CymaBay Therapeutics reported positive top-line results from the ENHANCE, a placebo-controlled, randomized, Phase 3 study evaluating the safety and efficacy of seladelpar for the treatment of primary biliary cholangitis (PBC). Seladelpar achieved the primary composite outcome with high statistical significance and was safe and well tolerated.
The Phase III ENHANCE study randomized 265 PBC patients to placebo, seladelpar 5 mg, or seladelpar 10 mg once daily. The study had been placed on clinical hold by the U.S. Food and Drug Administration in November of 2019 following safety concerns raised about the medication in a mid-stage trial assessing the drug as a treatment for non-alcoholic steatohepatitis (NASH). Studies of seladelpar were halted in following histological assessments of liver biopsies in a clinical the NASH study revealed atypical histological findings, including histology characterized as an interface hepatitis presentation, with or without biliary injury. The FDA lifted the holds in July after experts discovered the concerns were not related to seladelpar in the Phase IIb NASH study.
The primary outcome measure was the responder rate defined as a patient who achieved an ALP level < 1.67 x the ULN with at least a 15% decrease from baseline and a normal level of total bilirubin after 52 weeks. Due to the early termination of the study and the small number of patients who had reached the 52 week timepoint, the primary outcome measure was amended prior to database lock to a 3 month timepoint which was reached by 167 of 265 patients.
Seladelpar achieved the primary composite outcome with high statistical significance in 78.2% of patients in the 10 mg group (n=55) and 57.1% in the 5 mg group (n=56) compared to 12.5% on placebo (n=56) after 3 months. Rapid, dose-dependent reductions in ALP were observed as early as one month in seladelpar treated patients with mean decreases of 38%, 30%, and 2% in the 10 mg (n=78), 5 mg (n=78) and placebo groups (n=78), respectively. The anti-cholestatic effect of seladelpar was further substantiated with normalization of ALP levels at 3 months in 27.3% of patients in the 10 mg group vs 0% in the placebo group. Seladelpar also demonstrated a strong, dose-dependent reduction in pruritus (itch) after just 3 months of treatment in those patients with an NRS ≥4 when compared to placebo.
Based on these results, plans are underway to re-initiate the phase 3 program for PBC.
Seladelpar has received an orphan designation from the U.S. FDA and the European Medicine Agency for PBC. Seladelpar also received Breakthrough Therapy Designation from the FDA and PRIority MEdicine status from the EMA for PBC.
Seladelpar is a potent and selective peroxisome proliferator-activated receptor delta (PPARδ) agonist. Seladelpar is uniquely suited as a potential treatment for inflammatory liver diseases. In the liver, PPARδ is expressed in multiple cell types including hepatocytes, cholangiocytes, Kupffer cells and stellate cells. Preclinical and clinical data support its effect on regulating genes involved in bile acids synthesis, inflammation, fibrosis and lipid metabolism, storage and transport.
Primary biliary cholangitis (PBC) is a serious and potentially life-threatening autoimmune disease of the liver characterized by impaired bile flow (cholestasis) and accumulation of toxic bile acids. There is an accompanying inflammation and destruction of the intrahepatic bile ducts, which can progress to fibrosis, cirrhosis and liver failure. Other clinical symptoms of PBC include fatigue and pruritus, which can be quite disabling in some patients. PBC is primarily a disease of women: 1 in 1000 women over the age of 40 lives with PBC.