ProQR Therapeutics N.V. Ordinary Shares Investor update

Thank you all for joining us today. We're pleased to present our educational event, NTCP Modulation in Biliary Atresia via Liver-Targeted RNA Editing. During this presentation, we will make forward-looking statements, and actual results may differ materially from those described. Please refer to our SEC filings for a discussion of risks associated with an investment in ProQR. Let me now briefly walk you through today's agenda. We will start with opening remarks from our founder and CEO, Daniel de Boer. Next, Dr. Golnar Karimian, our Head of Hepatology, will discuss the rationale for NTCP modulation in biliary atresia and our recent target engagement clinical data with AX-0810.

We are also pleased to be joined today by Dr. Gideon Hirschfield, a leading hepatologist and professor of gastroenterology and hepatology at the Toronto Centre for Liver Disease, who will provide perspective on this and the role of bile acids in cholestatic liver disease. Dr. Cristina López-López, our Chief Medical Officer, will then discuss the next steps for our NTCP programs, including our clinical development plans in biliary atresia and how we will evaluate the upcoming AX-0811 phase I data. Finally, we will conclude with a Q&A session featuring today's speakers. With that, it is my pleasure to hand things over to Daniel.

Daniel? Thank you, Sarah. I'm Daniel de Boer, founder and CEO of ProQR, the leader in ADAR-mediated RNA editing.

Through our Axiomer RNA editing platform, we are building a diversified pipeline across a range of diseases with multiple clinical data readouts expected over the next 12 months. Most recently, we reported the first clinical data from our wholly-owned program, AX-0810. These results represent an important milestone for ProQR, providing the first clinical validation of our Axiomer platform in humans and demonstrating dose-dependent target engagement of NTCP, the main hepatic transporter involved in bile acid uptake in the liver. Beyond NTCP, we are also advancing wholly-owned programs in MPS I Hurler syndrome and PNPLA3-related MASH. In addition, our strategic partnership with Eli Lilly and Company, as well as our AI-enabled discovery efforts and collaboration with Ginkgo Bioworks, accelerate the potential of the platform.

Today, however, we are going to focus specifically on our NTCP programs and what the AX-0810 data tell us about the potential of this approach. AX-0810 has now demonstrated human target engagement of NTCP, and AX-0811, our next-generation AI-discovered NTCP program, is designed to build on that foundation with greater potency and durability. Earlier this month, we announced the AX-0811 phase I study is now underway, with initial data from the first two cohorts expected in early January 2027. These lead programs are being developed to address cholestatic liver disease, and our initial indication is biliary atresia, where we believe the biology of bile acid accumulation provides compelling rationale for NTCP modulation. The key question is how the human pharmacodynamics we have now observed with AX-0810 may translate into meaningful benefit for patients with biliary atresia.

Dr. Golnar Karimian will now take you through that rationale and data in more detail.

Golnar. Thank you, Daniel. Biliary atresia is a severe pediatric cholestatic disease that affects approximately 20,000 patients worldwide and is driven by toxic bile acid accumulation in the liver.

There are currently no approved pharmacological therapies that alter the course of the disease, and recent late-stage trial results underscore the need for approaches that act directly on liver. The current standard of care is early surgical intervention with the Kasai portoenterostomy, which is intended to restore some bile flow. However, Kasai is often not sufficient, and most patients will continue to progress, with 60%-80% ultimately requiring liver transplantation in early childhood. This highlights both the severity of the disease and the urgent need for therapies that can modify disease progression. Our approach aims to selectively modulate NTCP to reduce toxic bile acid re-uptake into the liver, lowering bile acid burden to reduce intrahepatic cholestasis.

Let's take a closer look at the normal enterohepatic cycle to understand the biology. In healthy individuals, bile acids are continuously recycled between the liver and the intestine, where they support digestion and absorption of lipids and fat-soluble vitamins. Approximately 95% of bile acids are reabsorbed from the intestine and return to the liver through blood circulation. NTCP is the main transporter responsible for recycling conjugated bile acids back into hepatocytes. In biliary atresia, however, this tightly regulated system is disrupted. Because bile flow is impaired, toxic bile acids accumulate in the liver and spill over into the circulation via increased activity of MRP3 and 4 transporters. This leads to an increase in conjugated and total bile acids in plasma. Persistent hepatic bile acid accumulation contributes to ongoing liver injury and intrahepatic cholestasis.

Early in the disease, this leads to an increase in liver enzymes such as ALT, AST, and GGT, as well as negative impact on liver function as seen with an increase in plasma bilirubin and other fibrosis biomarkers. In biliary atresia, this is associated with worse outcomes, including progression and reduced native liver survival. By modulating NTCP activity via RNA editing, our therapeutic approach aims to decrease the amount of bile acid re-entering hepatocytes, increasing bile acid levels in the plasma, and in turn, excretion in the urine of these bile acids. This pharmacodynamic pattern of relieving the burden of toxic bile acids in the liver aims to improve liver health biomarkers and ultimately clinical outcomes. The distinction between plasma and hepatic bile acids is central to understanding both our mechanism and the clinical data I will review shortly. Our in vivo preclinical data set supports this approach.

Starting on the left, in an advanced humanized mouse model, AX-0811 demonstrates a decrease in hepatocytes bile acid levels by 67%, showing effective modulation of NTCP-mediated bile acid uptake. There were corresponding reductions in bile acid levels downstream in the bile ducts in the middle of the slide and in the portal vein on the middle right. On the far right of the slide, the same model was challenged with a DDC diet, which induces bile duct obstruction and mimics key features of cholestatic liver disease. In that setting, Axiomer-mediated NTCP modulation reduced histological cholestasis scores by 67%, as assessed by an independent external histopathologist. Together, these data provide compelling proof of concept for the therapeutic mechanism that reducing NTCP-mediated bile acid uptake via RNA editing can protect the liver from toxic bile acid accumulation and substantially reduce intrahepatic cholestasis.

Turning now to the clinical data we reported earlier this year with AX-0810, the first in-human phase I study was designed to assess safety, tolerability, and pharmacokinetics, and to evaluate biomarker-based target engagement. Healthy volunteers received four weekly subcutaneous doses of AX-0810, and we assessed target engagement using three complementary biomarker approaches. First, we assessed clearance of orally administered TUDCA, which was intentionally selected because of its preferential NTCP-mediated hepatic uptake. Second, we assessed bile acids profile, including conjugated bile acids, which are specifically regulated through NTCP and provide a more direct assessment of the mechanism. Third, we measured total bile acids in plasma. With reduced NTCP-mediated hepatic uptake, we expected to see a concordant increase in bile acids in circulation. The current data set includes data from Cohorts 1 and 2, evaluating the 3 and 6 milligram per kilogram dose levels respectively.

Here are the baseline characteristics which show nice consistency across groups. Turning to safety, ability profile with Cohort 1 and 2 to date, there were no serious adverse events, and we observed no clinically significant changes in liver enzymes. In particular, we noted there was no occurrence of pruritus and no changes in hormone and vitamin D levels. We also saw no changes in bilirubin across cohorts, providing evidence that AX-0810 had no off-target effect on OATP, the main transporter of bilirubin, as expected with RNA editing. The pharmacokinetic profile was also consistent with our expectations, with the available data supporting an estimated half-life of eight weeks. Turning now to target engagement, we observed concordant, durable, statistically significant, and dose-dependent evidence of target engagement across all three independent biomarkers. The left and center panels demonstrate the specificity of our approach for NTCP rather than other hepatic transporters.