NEWARK, Calif.—Clinical-stage pharmaceutical company CymaBay Therapeutics Inc., which dedicates itself to developing therapies for liver diseases and other chronic diseases with high unmet need, presented new data from a second interim analysis of its Phase 2 study of seladelpar at this year’s International Liver Congress hosted by the European Association for the Study of Liver Diseases in Paris. The study is examining seladelpar in patients with primary biliary cholangitis (PBC), and the data was shared in a poster presentation titled “Treatment efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor delta agonist, in primary biliary cholangitis patients: 12- and 26-week analyses of an ongoing international, randomized, dose ranging Phase 2 study.”
PBC, according to the National Organization for Rare Disorders, is “a chronic, or long-lasting, progressive liver disorder that mostly affects women and usually appears during middle age. PBC leads to inflammation and scarring of the small bile ducts (the plumbing system of the liver which transports bile, the substance that helps digest fat). When PBC is very severe, it can lead to yellow discoloration of the skin (jaundice). If PBC is untreated, it can lead to cirrhosis, or scarring of the entire liver, which can lead to liver failure.”
Seladelpar is an orally administered, potent and selective peroxisome proliferator-activated receptor delta (PPARδ) agonist. CymaBay is advancing the drug candidate for both PBC and nonalcoholic steatohepatitis (NASH), with plans to advance seladelpar into Phase 3 and Phase 2 development for those indications, respectively. The U.S. Food and Drug Administration and the European Medicines Agency (EMA) have both issued an orphan designation for seladelpar for PBC, and the EMA has also awarded the drug PRIME (PRIority MEdicine) status.
“We are thrilled to have the opportunity to share new data from our development of seladelpar for patients with PBC in a late-breaking presentation at The International Liver Congress. This is the third consecutive year in which seladelpar will be featured in the late-breaker category at one of the key international liver meetings. We have now firmly established doses of seladelpar with compelling efficacy and tolerability, which we expect to further confirm in a Phase 3 study planned to start in the second half of the year,” said Dr. Pol Boudes, chief medical officer of CymaBay. “These data continue to support the potential for seladelpar to significantly improve treatment options for patients with PBC.”
According to the presentation data, seladelpar demonstrated potent, sustained anti-cholestatic and anti-inflammatory efficacy over 26 weeks of administration. As of this January, 71 patients had received at least one dose of seladelpar, 53 of whom received 12 weeks of treatment and 42 of whom had undergone 26 weeks of treatment. PBC is characterized by high alkaline phosphatase (AP) levels, and at baseline, those levels were 358, 333 and 262 U/L in the 2 mg, 5 mg and 10 mg groups, respectively. At 12 weeks of treatment, those levels had seen respective reductions of 21 percent, 33 percent and 45 percent. Dose titration was allowed after 12 weeks for patients whose AP was above normal and at a level at which lowering AP could reduce risk of disease progression. At 26 weeks of treatment, the 5 mg, 5 to 10 mg titration and 10 mg groups saw AP decreases of 45 percent, 43 percent and 43 percent, respectively. Also at 26 weeks, of those three respective dose regimens, 69 percent, 67 percent and 79 percent of patients presented with AP less than 1.67 times the upper limit of normal, with normal bilirubin and at least a 15-percent decrease in AP from baseline. Twenty-nine percent of patients had a normal AP at 26 weeks.
Prof. Gideon Hirschfield of the University of Birmingham, who presented the data, noted that, “Seladelpar continues to demonstrate an impressive level of activity that is now sustained over 26 weeks of treatment. The decreased level of pruritus that was noted in the 10 mg group, a group that demonstrated a clinically relevant level of pruritus at baseline, is particularly intriguing and needs to be confirmed in additional studies.”
Pruritus, or itching, is a common symptom of PBC. Seladelpar was not linked to drug-induced pruritus, and patients in the 10 mg group saw consistent reductions in pruritus while undergoing treatment. The drug was generally safe and well tolerated, and while there were six serious adverse events during the trial, none were ruled to be related to seladelpar.
The International Liver Congress also saw CymaBay present data supporting seladelpar’s mechanism of action as well as its pharmacodynamic and pharmacokinetic profile in two additional posters.
In terms of mechanism of action, the poster presentation reported that “In both mice and humans, seladelpar was found to lower transaminases, reduce triglycerides and cholesterol, and to have favorable effects on glucose homeostasis. The anti-cholestatic activity was mediated by the decrease in bile acid synthesis as well as decreases in the absorption and synthesis of cholesterol, the precursor of bile acids. Evidence of regulation of fatty acid oxidation was obtained both preclinically (mitochondrial fatty acid oxidation genes) and clinically (metabolomic analysis of acyl-carnitines). Reduction in hepatic and circulating lipids appeared associated with improvements seen preclinically in NASH pathology, fibrosis and features of dyslipidemicand diabetic inflammatory fatty liver disease.”
As for pharmacokinetics, seladelpar was rapidly absorbed and the data seem to support a once-daily dosing regimen for seladelpar, with CymaBay noting in a press release that it “appears to be dose-proportional, and the level of exposure correlates with its pharmacodynamic activities.”