ProQR Therapeutics (PRQR) Study Update summary

Strategic Overview and Scientific Rationale

• AX-0810, an RNA editing oligonucleotide, enters first-in-human trials after CTA approval in Europe, targeting NTCP to address cholestatic diseases such as PSC and biliary atresia.

• The Axiomer platform enables precise, single-nucleotide RNA editing using endogenous ADAR enzymes, offering potential to repair mutations and modulate protein function without altering DNA.

• NTCP modulation aims to reduce toxic bile acid accumulation in the liver, addressing a core driver of cholestatic disease progression.

• Human genetics and preclinical data support NTCP as a safe and effective target, with healthy individuals showing reduced bile acid uptake and no adverse effects.

• AX-0810 is positioned as a first-in-class, disease-modifying therapy for severe, unmet needs in cholestatic diseases.

Unmet Medical Need and Disease Background

• PSC and biliary atresia are severe, progressive diseases often leading to liver transplantation, with high recurrence and mortality rates.

• Biliary atresia accounts for nearly half of pediatric liver transplants in Europe.

• Cholestatic diseases result from bile acid accumulation in the liver, causing inflammation, cell death, and fibrosis.

• Current therapies like IBAT inhibitors are ineffective in many cases due to limited bile acid secretion; NTCP inhibition offers a direct approach.

• NTCP deficiency in humans is well-tolerated, with high plasma bile acids but minimal clinical symptoms, supporting the safety of this approach.

Mechanism of Action and Biomarker Strategy

• AX-0810 modulates NTCP via A-to-I RNA editing, limiting bile acid reuptake and reducing hepatocyte toxicity.

• Biomarker strategy includes measuring total and conjugated plasma bile acids, and TUDCA clearance to confirm NTCP specificity and target engagement.

• A TUDCA challenge is used to assess NTCP function and dose discrimination in healthy volunteers.

• Biomarker assessments are standardized and scheduled throughout the trial to minimize variability and ensure robust pharmacodynamic data.

• Exploratory biomarkers, including C4 and bile acid profiles, are collected to elucidate feedback mechanisms and safety.