Gilead Reports Positive Data for Seladelpar in Primary Biliary Cholangitis

Rare Daily Staff

Gilead Sciences, following its recent acquisition of CymaBay Therapeutics, reported interim results from the ongoing ASSURE study showed treatment with seladelpar led to improvements in markers of cholestasis and reduced inflammation in people living with the rare liver disease primary biliary cholangitis.

Additional findings showed that seladelpar can also help reduce the pruritus, or itching, that often occurs. There are currently no treatments indicated to treat PBC-related pruritis. This data will be shared in an oral presentation during the Presidential Plenary of the Digestive Disease Week 2024 Conference in Washington, DC.

Primary biliary cholangitis (PBC) is a chronic inflammatory disease primarily affecting women that is characterized by impaired bile flow (known as cholestasis) and the accumulation of toxic bile acids in the liver, leading to inflammation and destruction of the bile ducts within the liver and causing increased levels of ALP, ALT, and GGT, enzymes found primarily in the liver, as well as total bilirubin. The most common early symptoms of PBC are itching and fatigue, which can be debilitating for some patients. Progression of PBC is associated with an increased risk of liver-related mortality.

Seladelpar is a first-in-class oral, selective PPAR-delta agonist, or delpar. PPAR-delta has been shown to regulate critical metabolic and liver disease pathways. Preclinical and clinical data support its ability to regulate genes involved in bile acid synthesis, inflammation, fibrosis and lipid metabolism, storage, and transport.

ASSURE is an open-label study evaluating the long-term safety and efficacy of seladelpar. ASSURE enrolled adult patients with PBC who previously participated in a study of seladelpar where a key eligibility criterion included having an inadequate response or intolerance to ursodeoxycholic acid (UDCA). This interim data analysis did not include patients from the phase 3 RESPONSE study, which will be reported separately.

Of the 174 patients included, the majority had a gap of one year or more between completion of the respective primary study (seladelpar or placebo) and enrollment into ASSURE. Enrolled patients received an open-label oral dose of 10 mg seladelpar once daily, with the majority (97 percent) also receiving UDCA treatment.

Most patients enrolled in ASSURE were female (94 percent), with a mean age of 59 years. Baseline characteristics included mean alkaline phosphatase (ALP) 270.5 U/L and total bilirubin (TB) 0.75 mg/dL; 19 percent of enrolled patients met the criteria for cirrhosis. The study evaluated several prespecified biochemical endpoints, including the composite response of an alkaline phosphatase (ALP) below 1.67 x upper limit of normal (ULN), a decrease in ALP of at least 15 percent, and a total bilirubin (TB) below the ULN. Endpoints were evaluated over an interim observation period extending from enrollment through a data cutoff date of June 29, 2023, with the majority of those (85 percent) having at least 12 months of continuous treatment with seladelpar.

Seventy percent of the 148 patients who completed 12 months of treatment achieved the clinically meaningful composite response endpoint. Among those receiving seladelpar, 37 percent experienced ALP normalization, with a mean ALP change from baseline of -44 percent (-144.4 U/L). Of the 20 patients who completed 24 months of treatment, 70 percent achieved the composite response endpoint and 25 percent experienced ALP normalization. Seladelpar also reduced other important biomarkers of liver injury including TB, gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT) levels by 9 percent, 36 percent, and 25 percent from baseline, respectively. There were no treatment-related serious adverse events in the study, as determined by the study investigators. Seladelpar was generally well tolerated, with discontinuation due to adverse events occurring in 4.6 percent of patients.

“Seladelpar continues to demonstrate a significant impact on PBC disease in the liver, helps a significant proportion of patients achieve normalization of their ALP and importantly reduces pruritus, which is often a debilitating and unrelenting comorbidity. said Cynthia Levy, professor of Medicine, University of Miami and presenter of the study.

Patient-reported pruritus was monitored throughout the study using the numerical rating scale (NRS; 0-10). In the 60 patients with moderate-to-severe pruritus at baseline with an NRS score of ≥4, a rapid improvement in pruritus was observed at Month 1. By Month 6 the patients reported a mean reduction of 3.5 points, and this impact was sustained through Month 12.

A New Drug Application for seladelpar for the treatment of PBC, including pruritus, in adults without cirrhosis or with compensated cirrhosis who are inadequate responders or intolerant to UDCA, has been accepted for priority review by the U.S. Food and Drug Administration with an anticipated decision in August 2024. Seladelpar has also been accepted for review by the UK Medicines and Healthcare products Regulatory Agency and the European Medicines Agency.

“The initial data from ASSURE further support the efficacy and safety profile of seladelpar observed across the robust development program and continue to indicate that seladelpar has the potential to be a best-in-class therapy that could help transform treatment for people living with primary biliary cholangitis,” said Merdad Parsey, chief medical officer, Gilead Sciences.