Seladelpar NDA Submitted to FDA for Primary Biliary Cholangitis

CymaBay Therapeutics has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for seladelpar for the management of primary biliary cholangitis (PBC), additionally requesting a Priority Review of the NDA.

Announced on December 15, 2023, the submission is supported by data from the phase 3 RESPONSE and ENHANCE studies, the long-term open-label ASSURE study, and prior phase 2 studies.¹

"People living with PBC need new treatment options to reduce the risk of disease progression and the daily impact of their disease from debilitating symptoms like pruritus. Today's announcement of our submission of the NDA for seladelpar is an important milestone in our ongoing work to bring forward new innovative therapies with the potential to help people living with PBC," Klara Dickinson, chief regulatory and compliance officer at CymaBay Therapeutics, said in a press release.¹

Billed as a first-in-class oral, selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, seladelpar has been shown to regulate critical metabolic and liver disease pathways as well as genes involved in bile acid synthesis, inflammation, fibrosis and lipid metabolism, storage, and transport. Seladelpar was granted Breakthrough Therapy Designation by the FDA in 2019, although it was later revised in 2023 to reflect treatment of PBC, including pruritus, in adults without cirrhosis or with compensated cirrhosis. Of note, it is the only potent, selective, orally active PPARδ agonist with phase 3 trial results demonstrating a statistically significant improvement in markers of cholestasis related to risk of progression and PBC-related pruritus.^1,2

A 1 year double-blind, placebo-controlled, global study, RESPONSE included 193 patients with PBC in a 2:1 ratio to seladelpar 10 mg or placebo, once daily. To be included in the study, patients were required to have had an inadequate response or intolerance to ursodeoxycholic acid with serum alkaline phosphatase (ALP) ≥ 1.67× the upper limit of normal (ULN) after at least 12 months of treatment.³

The primary outcome was responder rate, which was defined as achieving an ALP level < 1.67× ULN with ≥ 15% decrease in ALP, and total bilirubin ≤ 1.0× ULN after 52 weeks. Secondary outcome measures included the proportion of patients with ALP ≤ 1.0× ULN at 12 months and change in the patient-reported level of pruritus from baseline at 6 months as assessed by the NRS in those patients with baseline NRS ≥4.³

Results were presented during a Late Breaker Session at the American Association for the Study of Liver Diseases' (AASLD) The Liver Meeting 2023 in Boston, Massachusetts, on November 13, 2023.³

Upon analysis, 61.7% of patients achieved the primary composite response endpoint with seladelpar compared to 20% with placebo (P < .0001). The secondary endpoint of ALP normalization occurred in 25% of those receiving seladelpar and 0% receiving placebo (P < .0001). The average decrease in ALP for seladelpar was -133.9 U/L and -16.9 U/L for placebo (P < .0001).³

Seladelpar lowered alanine aminotransferase by 23.5% and gamma-glutamyl transferase by 39.1%, compared to 6.5% and 11.4% for placebo, respectively. The key secondary pruritus endpoint was met at month 6 with seladelpar-treated patients with baseline NRS >4 reporting decreases of 3.2 compared to 1.7 for placebo (P < .005), with improvement of pruritus NRS on seladelpar sustained through month 12 (P < .005).³

Results from ENHANCE, a double-blind, placebo-controlled, global phase 3 study were published in Hepatology on April 21, 2023, further demonstrating seladelpar’s safety and efficacy in PBC and supporting the NDA submission.⁴

The study enrolled 167 patients with elevated alkaline phosphatase (≥ 1.67x ULN) who received treatment as an add-on to first-line UDCA, or as monotherapy, if patients were intolerant to UDCA. The primary endpoint, a composite of alkaline phosphatase and bilirubin, was achieved in 78.2% of patients on seladelpar 10 mg and 57.1% on seladelpar 5 mg versus 12.5% on placebo (both seladelpar doses P < .0001). Normal levels of alkaline phosphatase were met in 27.3% (P < .0001) and 5.4% (P = .08) in seladelpar 10 mg and 5 mg groups, respectively, versus none in the placebo group. Data also showed statistically significant improvement in pruritus (P < .02) for patients with moderate-to-severe itch (NRS ≥4) taking seladelpar 10 mg versus placebo.⁴

As noted in the release, CymaBay plans to file marketing authorization applications to the European Medicines Agency (EMA) and UK Medicines and Healthcare products Regulatory Agency (MHRA) in the first half of 2024.¹

References:

1. CymaBay Therapeutics. CymaBay Submits New Drug Application to FDA for Seladelpar for the Treatment of Primary Biliary Cholangitis. December 15, 2023. Accessed December 15, 2023. https://www.cymabay.com/investors-media/news-events/press-releases/detail/585/cymabay-submits-new-drug-application-to-fda-for-seladelpar
2. CymaBay Therapeutics. Seladelpar Granted Revised Breakthrough Therapy Designation for the Treatment of Primary Biliary Cholangitis Including Pruritus in Patients Without Cirrhosis or With Compensated Cirrhosis. October 23, 2023. Accessed December 15, 2023. https://www.cymabay.com/investors-media/news-events/press-releases/detail/577/seladelpar-granted-revised-breakthrough-therapy-designation
3. Brooks, A. Seladelpar Improves Markers of Cholestasis, Pruritus in Patients with PBC. HCPLive. November 12, 2023. Accessed December 15, 2023. https://www.hcplive.com/view/gideon-hirschfield-phd-mb-bchir-seladelpar-for-primary-biliary-cholangitis
4. CymaBay Therapeutics. CymaBay Therapeutics Announces Publication of Results From the ENHANCE, Phase 3 Study of Seladelpar in Patients with Primary Biliary Cholangitis (PBC). April 21, 2023. Accessed December 15, 2023. https://www.cymabay.com/investors-media/news-events/press-releases/detail/558/cymabay-therapeutics-announces-publication-of-results-from