ProQR Reports First Human Validation of RNA Editing Platform in Liver Disease

Key Points

• First-in-human validation: ProQR reported dose-dependent target engagement for AX-0810, its RNA-editing treatment designed to modulate the NTCP liver transporter. The company said no serious adverse events or clinically significant liver-enzyme changes occurred in the first two cohorts.
• Potential for cholestatic liver disease: AX-0810 increased plasma bile acids by up to eightfold and showed evidence of urinary elimination, supporting ProQR’s strategy to reduce bile-acid retention in the liver. The program initially targets pediatric biliary atresia, a disease in which 60% to 80% of patients may ultimately need a liver transplant.
• Next development milestones: ProQR expects initial data from the first two cohorts of more potent, longer-lasting AX-0811 in early January 2027. An investigator-initiated study in 10 post-Kasai biliary atresia patients in China is expected to begin interim analysis in the first half of 2027.

ProQR Therapeutics NASDAQ: PRQR said its first-in-human data for AX-0810 provided dose-dependent evidence that its RNA-editing approach can modulate NTCP, a liver transporter involved in bile acid uptake. The company is developing NTCP programs for cholestatic liver diseases, initially focusing on pediatric biliary atresia.

At a virtual investor and analyst educational event, Chief Executive Officer Daniel de Boer said AX-0810 represents the first clinical validation of ProQR’s Axiomer ADAR-mediated RNA-editing platform in humans. He said the company’s next-generation candidate, AX-0811, is designed to offer greater potency and durability. AX-0811 has entered a phase I study, with initial data from its first two cohorts expected in early January 2027.

AX-0810 Target-Engagement Findings

ProQR’s Head of Hepatology, Golnar Karimian, said biliary atresia is a severe pediatric cholestatic disease affecting approximately 20,000 patients globally. The disease involves impaired bile flow and accumulation of toxic bile acids in the liver. While patients typically receive a Kasai portoenterostomy surgery early in life, Karimian said 60% to 80% ultimately require liver transplantation in early childhood.

The company’s strategy is to use RNA editing to selectively reduce NTCP-mediated reuptake of conjugated bile acids into liver cells. According to ProQR, this could shift bile acids from the liver into the bloodstream and support their elimination through urine, with the aim of reducing intrahepatic cholestasis.

In the phase I AX-0810 trial, healthy volunteers received four weekly subcutaneous doses at 3 milligrams per kilogram or 6 milligrams per kilogram. ProQR evaluated target engagement through clearance of orally administered TUDCA, changes in conjugated bile acids and total plasma bile acids.

• ProQR reported no serious adverse events in the first two cohorts and no clinically significant changes in liver enzymes.
• The company said there were no observed cases of pruritus, no changes in hormone or vitamin D levels, and no bilirubin changes across cohorts.
• Available pharmacokinetic data supported an estimated AX-0810 half-life of eight weeks, according to the company.
• ProQR reported statistically significant, dose-dependent target engagement across its three planned biomarker measures, including up to an eightfold increase in serum total bile acids.

Karimian said urinary data indicated that conjugated bile acids were eliminated through renal excretion in a pattern aligned with their plasma increase. In response to an analyst question, ProQR said it had not measured fecal bile acid excretion in the study.

Biliary Atresia Rationale

Gideon Hirschfield, professor of gastroenterology and hepatology at the University of Toronto, said toxic bile acid retention is an important contributor to cholestatic liver injury, inflammation and fibrosis. He noted that biliary atresia includes both extrahepatic and intrahepatic cholestasis and can progress despite surgical intervention.

Hirschfield said patients with rare genetic NTCP deficiency can have elevated conjugated bile acids in circulation without significant liver injury, pruritus or renal injury. He said this observation supports the rationale for selectively targeting NTCP to reduce bile acid retention in the liver.

ProQR also cited preclinical results for AX-0811 in a humanized mouse model. The company said AX-0811 reduced hepatocyte bile acid levels by 67% and reduced histological cholestasis scores by 67% in a model of bile duct obstruction. These results have not yet been demonstrated in patients with biliary atresia.

Next Steps for AX-0811 and Biliary Atresia

Chief Medical Officer Cristina López-López said preclinical modeling projects approximately 40% RNA editing at a 2 mg/kg dose of AX-0811 and approximately 65% editing at 4 mg/kg. The company expects AX-0811 to have a projected half-life of more than three months and potentially support dosing less frequently than once per quarter.

ProQR plans to use the same target-engagement measures for AX-0811 as it used for AX-0810, with TUDCA clearance serving as a key measure of NTCP-specific pharmacodynamic activity. De Boer said the initial AX-0811 data will inform the decision on whether AX-0810 or AX-0811 advances into a biliary atresia investigator-initiated trial, although the company expects AX-0811 to move forward based on its preclinical profile.

The planned investigator-initiated study in China will evaluate two dose levels in 10 post-Kasai biliary atresia patients ages 5 to 11 who retain their native livers. The study is expected to assess safety, pharmacokinetics, target engagement, liver enzymes, fibrosis and liver-function biomarkers, and liver stiffness measured by ultrasound elastography. ProQR expects an interim analysis in the first half of 2027.

The company’s planned phase II program is expected to include two cohorts of post-Kasai patients with native livers. ProQR said it currently expects a 12-week interim analysis in mid-2028 and plans to provide further information on endpoints and the registration path following discussions with regulators.

About ProQR Therapeutics (NASDAQ:PRQR)

ProQR Therapeutics N.V. NASDAQ: PRQR is a biotechnology company focused on developing RNA-based medicines for genetic and other serious diseases. The company's research platform is designed to modify RNA and potentially correct disease-causing genetic defects without permanently changing a patient's DNA.

ProQR has primarily pursued treatments for inherited retinal disorders and other conditions affecting the eye. Its pipeline has included investigational RNA therapies such as sepofarsen, developed for Leber congenital amaurosis type 10, and ultevursen, developed for Usher syndrome type 2A.

This instant news alert was generated by narrative science technology and financial data from MarketBeat in order to provide readers with the fastest reporting and unbiased coverage. Please send any questions or comments about this story to contact@marketbeat.com.