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

Dannielle Appelhans

Credit: COUR Pharmaceuticals

COUR Pharmaceuticals has announced the US Food and Drug Administration has granted Orphan Drug Designation to CNP-104 for the treatment of primary biliary cholangitis (PBC).¹

According to a January 8, 2025, press release, the designation follows the presentation of positive topline data from the phase 2a clinical trial of CNP-104 in PBC at the American Association for the Study of Liver Diseases’ The Liver Meeting in 2024.¹

“Receiving Orphan Drug Designation for CNP-104 underscores its potential to become the first disease-modifying treatment for individuals with PBC,” said Dannielle Appelhans, president and chief executive officer of COUR, in a press release.¹ “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.”

The PBC treatment landscape underwent drastic changes in 2024 with the addition of 2 new second-line therapies, elafibranor (Iqirvo) and seladelpar (Livdelzi), both of which received accelerated approval from the FDA.^2,3 Shortly after the introduction of these agents, the FDA issued a Complete Response Letter to Intercept Pharmaceuticals’ obeticholic acid (Ocaliva), a long-standing second-line treatment option for PBC that initially earned accelerated approval in 2016 and served as a key component of PBC management for many years.⁴

A biodegradable nanoparticle encapsulating the E2 component of the mitochondrial pyruvate dehydrogenase complex (PDC), a key autoantigen in PBC, CNP-104 aims to address the root cause of PBC by inducing tolerance to pathogenic activated PDC-E2 T-cells that drive inflammation in bile ducts, leading to improvement in clinical outcomes of liver health. Of note, CNP-104 received Fast Track Designation from the FDA in January 2022, making it potentially eligible for Accelerated Approval and Priority Review if the necessary criteria are met.¹

Findings from a phase 2a first-in-human randomized controlled trial of CNP-104 were presented during a late-breaking session at The Liver Meeting. It included 42 patients with PBC with an ALP > 1.5 x the upper limit of normal after treatment with ursodeoxycholic acid and/or obeticholic acid. They were randomly assigned in a 2:1 ratio to receive 2 loading doses of CNP-104 or placebo 1 week apart and were followed for 120 days to assess safety and treatment durability.⁵

No significant safety risks were identified during the trial. A total of 38 drug-related adverse events were observed in 8 subjects receiving CNP-104, all of which were mild. Investigators noted there were no drug-related severe adverse events, deaths, and biochemical deviations, on hematology, coagulation, liver, and renal assessments.⁵

Results showed participants receiving CNP-104 had a reduction in the percentage of antigen-specific Th17 T cells compared to placebo at day 120. Although ALP was not different between groups, liver stiffness as measured by vibration-controlled transient elastography at day 120 was statistically significantly different between treatment arms, with an increase observed in the placebo cohort and stability in the CNP-104 cohort. Findings from 4 subjects who consented to a liver biopsy (3 CNP-104; 1 placebo) suggested a reduction in PanCK+ and CD3–CD4+ cells in CNP-104, markers of ductal pathology.⁵

“We are now collaborating with our distinguished clinical advisors and key opinion leaders to advance CNP-104 to the next phase of clinical development,” Appelhans said.¹

References

1. ^{COUR Pharmaceuticals Secures FDA Orphan Drug Designation for CNP-104 in Primary Biliary Cholangitis. 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. ^{Brooks A. FDA Grants Accelerated Approval to Elafibranor (Iqirvo) for PBC. HCPLive. June 10, 2024. Accessed January 8, 2025. 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 January 8, 2025. https://www.hcplive.com/view/fda-grants-accelerated-approval-to-seladelpar-livdelzi-for-primary-biliary-cholangitis}
4. ^{Brooks A. FDA Issues CRL to Obeticholic Acid (Ocaliva), Denies Full Approval for PBC. HCPLive. November 12, 2024. Accessed January 8, 2025. https://www.hcplive.com/view/fda-issues-crl-obeticholic-acid-ocaliva-denies-full-approval-pbc}
5. ^{Frey M, Bowlus C, Elhofy A, et al. Tolerogenic treatment with CNP-104 results in regulation Th17 cells slowing progression of PBC on liver stiffness. Paper presented at: AASLD’s The Liver Meeting 2024. San Diego, California. November 15-19, 2024.}