Seladelpar Achieves Primary, Secondary Endpoints in Phase 3 RESPONSE Trial

Gideon Hirschfield, MD

Credit: UHN Foundation

CymaBay Therapeutics has announced positive topline results from the phase 3 RESPONSE trial evaluating the safety and efficacy of seladelpar for the treatment of adult patients with primary biliary cholangitis (PBC).

Announced on on September 7, 2023, the registration trial, which achieved the primary and all key secondary endpoints, will be used to support filing for regulatory approval with the U.S. Food and Drug Administration, the Medicines and Healthcare products Regulatory Agency, and the European Medicines Agency, according to the release from CymaBay Therapeutics.¹

"The topline results seen in the RESPONSE trial are exciting for highlighting the potential for an efficacious and safe new therapy that not only achieves the composite improvements in liver tests, but for a significant proportion of patients, normalizes these measures. Further, the results support that seladelpar reduced itch, a particularly challenging symptom that continues to negatively impact quality of life for many PBC patients," said Gideon Hirschfield, MD, Lily and Terry Horner Chair in Autoimmune Liver Disease Research at the Toronto Centre for Liver Disease.¹

Billed as a first-in-class oral, selective peroxisome proliferator-activated receptor delta agonist, or delpar, seladelpar has been shown to regulate critical metabolic and liver disease pathways through regulation of genes involved in bile acid synthesis, inflammation, fibrosis and lipid metabolism, storage, and transport. 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.¹

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. 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 ≥4.¹

According to the release from CymaBay Therapeutics, 61.7% of patients on seladelpar 10 mg met the primary composite endpoint related to serum alkaline phosphatase and bilirubin at 12 months compared to 20.0% of patients on placebo (P < .0001). Seladelpar’s anti-cholestatic effect was supported by the normalization of alkaline phosphatase at 12 months in 25.0% of patients on seladelpar compared to 0% on placebo (P < .0001). The least-squares mean percent reduction in alkaline phosphatase at 12 months was 42.4% in the seladelpar group vs. 4.3% in the placebo group (P < .0001).¹

Seladelpar also demonstrated a statistically significant reduction in pruritus after 6 months of treatment. Patients treated with seladelpar with a baseline NRS ≥4, indicating moderate to severe pruritus, had a least-square mean reduction of 3.2 points in pruritus NRS (n=49) compared to 1.7 points for patients in the placebo group (n=23; P <.005).¹

Investigators noted safety was comparable between the placebo and seladelpar groups and remained consistent with previous studies. No treatment-related serious adverse events occurred in the study.¹

"The results from RESPONSE support our conviction that seladelpar has the potential to advance patient care by improving measures of disease activity and reducing symptom burden. They are consistent with previous findings in what we believe has been an exceptionally robust development program in PBC. We believe that the delpar mechanism is unique with its ability to normalize markers of cholestasis coupled with reductions in pruritus," said Sujal Shah, president and CEO of CymaBay.¹

RESPONSE is not the only phase 3 trial examining seladelpar. On August 10, 2023, CymaBay Therapeutics announced the initiation of the IDEAL trial, a 52-week, placebo-controlled, randomized study examining the effects of seladelpar on the normalization of ALP levels in patients with PBC.²

“We know that even patients who are on treatment with UDCA can progress toward cirrhosis, decompensation, and death or transplant. Those are usually the patients who have not normalized their ALP or who started with more significant fibrosis. If seladelpar can halt or slow down progression for those patients, it could have a major impact on the overall prognosis. Given the beneficial impact on itching and sleep, the drug could significantly improve their quality of life,” said Cynthia Levy, MD, professor of medicine at the University of Miami, in an interview with HCPLive.³

References

1. PRNewswire. CymaBay's Seladelpar Achieves High Statistical Significance for the Primary and Key Secondary Endpoints in the Phase 3 RESPONSE Trial in Primary Biliary Cholangitis. News. September 7, 2023. Accessed September 8, 2023. https://www.prnewswire.com/news-releases/cymabays-seladelpar-achieves-high-statistical-significance-for-the-primary-and-key-secondary-endpoints-in-the-phase-3-response-trial-in-primary-biliary-cholangitis-301920135.html?tc=eml_cleartime

2. CymaBay Therapeutics. CymaBay Initiates IDEAL, a Phase 3 Placebo-Controlled, Randomized Study of Seladelpar in Patients with Primary Biliary Cholangitis and Incomplete Control of Alkaline Phosphatase. Press Releases. August 10, 2023. Accessed September 8, 2023.

3. Kunzmann, K. Cynthia Levy, MD: Seladelpar for PBC and the IDEAL Trial. HCPLive. September 6, 2023. Accessed September 8, 2023. https://www.hcplive.com/view/cynthia-levy-md-seladelpar-pbc-ideal-trial