FDA Grants Orphan Drug Designation to CNP-104 for Primary Biliary Cholangitis

Key Takeaways

CNP-104 targets the root cause of PBC by inducing tolerance to pathogenic PDC-E2 T-cells, improving liver health outcomes.
The phase 2a trial showed CNP-104 reduced antigen-specific Th17 T cells and stabilized liver stiffness, indicating potential disease-modifying effects.
No serious adverse events were reported, and the trial demonstrated a favorable safety profile for CNP-104.
The trial's small size and data variability were noted as limitations, but results support further development of CNP-104 for PBC.

The designation follows positive phase 2a trial results (NCT05104853) presented at the 2024 AASLD The Liver Meeting.

The FDA granted orphan drug designation to CNP-104 (COUR Pharmaceuticals) for the treatment of patients with primary biliary cholangitis (PBC).¹ The designation follows positive top line data from a phase 2a clinical trial (NCT05104853) which were presented at the 2024 American Association for the Study of Liver Diseases (AASLD) The Liver Meeting held November 15 through 19, in San Diego, California.^1,2

Image credit: syahrir | stock.adobe.com

CNP-104 is a biodegradable nanoparticle that encapsulates the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC), which is a key autoantigen in PBC. The agent addresses the root cause of PBC and induces tolerance to pathogenic activated PDC-E2 T-cells—which are drivers behind the inflammation in bile ducts—leading to an improvement in clinical outcomes of liver health. In January 2022, CNP-104 received a fast track designation by the FDA.¹

The randomized, controlled, first-in-human phase 2a trial (NCT05104853) evaluated the potential role of CNP-104 in patients aged 18 to 75 years with PBC following treatment with ursodeoxycholic acid and/or obeticholic acid. Patients were randomly assigned to receive either 4mg/kg or 8 mg/kg of CNP-104 (25 patients between both dose groups) or matching placebo (n = 16), all of which were administered via 200-mL intravenous infusions on days 1 and 8. Following treatment, patients were followed for 120 days to assess safety and treatment durability.^2,3

About the Trial

Trial Name: Study to Evaluate the Safety, Tolerability, PDs, and Efficacy of CNP-104 in Subjects with Primary Biliary Cholangitis

ClinicalTrials.gov ID: NCT05104853

Sponsor: COUR Pharmaceutical Development Company, Inc.

Completion Date (Estimated): January 30, 2026

The primary end points of the study included frequency of adverse events (AEs) and serious AEs, laboratory safety assessments, and serum cytokines. Secondary end points included changes from baseline to in alkaline phosphatase (ALP) levels, liver fibrosis (measured by FibroScan), modified PBC-40 score, mean weekly itch score, and the change in antigen-specific CD4+ and CD8+ T cells.²

According to the results, patients who received CNP-104 had a reduction in the percentage of antigen-specific Th17 T cells compared with placebo at follow-up on day 120. No differences in ALP levels were observed between the groups; however, differences in liver stiffness by vibration-controlled transient elastography was considered statistically significant between treatment groups, with an observed increase in the placebo cohort and stability in CNP-104. A total of 4 subjects consented to a liver biopsy (CNP-104: n = 3; placebo: n = 1), suggesting a reduction in PanCK+ and CD3–CD4+ cells in CNP-104, which are markers of ductal pathology. The main limitations of the trial were its small size and variability in data.³

A total of 38 drug-related AEs occurred in 8 patients receiving CNP-104, all of which mild in severity. There were no observed drug-related serious AEs and no deaths. Additionally, there were no biochemical deviations, on hematology, coagulation, liver, and renal assessments. Further, no important safety risks identified.³

“Receiving orphan drug designation for CNP-104 underscores its potential to become the first disease-modifying treatment for individuals with PBC. This designation follows our presentation of positive topline data from the phase 2a clinical trial of CNP-104 in PBC at The Liver Meeting 2024,” said Dannielle Appelhans, president and CEO of COUR Pharmaceuticals in a news release. “Notably, in addition to demonstrating favorable T cell responses among treated participants, CNP-104 slowed disease progression, as evidenced by a statistically significant reduction in liver stiffness measured by FibroScan by day 120 of the study period.”¹

REFERENCES

1. GlobeNewswire. COUR Pharmaceuticals Secures FDA Orphan Drug Designation for CNP-104 in Primary Biliary Cholangitis. News release. January 8, 2025. Accessed January 8, 2025. https://www.globenewswire.com/news-release/2025/01/08/3006227/0/en/COUR-Pharmaceuticals-Secures-FDA-Orphan-Drug-Designation-for-CNP-104-in-Primary-Biliary-Cholangitis.html

2. Study to Evaluate the Safety, Tolerability, PDs, and Efficacy of CNP-104 in Subjects with Primary Biliary Cholangitis. ClinicalTrials.gov identifier: NCT05104853. Updated November 25, 2024. Accessed January 8, 2025. https://clinicaltrials.gov/study/NCT05104853

3. Frey M, Bowlus C, Elhofy A, et al. 5039 | Tolerogenic treatment with CNP-104 results in regulation of Th17 cells, slowing progression of PBC on liver stiffness. Presented at: American Association for the Study of Liver Diseases The Liver Meeting; San Diego, California. November 15-19, 2024.