. Clin Gastroenterol Hepatol. 2022 Aug;20(8):1687-1700.e4; Schreiber RA, et al. J Clin Med. 2022 Feb 14;11(4):999; Tsao CW, et al.<br>Circulation. 2022;145(8):e153–e639. World Health Organization, World Gastroenterology Organization<br>94<br>Progress undisclosed<br>TARGET DISCOVERY NON-CLINICAL CLINICAL NEXT MILESTONE<br>ESTIMATED<br>POPULATION |
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| AX-0810 for Cholestatic disease<br> • CTA submission Q2 2025<br> • Top-line data Q4 2025<br>AX-2402 for Rett Syndrome<br> • Clinical candidate selection in 2025<br> • Anticipated trial start and top-line data in<br>2026<br>AX-1412 for Cardiovascular disease<br> • Non-clinical data update in mid 2025<br>AX-2911 for MASH<br> • Clinical candidate selection in 2025<br> • Anticipated trial start and top-line data in<br>2026<br>Partnerships<br> • Opportunity to earn up to $3.75B in<br>milestones in the Lilly partnership<br> • Opportunity to receive a $50 M opt-in fee<br>from Lilly for expansion to 15 targets<br> • Opportunity for other strategic<br>partnerships<br>ProQR Therapeutics – Investor and Analyst Event 2024 95<br>Catalyst overview<br>4 trial readouts expected in 2025-2026, cash runway into mid-2027 | |
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| Well positioned<br>to advance Axiomer<br>ProQR Therapeutics – Investor and Analyst Event 2024 96<br> €<br>Clinical trial results across 4 trials in<br>2025 and 2026 expected<br> • Clinical PoC data of NTCP trial in 2025<br> • Up to 4 clinical trials with data readouts in 2025/2026<br>Rich discovery pipeline with potential<br>for broad pipeline expansion<br> • Large number of potential therapeutic applications in<br>discovery pipeline<br> • Broad applicability beyond current discovery pipeline<br>Leading IP position<br> • Axiomer is protected by >20 published patent families<br> • Continuously investing in expanding IP estate<br>Validating Strategic Partnerships<br> • Eli Lilly collaboration valued up to $3.9B, with opportunity<br>for near-term milestones<br> • Rett Syndrome Research Trust cofinancing of AX-2402<br>program<br> • Selectively form additional partnerships<br>Strong balance sheet<br> • €89.4 million cash and cash equivalents as of end of Q3,<br>plus $82.1 million gross proceeds from October financing<br> • Cash runway to mid-2027, excluding potential for<br>additional BD-related upside | |
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| Q&A | |
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| Daniel de Boer<br>Founder and<br>Chief Executive Officer<br>Gerard Platenburg<br>Chief Scientific Officer<br>René Beukema<br>Chief Corporate<br>Development Officer<br>Q&A | |
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| IT’S IN<br>OUR RNA | |
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