RESPONSE: Seladelpar Normalizes Alkaline Phosphatase, Reduces Pruritus in PBC

Gideon Hirschfield, PhD, MB BChir

Credit: UNH Foundation

New data from the phase 3 RESPONSE trial of seladelpar in patients with primary biliary cholangitis (PBC) and incomplete response or intolerance to ursodeoxycholic acid showed treatment with the peroxisome proliferator-activated receptor delta (PPARδ) agonist elicited biochemical response while also reducing pruritus.¹

Results published in The New England Journal of Medicine showed the percentage of patients who met the primary endpoint criteria for biochemical response and alkaline phosphatase normalization was significantly greater among those who received seladelpar compared to placebo. Additionally, seladelpar significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline.¹

Currently, ursodeoxycholic acid is the only agent currently approved by the US Food and Drug Administration (FDA) for first-line treatment of PBC, and obeticholic acid is the only approved second-line treatment. However, not all patients achieve an adequate response to either treatment and symptoms may not improve, with pruritus and serious adverse events remaining concerns and leaving many with no way to treat their condition.^1,2

“If left untreated, primary biliary cholangitis can result in liver failure and death. Patients with primary biliary cholangitis also have debilitating symptoms, notably pruritus and fatigue,” David Assis, MD, associate professor of medicine and director of the fellowship program for digestive diseases at Yale School of Medicine, said in an accompanying editorial.³ “Effective treatment is essential to prevent disease progression and, ideally, also improve quality of life.”

A selective PPARδ agonist, seladelpar releases fibroblast growth factor 21 from hepatocytes, reducing the accumulation of bile acids by inhibiting the expression of cholesterol 7α-hydroxylase and also decreasing proinflammatory macrophages. On February 12, 2024, the FDA accepted CymaBay Therapeutics’ New Drug Application for seladelpar and granted Priority Review granted priority review with a Prescription Drug User Fee Act target action date of August 14, 2024. The acceptance was supported by the phase 3 RESPONSE and ENHANCE studies, the long-term open-label ASSURE study, and prior phase 2 studies.^1,4,5

A phase 3, double-blind, placebo-controlled trial, RESPONSE evaluated the efficacy and safety of oral, once-daily seladelpar for 12 months in patients 18-75 years of age with PBC and an inadequate response to or a history of unacceptable side effects with ursodeoxycholic acid. Gideon Hirschfield, PhD, MB BChir, Lily and Terry Horner Chair in Autoimmune Liver Disease Research at the University of Toronto, and a team of investigators recruited participants at 90 sites in 24 countries and randomly assigned them in a 2:1 ratio to receive oral seladelpar 10 mg daily or placebo, along with ursodeoxycholic acid or without ursodeoxycholic acid in patients who had a history of unacceptable side effects.¹

The primary endpoint was a biochemical response, defined as an alkaline phosphatase level < 1.67 times the ULN, with a decrease of ≥ 15% from baseline, and a normal total bilirubin level at month 12. Key secondary endpoints were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (NRS) from baseline to month 6 among patients with a baseline score of ≥ 4.¹

A total of 193 patients underwent randomization and received either seladelpar (n = 128) or placebo (n = 65). Among the cohort, 93.8% of patients received ursodeoxycholic acid as standard-of-care background therapy.¹

Investigators noted a greater percentage of the patients in the seladelpar group elicited a biochemical response (61.7%) compared to those in the placebo group (20.0%; difference, 41.7 percentage points; 95% CI, 27.7 to 53.4; P <.001). They also pointed out results were generally consistent among patients with and without cirrhosis and among patients who received seladelpar alone versus those who received seladelpar with ursodeoxycholic acid.¹

Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than those who received placebo (25.0% vs 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2; P <.001). Additionally, a total of 49 (38.3%) patients in the seladelpar group and 23 (35.4%) in the placebo group had moderate-to-severe pruritus at baseline. Among these patients, the reduction from baseline in the pruritus NRS score at month 6 was significantly greater in patients who were treated with seladelpar than in patients who received placebo (least-squares mean [LSM] change from baseline, −3.2 vs −1.7; LSM difference, −1.5; 95% CI, −2.5 to −0.5 P = .005).¹

A total of 166 patients had adverse events, with a similar incidence in the two groups – adverse events were reported in 86.7% of patients in the seladelpar group and 84.6% in the placebo group, the most common being COVID-19 and pruritus. Serious adverse events occurred in 7.0% of patients receiving seladelpar and 6.2% receiving placebo.¹

References:

1. ^{Hirschfield GM, Bowlus CL, Mayo MJ, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Eng J Med. doi:10.1056/NEJMoa2312100}
2. ^{Brooks, A. Seladelpar Improves Markers of Cholestasis, Pruritus in Patients with PBC. HCPLive. November 12, 2023. Accessed February 21, 2024. https://www.hcplive.com/view/gideon-hirschfield-phd-mb-bchir-seladelpar-for-primary-biliary-cholangitis}
3. ^{Assis DN. Advancing Second-Line Treatment for Primary Biliary Cholangitis. Editorial. N Eng J Med.}
4. ^{CymaBay Therapeutics. CymaBay Announces FDA Acceptance of NDA and Priority Review for Seladelpar for the Treatment of Primary Biliary Cholangitis. Press Releases. February 12, 2024. Accessed February 21, 2024. https://www.cymabay.com/investors-media/news-events/press-releases/detail/592/cymabay-announces-fda-acceptance-of-nda-and-priority-review}
5. ^{Brooks, A. Seladelpar NDA Submitted to FDA for Primary Biliary Cholangitis. HCPLive. December 15, 2023. Accessed February 21, 2024. https://www.hcplive.com/view/seladelpar-nda-submitted-to-fda-for-primary-biliary-cholangitis}