Seladelpar effective, safe in PBC with cirrhosis

Treating patients who have primary biliary cholangitis and cirrhosis with seladelpar — a peroxisome proliferator-activated receptor agonist — led to improved liver biochemistries and improved pruritus scores, according to a presenter at the International Liver Congress.

“The cirrhotics are obviously our most vulnerable population. These are the people who may be at risk of developing decompensation and liver transplant down the road so that’s why it’s so important to determine whether this new agent is safe and effective in this population,” Stuart C. Gordon, MD, director of hepatology at Henry Ford Health Systems, told Healio. “What we found in essence was that seladelpar [CymaBay Therapeutics] in patients with primary biliary cholangitis and cirrhosis was safe and well tolerated. A 3-month course of treatment led to either stable or improved liver biochemistries in these patients. The safety and efficacy appeared to be similar in the compensated cirrhotic PBC patients and in the non-cirrhotics.”

Gordon and colleagues performed a pooled analysis from two studies — an open-label phase 2 study and a placebo-controlled phase 3 study — to assess safety and efficacy of seladelpar in patients with PBC and compensated cirrhosis who had an inadequate response or intolerance to ursodeoxycholic acid (UDCA).

In the studies, clinicians diagnosed cirrhosis via biopsy, imaging tests or liver elastography. Patients received either oral placebo, seladelpar 5 mg or 10 mg and UDCA if tolerated. This analysis comprised 53 patients with compensated cirrhosis.

At the 3-month mark, 39 patients received treatment. Of those, 50% given 5-mg dosing and 63% given 10-mg dosing met the composite endpoint of alkaline phosphatase (ALP) less than 1.67 times the upper level of normal, ALP decrease of 15% or more and total bilirubin less than or equal to the upper limit of normal. None in the placebo group met that endpoint.

ALP lowered in just 2.6% of the placebo group vs. 31% of the 5-mg group (P = .0003) and 41% of the 10-mg group (P < .0001). ALP normalized in three patients in each seladelpar group (17%-19%) but none in the placebo group.

“The conclusions were that seladelpar was safe and effective in patients with compensated cirrhosis. In looking at more than 50 patients for a 3-month course led to stable or improved liver biochemistries and the efficacy was the same in both the compensated and the non-cirrhotic populations,” Gordon said. “The hope then is that seladelpar may potentially offer an effective treatment for patients with cirrhosis and PBC and the next steps then are the RESPONSE trial, which is the phase 3 trial where we will look at both cirrhotics and non-cirrhotic patients for safety, biochemical response and pruritus.”

One patient receiving 10 mg of seladelpar discontinued use due to pruritis. Three others — two in the 5-mg group and one in the 10-mg group — reported serious adverse events of febrile neutropenia, procedural pain and angina pectoris, but all were deemed unrelated to the seladelpar.

Efficacy, safety and tolerability were similar in this group with cirrhosis as in those without cirrhosis.

“It’s a very exciting option because it was very safe and very well tolerated and it was often improving their pruritis scores as well. These are all people who were on ursodeoxycholic acid therapy for the treatment of their PBC and had not been responding. This is potentially offering a treatment option that shows biochemical improvement. This is a potential treatment option for patients with cirrhosis who often are limited in terms of their options. The hope is that this could translate into improved clinical outcomes as well,” Gordon said. “It’s reassuring to know we aren’t witnessing any signals that would be of concern. If we validate this in the phase 3 clinical trials that are upcoming, it’s a potentially good option to be able to offer our cirrhotic PBC patients who aren’t responding to [ursodeoxycholic acid].”