Positive Phase 2a Data Suggest Disease-Modifying Potential of CNP-104 in PBC

Christopher Bowlus, MD

Credit: UC Davis Health

COUR Pharmaceuticals has announced positive 120-day data from its phase 2a study evaluating CNP-104 as a potential treatment for patients with primary biliary cholangitis (PBC).¹

Study findings suggest CNP-104 may be poised to become the first disease-modifying treatment for PBC, with results through 120 days highlighting its potential efficacy across multiple immunological and clinical measurements as well as its safety and tolerability.¹

“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,” Christopher Bowlus, MD, the Lena Valente Professor and chief of the division of gastroenterology and hepatology at UC Davis, and principal investigator for the study, said in a press release.¹ “While these data are early and from a small number of patients, they are incredibly promising and merit future investigation.”

Ursodeoxycholic acid (UDCA) serves as first-line therapy for patients with PBC, but many do not respond or are unable to tolerate the treatment, necessitating second-line alternatives. For many years, obeticholic acid (OCA) was the only other option for these patients. However, the recent accelerated approvals of a pair of PPAR agonists, elafibranor (Iqirvo) and seladelpar (Livdelzi), as second-line therapies have greatly expanded the PBC treatment landscape.^2,3

A biodegradable nanoparticle encapsulating the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC), CNP-104 may be poised to become another therapy in the growing PBC treatment armamentarium. Unlike current therapies, it aims to address the root cause of PBC by inducing tolerance to pathogenic activated PDC-E2 T-cells driving inflammation in bile ducts, leading to improvement in clinical outcomes of liver health. Of note, CNP-104 received Fast Track Designation from the United States Food and Drug Administration in January 2022.^1,4

The phase 2a first-in-human, proof-of-concept, randomized clinical trial is designed to assess the safety, tolerability, pharmacodynamics, and efficacy of CNP-104 in patients 18-75 years of age 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, with all patients receiving 2 IV loading doses administered 1 week apart.¹

Of the 41 subjects dosed, the final randomization ratio approximated 1:1:1 placebo to 4 mg/kg CNP-104 to 8 mg/kg CNP-104. Data announced by COUR consider the 120-day primary study period while the 20-month long-term safety evaluation is ongoing.¹

According to the press release, treatment with CNP-104 led to a slowing of disease progression in liver stiffness on Fibroscan, reaching a statistically significant decrease on day 120 in the active arms compared with placebo (P = .011). Additionally, study participants in the placebo arm experienced a greater trending decrease in albumin levels compared with patients treated with CNP-104.¹

Results showed CNP-104 demonstrated a favorable T cell response in pathogenic CD4 T cell populations and tolerance inducin- CD8 T cells, and 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). Of note, CNP-104 was safe and well tolerated, with all drug-related adverse events being mild and no drug-related severe adverse events reported.¹

“These data highlight the potential of CNP-104 to be the first disease-modifying treatment for people living with PBC,” Paul Peloso, MD, Chief Medical Officer of COUR Pharmaceuticals, said in a press release.¹ “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, with Fibroscan being a surrogate for reductions in fibrosis. These data suggest that CNP-104 has the potential to halt disease progression which would be a transformational advancement for people living with PBC. We look forward to presenting these encouraging data at an upcoming scientific meeting.”

References

1. ^{Cour Pharmaceuticals. COUR Pharmaceuticals Announces Positive Top-line Results from Phase 2a Study of CNP-104 in Primary Biliary Cholangitis. September 30, 2024. Accessed September 30, 2024. https://www.globenewswire.com/en/news-release/2024/09/30/2955143/0/en/COUR-Pharmaceuticals-Announces-Positive-Top-line-Results-from-Phase-2a-Study-of-CNP-104-in-Primary-Biliary-Cholangitis.html}
2. ^{Brooks, A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed September 30, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-elafibranor-iqirvo-for-pbc}
3. ^{Brooks, A. FDA Grants Accelerated Approval to Seladelpar (Livdelzi) for Primary Biliary Cholangitis. HCPLive. August 14, 2024. Accessed September 30, 2024. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis}
4. ^{Cour Pharmaceuticals. COUR Pharmaceuticals Receives FDA Fast Track Designation for CNP-104 for the Treatment of Primary Biliary Cholangitis. January 10, 2022. Accessed September 30, 2024. https://www.prnewswire.com/news-releases/cour-pharmaceuticals-receives-fda-fast-track-designation-for-cnp-104-for-the-treatment-of-primary-biliary-cholangitis-301456793.html}