COUR Pharmaceuticals has announced positive 120-day data from its phase 2a study evaluating CNP-104 as a potential disease-modifying treatment for patients with primary biliary cholangitis (PBC). The study suggests CNP-104 could be the first therapy to address the root cause of PBC by inducing tolerance to pathogenic activated PDC-E2 T-cells, which drive inflammation in bile ducts.
Addressing Unmet Needs in PBC Treatment
While ursodeoxycholic acid (UDCA) is the first-line therapy for PBC, many patients do not respond or cannot tolerate it, necessitating second-line alternatives like obeticholic acid (OCA), elafibranor (Iqirvo), and seladelpar (Livdelzi). However, these current therapies do not address the underlying autoimmune cause of the disease.
"Despite the recent evolution of the PBC treatment landscape, there remains a significant unmet need for new treatments. Unlike CNP-104, current therapies do not address the root cause of the disease," said Christopher Bowlus, MD, principal investigator for the study.
CNP-104: A Novel Approach
CNP-104 is a biodegradable nanoparticle encapsulating the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC). It aims to induce tolerance to pathogenic activated PDC-E2 T-cells, which drive inflammation in bile ducts, potentially improving clinical outcomes of liver health. The FDA granted CNP-104 Fast Track Designation in January 2022.
Phase 2a Trial Design and Results
The phase 2a trial is a first-in-human, proof-of-concept, randomized clinical trial designed to assess the safety, tolerability, pharmacodynamics, and efficacy of CNP-104 in patients aged 18-75 years who are unresponsive to treatment with UDCA and/or OCA. Participants received 4 mg/kg or 8 mg/kg of CNP-104 or placebo on days 1 and 8, administered intravenously one week apart.
Of the 41 subjects dosed, the randomization ratio approximated 1:1:1 (placebo to 4 mg/kg CNP-104 to 8 mg/kg CNP-104). The data announced by COUR consider the 120-day primary study period, while the 20-month long-term safety evaluation is ongoing.
Treatment with CNP-104 led to a statistically significant slowing of disease progression in liver stiffness on Fibroscan at day 120 in the active arms compared with placebo (P = .011). Additionally, participants in the placebo arm experienced a greater decrease in albumin levels compared with patients treated with CNP-104.
Results also demonstrated a favorable T cell response in pathogenic CD4 T cell populations and tolerance-inducing CD8 T cells. Th17 T cells decreased in both number and percentage mean change, with statistically significant higher rates of response in the active arms versus placebo at day 120 (P = .0037). CNP-104 was safe and well-tolerated, with all drug-related adverse events being mild and no drug-related severe adverse events reported.
Implications for PBC Treatment
"These data highlight the potential of CNP-104 to be the first disease-modifying treatment for people living with PBC," said Paul Peloso, MD, Chief Medical Officer of COUR Pharmaceuticals. "In addition to safety and tolerability data supporting further studies, we observed multiple immunological and clinical measurements supporting mechanistic proof of concept for CNP-104. Additionally, we observed positive clinical endpoints such as a reduction in liver stiffness measured on Fibroscan in the active arms compared to placebo... These data suggest that CNP-104 has the potential to halt disease progression which would be a transformational advancement for people living with PBC."
