Targeting cholestasis with bile acids and related novel agents has attracted increasing interest in recent years. Some new agents for the treatment of cholestatic liver diseases have progressed through to approval recently, while others are now in various stages of clinical development.
“Effective medical therapy for patients with chronic cholestatic liver diseases is still an unmet clinical need and novel drugs are urgently needed,” said Marina G. Silveira, MD, of Yale School of Medicine. She discussed the recent progress in this field during the Cholestatic and Biliary Diseases and Liver Fibrosis SIG Program yesterday.
One of the most promising categories of agent is the FXR ligands, including obeticholic acid (OCA) and other non-bile acids in earlier phases of development. FXR activation leads to inhibition of bile acid synthesis and may have a positive effect on inflammatory and fibrotic pathways as well, Dr. Silveira said.
OCA received approval for treatment of primary biliary cholangitis (PBC) in 2016, based on results of the phase III POISE trial. That trial found significant reductions in alkaline phosphatase (ALP) in PBC patients treated with OCA compared with placebo.
“While the approval of an alternative therapy for PBC is quite exciting, there are still some concerns about the use of OCA in PBC,” Dr. Silveira said. The most common adverse event in trials of the agent was pruritis, which she pointed out is already a common symptom at baseline in PBC. The approval was also based on a surrogate endpoint, and there is still a need for data on clinically relevant outcomes including transplant-free survival and overall survival. The post-marketing COBALT study is currently enrolling patients.
Furthermore, last month the U.S. Food and Drug Administration issued a warning regarding the use of OCA in PBC, highlighting a risk of serious liver injury or death due to incorrect dosing of the drug.
Investigators are also testing OCA in trials of primary sclerosing cholangitis (PSC); results of a phase II study will be presented on Monday during a late-breaking abstracts session, and Dr. Silveira said there are promising signs that OCA can reduce ALP levels in this setting as well. Concerns do remain about the strategy, she said, including the potential that long-term exposure to fibroblast growth factor 19 (FGF19) may be carcinogenic. FGF19 is produced in the terminal ileum upon FXR activation.
Another promising bile acid therapy is 24-nor-ursodeoxycholic acid (norUDCA), which has been shown to have anti-proliferative, anti-inflammatory, and anti-fibrotic effects. After promising preclinical data from a mouse model, the agent was tested in a phase II trial including 161 PSC patients across 12 countries in Europe.
After 12 weeks of therapy, norUDCA resulted in a pronounced, dose-dependent reduction in ALP in these patients; this was the case in both UDCA-treated and UDCA-naïve patients. The drug was very well tolerated, with similar rates of treatment-emergent adverse events across dose groups and compared with placebo. A phase III trial is now planned, Dr. Silveira said.
Recent insights into the signaling function of bile acids and bile acid receptors has given momentum to this relatively new field, Dr. Silveira said. “Additional agents are needed to improve symptoms and long-term outcomes in patients with chronic cholestatic diseases, with emphasis on safety and cost effectiveness.”