PPARα/γ Agonist(University of Milan)

Chicago-based COUR Pharma announced one-year results from its Phase IIa study of CNP-104 in primary biliary cholangitis (PBC), reporting that two doses of the antigen-specific nanoparticle therapy produced durable improvements in cholestatic and fibrosis-related endpoints relative to placebo. The data provide continued support for a mechanistic approach — antigen-specific immune tolerance induction — that has no approved precedent in PBC and that COUR Pharma is pursuing without a large pharma partner for this indication. Trial specifics The Phase IIa first-in-human randomized study (NCT05104853) is a double-blind, placebo-controlled trial enrolling adults aged 18–75 with PBC who had an inadequate response to ursodeoxycholic acid and/or obeticholic acid. Patients received two intravenous doses of CNP-104 administered one week apart, followed by long-term observation extending to 20 months. The primary study period covered the first 120 days, with one-year data now reported as a prespecified follow-up analysis. At 12 months, COUR reported separation from placebo on a composite biochemical response endpoint defined as serum alkaline phosphatase below 1.67× the upper limit of normal, at least a 15% reduction from baseline, and total bilirubin at or below the upper limit of normal. The company also reported statistically significant separation from placebo in liver stiffness measured by transient elastography, improvements in albumin as a marker of hepatic synthetic function, and improvement in the UK-PBC prognostic risk score. All drug-related adverse events were graded mild or moderate, with no drug-related serious adverse events through one year. Exact numerical values for endpoints were not disclosed; the company said full results will be submitted for presentation at a future scientific conference. CEO Dannielle Appelhans said the data “support the potential of CNP-104 as a novel therapeutic option” and “inform our ongoing evaluation of the program’s development strategy, including potential collaboration with a strategic partner”. CNP-104 holds both Orphan Drug Designation and Fast Track Designation from the US FDA. No timeline for a Phase III study or regulatory filing has been disclosed. Research context CNP-104 is a biodegradable PLGA nanoparticle encapsulating PDC-E2, the E2 subunit of the mitochondrial pyruvate dehydrogenase complex. In PBC, loss of immune tolerance to PDC-E2 drives T-cell-mediated destruction of intrahepatic bile ducts, leading to cholestasis, fibrosis, and eventual liver failure. By delivering PDC-E2 in a tolerogenic context to antigen-presenting cells, CNP-104 aims to selectively silence the pathogenic autoimmune response without broad immunosuppression. This mechanism is distinct from all currently approved PBC therapies, which primarily target bile acid metabolism or downstream inflammatory pathways rather than the underlying autoimmune trigger. PBC predominantly affects women aged 40–60. First-line therapy remains ursodeoxycholic acid, to which roughly 40% of patients respond inadequately. Two second-line agents have received US FDA approval: obeticholic acid (Ocaliva, Intercept/Advanz, approved in 2016) and seladelpar (Livdelzi, originally developed by CymaBay Therapeutics and approved in 2024; now part of Gilead Sciences following its acquisition of CymaBay). Both act on bile acid or PPAR signaling pathways rather than directly addressing the autoimmune driver of the disease. Additional therapies in development include Zydus Therapeutics’ saroglitazar magnesium, a dual PPARα/γ agonist approved for PBC in India and currently being evaluated in Phase II/III and Phase III studies for broader regulatory markets. No other antigen-specific immune tolerance therapy for PBC is currently in clinical development. COUR Pharma’s nanoparticle platform also underpins two additional clinical programs — CNP-101 for celiac disease, partnered with Takeda, and a program in type 1 diabetes currently enrolling a Phase Ib/IIa study — as well as an undisclosed collaboration with Genentech.