ProQR Announces Preclinical Proof of Concept Data for AX-0810 Axiomer RNA Editing Program Targeting NTCP for Cholestatic Diseases

ProQR Therapeutics NV recently announced new preclinical data for its proprietary Axiomer RNA editing technology platform, including the first preclinical proof of concept data for its AX-0810 pipeline program for cholestatic diseases targeting NTCP.

“Our Axiomer ADAR RNA editing data at ASGCT show the exciting potential of our technology and for the first time in the field we report proof of target engagement leading to meaningful changes in biomarkers in NHPs,” said Gerard Platenburg, Chief Scientific Officer and co-founder, ProQR. “In our AX-0810 program targeting NTCP for cholestatic diseases, we have demonstrated preclinical proof of concept showing that Axiomer RNA editing oligonucleotides can have a meaningful effect on levels of serum biomarker bile acid. We believe this is a significant derisking step as we approach the clinic as our NHP studies closely resemble the design of the first in human trial that will focus on target engagement and biomarkers. We look forward to sharing translational data for our AX-0810 program and to announcing our clinical program candidate later this year, as we progress to enter the clinic in late 2024/early 2025.”

AX-0810 is an editing oligonucleotide (EON) development program targeting the SLC10A1 RNA using the Axiomer technology, providing a transient and controlled approach that aims to reduce bile acids concentration in the liver. By specifically affecting the main transporter for bile acids reuptake from the portal vein circulation to the liver, called NTCP (Na-taurocholate transporting polypeptide, SLC10A1 gene), the AX-0810 program represents a promising avenue to ameliorate the progression of cholestatic disorders.

As reported [ASGCT 2024, P-705], modulation of NTCP at different levels of editing leads to an increase in the biomarker Total Bile Acid in serum. Data presented include:

• Axiomer EONs can specifically modulate NTCP protein bile acids reuptake function while preserving expression of the protein. A strong correlation (R² = 0.51) was reported between editing levels of NTCP and bile acids change in the serum in NHP in vivo.
• An early generation of ProQR’s Axiomer editing oligonucleotides (EONs), EON1, yielded up to 29% editing of NTCP in the liver of non-human primates (NHPs) after a single dose and, importantly, this led to an 8-fold change in the serum biomarker bile acids 72 hours after treatment.
• Further optimizations for EONs targeting NTCP have enabled achievement of up to 60% editing (in vitro).
• Results reported in NHPs confirmed findings in in vitro models and showed translatability across models.

ProQR is developing its AX-0810 program targeting NTCP for Cholestatic Diseases and plans to advance the program to the clinic in late 2024/early 2025. ProQR also expects the following Axiomer pipeline program milestones in 2024:

• AX-0810 clinical development candidate translational data to be reported in H2 2024, with further detail on design for the clinical trial.
• AX-1412 preclinical proof of concept data and translational data to be reported in H2 2024, with program to advance to the clinic in late 2024/early 2025. AX-1412 is the Company’s Axiomer program targeting B4GALT1 for cardiovascular disease.

ProQR is pioneering a next-generation RNA base editing technology called Axiomer, which could potentially yield a new class of medicines for diverse types of diseases. Axiomer “Editing Oligonucleotides”, or EONs, mediate single nucleotide changes to RNA in a highly specific and targeted way using molecular machinery that is present in human cells called ADAR (Adenosine Deaminase Acting on RNA). Axiomer EONs are designed to recruit and direct endogenously expressed ADARs to change an Adenosine (A) to an Inosine (I) in the RNA – an Inosine is translated as a Guanosine (G) – correcting an RNA with a disease-causing mutation back to a normal (wild type) RNA, modulating protein expression, or altering a protein so that it will have a new function that helps prevent or treat disease.

ProQR Therapeutics is dedicated to changing lives through the creation of transformative RNA therapies. ProQR is pioneering a next-generation RNA technology called Axiomer, which uses a cell’s own editing machinery called ADAR to make specific single nucleotide edits in RNA to reverse a mutation or modulate protein expression and could potentially yield a new class of medicines for both rare and prevalent diseases with unmet need. Based on our unique proprietary RNA repair platform technologies we are growing our pipeline with patients and loved ones in mind. For more information, visit www.proqr.com.