ProQR Therapeutics has submitted a Clinical Trial Application (CTA) to the European Medicines Agency (EMA) to initiate a Phase 1 clinical trial of AX-0810, an investigational RNA editing oligonucleotide targeting NTCP for cholestatic liver disease treatment. This submission represents the first clinical advancement of ProQR's proprietary Axiomer RNA editing technology platform.
Novel Therapeutic Approach for Cholestatic Liver Disease
AX-0810 is designed to treat cholestatic liver diseases by targeting NTCP, a liver cell protein that transports bile acids into cells. These diseases are characterized by toxic bile acid accumulation due to impaired bile flow, leading to progressive liver damage including inflammation, fibrosis, and potential progression toward liver failure.
The investigational drug offers a novel therapeutic mechanism by selectively modulating NTCP function to decrease bile acid reuptake into the liver. This approach is supported by human genetics data demonstrating that naturally occurring NTCP variants safely reduce bile acid reuptake, reinforcing the therapeutic potential of NTCP modulation through ADAR-mediated RNA editing.
"Cholestatic liver diseases represent an area of high unmet medical need and by targeting NTCP, AX-0810 introduces a novel therapeutic approach underpinned by human genetics and compelling preclinical data," said Cristina Lopez Lopez, MD, PhD, Chief Medical Officer of ProQR.
Phase 1 Study Design and Timeline
The proposed Phase 1 study will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AX-0810 in healthy adult volunteers. The study will also explore biomarkers to assess early signals of target engagement. Pending regulatory clearance, the study is expected to commence at a single site in the Netherlands with initial data anticipated in Q4 2025.
AX-0810 is formulated as a GalNac-delivered RNA editing oligonucleotide, utilizing ProQR's Axiomer platform technology for targeted delivery and precise RNA editing.
Axiomer RNA Editing Technology Platform
ProQR's Axiomer platform represents a next-generation RNA base editing technology that could potentially yield a new class of medicines for diverse diseases. Axiomer "Editing Oligonucleotides" (EONs) mediate single nucleotide changes to RNA using endogenous cellular machinery called ADAR (Adenosine Deaminase Acting on RNA).
The technology works by recruiting and directing endogenously expressed ADARs to change an Adenosine (A) to an Inosine (I) in RNA, which is translated as a Guanosine (G). This mechanism can correct disease-causing mutations back to normal RNA, modulate protein expression, or alter proteins to gain new therapeutic functions.
Clinical Development Milestone
"The submission of this CTA marks a significant milestone for ProQR, representing the first to advance our Axiomer RNA editing platform and pipeline into clinical development," Lopez Lopez stated. "This step brings us into the clinic with AX-0810 as we initiate a Phase 1 study to evaluate safety and target engagement in healthy volunteers."
The advancement of AX-0810 into clinical trials demonstrates the maturation of ProQR's RNA editing platform from preclinical research to human testing, potentially opening new therapeutic avenues for both rare and prevalent diseases with unmet medical needs.
