ProQR Therapeutics (NASDAQ:PRQR) outlined multiple pipeline updates and development priorities during its virtual investor and analyst event, highlighting upcoming clinical readouts for its lead RNA editing program AX-0810, a next-generation follow-on candidate (AX-0811), and the addition of two programs, AX-0422 for Hurler syndrome and AX-2911 for metabolic dysfunction-associated steatohepatitis (MASH).
AX-0810: Phase I target engagement data expected this quarter
Chief Executive Officer Daniel de Boer said ProQR remains on track to report target engagement data from its ongoing Phase I healthy volunteer study of AX-0810 “later this quarter,” describing it as a key milestone designed to demonstrate engagement on bile acid transport. Chief Medical Officer Dr. Cristina López-López said initial data from the first cohort showed a “favorable safety and tolerability profile,” with pharmacokinetics consistent with non-clinical observations.
The Phase I study’s biomarker-based target engagement strategy includes three readouts, according to López-López:
- Total bile acids in serum (with a two-fold increase described as a meaningful indicator of NTCP modulation)
- Bile acid profile, with focus on changes in conjugated bile acids
- A TUDCA challenge test as a functional readout of NTCP-mediated transport
In the Q&A, López-López clarified that the two-fold threshold for total bile acids would be evaluated “both compared to baseline as well as compared to placebo.” Management also emphasized the trial remains double-blind and placebo-controlled, and the company has not reviewed unblinded data.
Following healthy volunteer assessments, López-López said ProQR plans to open a patient cohort in primary sclerosing cholangitis (PSC), with data expected “at the end of this year.” She said the PSC cohort is intended to help bridge translation from healthy volunteers to disease context and inform dose frequency and expected effect size as the company advances toward pediatric development in biliary atresia.
Biliary atresia selected as initial Phase II indication; PSC remains a follow-on
López-López announced ProQR has selected biliary atresia as the initial indication for Phase II development of AX-0810. She described biliary atresia as a severe pediatric cholestatic disease affecting “approximately 20,000 patients worldwide,” with no approved pharmacological therapies that modify disease progression. She added that biliary atresia accounts for “approximately 45% of all pediatric liver transplants,” and that “60%-80% of patients ultimately require liver transplantation before adulthood” even with Kasai portoenterostomy.
In response to analyst questions, López-López said the company is “not moving away from PSC,” but is prioritizing biliary atresia based on the combination of unmet need, biological clarity, and development feasibility. On development strategy, she said the company expects to pursue an accelerated pathway using liver biomarkers and measures of liver health and stiffness, with longer-term follow-up as a post-market commitment, pending regulatory discussions. She also noted ProQR expects to treat “different stages of the disease post Kasai procedure,” with Phase II design details still to come.
Next-generation NTCP program AX-0811 to advance in parallel
De Boer and management positioned AX-0811 as a next-generation exomer editing oligonucleotide targeting NTCP, generated using ProQR’s AI-enabled discovery engine. De Boer said ProQR expects to file a CTA for AX-0811 in “mid-2026,” with initial clinical data expected “by the end of this year.” (Later in the event, management also described a CTA filing “this year” with initial healthy-volunteer data before year-end.)
López-López highlighted platform-driven improvements, stating ProQR’s AI-driven high-throughput screening model has reduced discovery timelines from up to three years to roughly six months, and can produce editing oligonucleotides with up to sixfold increases in editing efficiency compared to earlier designs. For AX-0811 specifically, she said humanized mouse models showed editing efficiencies “around 60%,” a roughly threefold increase versus the prior generation, with improved stability. In Q&A, management attributed gains to AI-guided optimization across factors including sequence length and chemical modifications, without disclosing specifics.
AX-0422 for Hurler syndrome returns to ProQR; CNS expansion strategy
ProQR introduced AX-0422 (also referred to as AXS-422 during the event), an RNA editing therapy targeting IDUA for Hurler syndrome (MPS I). De Boer said the program originated from internal discovery and was advanced under the company’s partnership with Eli Lilly, but following a portfolio review ProQR will regain full rights, allowing it to advance AX-0422 as a wholly owned asset. De Boer said the broader Lilly collaboration continues “without any change in priority,” with multiple programs progressing.
López-López said AX-0422 is designed to correct the Trp402X nonsense variant—described as the most common severe mutation in IDUA—back to wild type at the RNA level. She presented preclinical data showing approximately 20% of wild-type IDUA enzymatic activity restored in liver at eight weeks after subcutaneous delivery, along with dose-dependent reductions in glycosaminoglycans (GAGs), including “almost 90%” reduction in urine versus control. She also cited head-to-head animal model data comparing RNA editing to enzyme replacement therapy (ERT), describing urinary GAG reductions of “over 90%” with RNA editing versus “around 60%” with ERT, and improvement in a motor skill test.
Beyond systemic effects, López-López said preclinical brain delivery showed restoration of enzymatic activity across multiple brain regions. Management described a two-step clinical approach: liver-directed editing first, followed by intrathecal administration to address CNS manifestations. In Q&A, López-López said ProQR anticipates intrathecal dosing “once every 9-12 months” and subcutaneous dosing “once every 3-6 months,” noting CNS dosing durability is generally longer than liver residence time for oligonucleotides.
On timing, management said CTA-enabling activities are ongoing, with a CTA filing expected in early 2027 and initial clinical data anticipated in the first half of 2027. Gerard Platenburg, ProQR’s Chief Scientific Officer, said the literature suggests restoration of approximately “1%-15%” of normal IDUA enzymatic function can improve disease phenotype, and said the company observed ~21% restoration associated with near normalization of urinary GAGs in its data.
AX-2911 targets PNPLA3 for MASH; China investigator-initiated trial planned
ProQR also highlighted AX-2911, targeting the PNPLA3 I148M variant, which López-López called the “strongest known genetic risk factor” for liver disease progression in MASH and said is carried by about half of MASH patients. She estimated homozygous carriers represent “approximately 8 million individuals in the U.S. and EU.”
Discussing preclinical proof-of-concept, López-López said ProQR used a humanized model incorporating primary human hepatocytes carrying the homozygous variant. In the comparison presented, an antisense oligonucleotide (ASO) knockdown approach achieved ~90% PNPLA3 mRNA knockdown and a 36% reduction in lipid droplets, while AX-2911 achieved 23% RNA editing with an approximately 80% reduction in lipid droplets. Platenburg said ProQR believes correcting the mutation to restore a functional protein is a key differentiator versus knockdown.
On development strategy, López-López said ProQR declared a development candidate earlier this year and plans to advance AX-2911 through an investigator-initiated trial (IIT) in China to generate early clinical data while maintaining “capital discipline and flexibility.” She said the study is designed to assess safety, pharmacokinetics, and exploratory biomarkers related to liver fat and disease activity.
In closing remarks, management reiterated expectations for multiple data catalysts within the company’s cash runway, stating it remains funded into “mid-2027,” consistent with prior guidance. De Boer also highlighted platform initiatives, including an AI model built over the last 18 months, a strategic partnership with Ginkgo Bioworks to enable roboticized high-throughput data generation, and the creation of an AI advisory board to support AI and machine learning efforts.
About ProQR Therapeutics (NASDAQ:PRQR)
ProQR Therapeutics N.V. is a clinical-stage biotechnology company dedicated to developing RNA-based therapies for severe genetic diseases. Utilizing its proprietary Axiomer® RNA editing platform, ProQR aims to correct disease-causing mutations directly at the messenger RNA level. The company’s pipeline features several investigational candidates, including sepofarsen (formerly QR-110) for Leber congenital amaurosis type 10, QR-421a targeting Usher syndrome and certain forms of retinitis pigmentosa, and QR-313 for dystrophic epidermolysis bullosa.
Founded in 2012 and headquartered in Leiden, the Netherlands, ProQR maintains a significant presence in Cambridge, Massachusetts, to support its clinical research and regulatory initiatives.
