Two-year Interim Analysis of Trial Data Show Sustained Efficacy of Seladelpar Treating Primary Biliary Cholangitis

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Two-year interim data from the Phase III ASSURE trial (NCT03301506) show sustained and long-term efficacy with seladelpar in the treatment of primary biliary cholangitis (PBC). The investigational therapy—developed by CymaBay Therapeutics, which was acquired by Gilead Sciences in March 2024—produced a quick and sustained improvement in markers of cholestasis, such as elevated normalization rates in liver biomarkers and a clinically significant decrease in pruritus.¹ These findings were recently shared at the European Association for the Study of the Liver (EASL) Congress 2024.

“The data presented at EASL further support the sustained efficacy and safety profile of seladelpar observed across its robust development program, including a capacity to normalize ALP values for many of the people studied with PBC. Given ALP is recognized as an important surrogate marker of disease progression in PBC, providers are shifting to normalization as a treatment goal, which could potentially be enabled by seladelpar, if approved,” Timothy Watkins, MD, MSc, vice president, Clinical Development of Inflammation Therapeutics, Gilead Sciences, said in a press release. “Seladelpar is a potential best-in-class therapy that could transform the treatment landscape for people living with PBC by not only improving or even normalizing markers of liver function, but also improving pruritis or itch. Pruritis is a particularly burdensome symptom of PBC which can significantly disrupt a person’s quality of life. We’re committed to transforming the management of PBC and the lives of those impacted by this rare disease as we work together to bring seladelpar to the community, if approved.”¹

Seladelpar is a first-in-class, oral, selective peroxisome proliferator-activated receptor-delta agonist, that regulates critical metabolic and liver disease pathways. In prior clinical research, the drug has demonstrated the ability to regulate genes that are involved in bile acid synthesis, inflammation, fibrosis, and the metabolism, storage, and transport of lipids. PBC is a rare, potentially life-threatening autoimmune disease of the liver in which bile flow is impaired, leading to the accumulation of toxic bile acids. PBC can result in inflammation and destruction of the intrahepatic bile ducts, which can progress to fibrosis, cirrhosis, and liver failure.

Seladelpar was granted Breakthrough Therapy Designation by the FDA in combination with ursodeoxycholic acid (UDCA) for the treatment of early stage PBC in 2019 after previously being granted Orphan Drug designation.²

The ongoing, open label ASSURE trial analyzed the long-term safety and tolerability of seladelpar in patients with PBC who participated in legacy studies of the drug and in the pivotal Phase III RESPONSE (NCT04620733) trial.^3,4 Investigators are currently enrolling up to 500 patients with PBC in the trial to assess the long-term efficacy of seladelpar and its impact on clinically meaningful patient-reported outcomes, including cholestatic pruritis. The two-year interim analysis had a data cutoff date of January 31, 2024, and included 179 patients from legacy studies and 158 participants from the RESPONSE trial.

Among 99 patients who completed 24 months of therapy with seladelpar, 70% achieved the composite response endpoint and alkaline phosphatase (ALP) levels under 1.67 x the upper limit of normal (ULN). This translates to a reduction in ALP levels of at least 15%, with total bilirubin levels at or below the ULN. Further, 42% of these patients reached ALP normalization at 24 months, which investigators noted is a marker of liver disease progression. Among 164 patients from legacy studies who completed one year of treatment with seladelpar, 73% achieved a clinically meaningful composite response endpoint and 42% ALP normalization.

Among patients randomly assigned to seladelpar treatment who completed the 12-month RESPONSE trial and who continued into the ASSURE trial to receive continuous seladelpar for a total of 18 months (n=102), 62% achieved the composite response endpoint and 33% achieved ALP normalization. Among those administered seladelpar for 24 continuous months (n=29), 72% and 17% achieved the composite response endpoint and ALP normalization, respectively.

Further, among 52 patients randomly assigned to the placebo cohort in the RESPONSE trial, 75% achieved the composite response endpoint and 27% achieved ALP normalization after crossing over to six months of treatment with seladelpar in the ASSURE trial. After 12 months of treatment, 94% of these patients achieved the composite response endpoint and 50% reached ALP normalization (n=16). In terms of safety, seladelpar was generally well-tolerated with long-term use, and no treatment-related serious adverse events were reported.

The FDA has granted Priority Review status to a New Drug Application (NDA) for seladelpar in the treatment of PBC in adults without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have shown an inadequate response or who are intolerant to UDCA. The agency is expected to issue a decision on the NDA in August 2024.¹

“Currently, there is no cure for PBC. While there are lifelong medicines that may slow liver damage and stop it from progressing, current medications fall short in about 40% of people. This is because many individuals continue to have abnormal liver tests on the current treatment options, and these treatments don’t reduce one of the main relentless symptoms, pruritis, which impacts the quality of life in people living with PBC,” study presenter Palak Trivedi, BSc, MBBS, MRCP, PhD, professor and consultant hepatologist, University of Birmingham, said in the release. “The long-term efficacy and safety interim results from ASSURE demonstrate that seladelpar may meaningfully raise the bar in PBC. Seladelpar can help people achieve significant reduction, and in some cases, normalization of liver blood tests. At the same time, seladelpar can also help lower itch intensity.”¹

References

1. Gilead’s Seladelpar Demonstrated a Sustained and Consistent Long-Term Efficacy and Safety Profile in Primary Biliary Cholangitis. News release. Gilead Sciences. June 5, 2024. Accessed June 11, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/6/gileads-seladelpar-demonstrated-a-sustained-and-consistent-long-term-efficacy-and-safety-profile-in-primary-biliary-cholangitis

2. CymaBay Therapeutics Announces Seladelpar Granted Breakthrough Therapy Designation by the FDA for the Treatment of Primary Biliary Cholangitis [news release]. CymaBay Therapeutics. https://ir.cymabay.com/press-releases/detail/446/cymabay-therapeutics-announces-seladelpar-granted-breakthrough-therapy-designation-by-the-fda-for-the-treatment-of-primary-biliary-cholangitis.

3. Seladelpar in Subjects With Primary Biliary Cholangitis (PBC). ClinicalTrials.gov. Updated February 15, 2024. Accessed June 11, 2024. https://clinicaltrials.gov/study/NCT03301506

4. RESPONSE: Response to Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Control to or an Intolerance to Ursodeoxycholic Acid (UDCA). ClinicalTrials.gov. Updated September 29, 2023. Accessed June 11, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04620733