The New England Journal of Medicine Publishes Positive Phase 3 RESPONSE Data of CymaBay's Seladelpar in Primary Biliary Cholangitis

-  Seladelpar demonstrated normalization of liver biomarkers and significant reductions across three measures of patient-reported itch vs. placebo - 

NEWARK, Calif., Feb. 21, 2024 /PRNewswire/ -- CymaBay Therapeutics, Inc. (NASDAQ:CBAY), a biopharmaceutical company focused on innovative therapies for patients with liver and other chronic diseases, today announced that The New England Journal of Medicine (NEJM) has published detailed results from the RESPONSE Phase 3 trial evaluating seladelpar, an investigational agent, and the only potent, selective peroxisome proliferator-activated receptor delta (PPARδ) agonist or delpar, being studied in adults with primary biliary cholangitis (PBC). Results showed rapid and sustained improvements in reducing cholestasis and liver injury, together with significant reductions in pruritus (itching) across the numerical rating scale (NRS), 5-D Itch Scale, and the PBC-40 questionnaire. Publication of these detailed findings from RESPONSE follows topline data presented as a late breaker at The Liver Meeting® 2023 of the American Association for the Study of Liver Diseases (AASLD) in November 2023.

RESPONSE was a double-blind, placebo-controlled, global study of one-year duration that randomized 193 people with PBC in a 2:1 ratio to receive seladelpar 10 mg or placebo, once daily. Eligible participants had an inadequate response or intolerance to ursodeoxycholic acid (UDCA) with alkaline phosphatase, or ALP ≥ 1.67× the upper limit of normal (ULN) after at least 12 months of treatment. The primary endpoint was a composite of ALP and total bilirubin at Month 12, which supported authorization for current second line treatment in PBC by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for registrational studies in PBC. The primary endpoint was achieved in 61.7% (79/128) of patients treated with seladelpar vs. 20.0% (13/65) treated with placebo (95% CI 27.7 to 53.4; P<0.001) at Month 12.

"Many people living with PBC do not experience a normalization of ALP or meaningful symptom relief with currently available treatments. Pruritus or severe itch significantly impairs the quality of life of our patients, and current second-line treatment frequently worsens itch. New options, that are potent, effective, and safe, are needed for people living with this chronic debilitating autoimmune condition," said Gideon Hirschfield, M.D., Lily and Terry Horner Chair in Autoimmune Liver Disease Research, Toronto Centre for Liver Disease. "The RESPONSE data are genuinely exciting. The data, together with the existing substantial experience gained from prior studies, robustly support the potential for seladelpar to raise the bar in PBC treatment. In this rigorous international trial, people living with PBC saw substantial rates of normalization of serum liver tests, and clear statistically significant improvement in itch. Benefits were also noted in those people living with compensated cirrhosis."

The key secondary endpoint of ALP normalization was reached in 25.0% (32/128) of patients treated with seladelpar vs. 0.0% for patients treated with placebo (95% CI 18.3 to 33.2; p<0.001). The average decrease in ALP for patients on seladelpar was 42.4% vs. 4.3% for patients on placebo. Compared to placebo, seladelpar reduced alanine aminotransferase (ALT) at Month 12 by 23.5% vs. 6.5% (p=0.003), and gamma-glutamyl transferase (GGT) by 39.1% vs. 11.4% (p<0.0001). 

The study also measured change in patient-reported pruritus as a key secondary endpoint using the daily numerical rating scale (NRS; 0-10). Approximately 37.3% of patients enrolled had moderate-to-severe pruritus based on an NRS (0-10) score ≥ 4 at baseline. Improvement in pruritus was seen as soon as Week 4 and significance achieved at Month 6 among patients with baseline NRS > 4 reporting decreases of 3.2 points with seladelpar (n=49) vs. 1.7 for patients on placebo (n=23; least-squares mean difference -1.5 points, 95% CI -2.5 to -0.5; P<0.005). These improvements were sustained through Month 12 (p<0.005). A statistically significant reduction in pruritus was also observed at Month 6 and at Month 12 for patients in the intent-to-treat population, which includes all patients irrespective of their NRS score at baseline. Further, 5D-itch results in both the moderate-to-severe population and overall population, showed significance as early as 4 weeks which continued through Month 12 and had a positive impact on sleep. Similar results demonstrating reductions in itch and improvements in sleep were observed using the PBC-40 questionnaire.

Safety as reflected in adverse events (AEs) was similar in the seladelpar-treated and placebo-treated groups. The most common adverse events (AEs) in the study overall (≥10% in either the seladelpar or placebo group) were COVID-19 and pruritus. Consistent with the positive effect of seladelpar on pruritus NRS, pruritus AEs were reported more frequently in participants receiving placebo compared with seladelpar. Serious AEs (SAEs) were reported in 7.0% and 6.2% of seladelpar-treated and placebo-treated patients, respectively. No SAE occurred in more than one patient, and none were considered to be associated with seladelpar treatment.

"The publication of the pivotal Phase 3 data for seladelpar in The New England Journal of Medicine recognizes the importance of these findings, the potential of this investigational agent to help people living with PBC, and the significant need for innovation in this area," said Charles McWherter, Ph.D., Chief Scientific Officer and President of Research and Development at CymaBay. "We are thrilled that these results are now available to benefit researchers, patients, and the broader medical community in our collective pursuit of PBC treatment transformation."

A New Drug Application (NDA) for seladelpar for the treatment of primary biliary cholangitis, including pruritus in adults without cirrhosis or with compensated cirrhosis (Child Pugh A) who are inadequate responders or intolerant to UDCA, was accepted for priority review by the FDA in February 2024. This application reflects the updated breakthrough designation that was granted by the agency in October 2023.  The company also plans to file marketing authorization applications in the first half of 2024 with the EMA where seladelpar has received Priority Medicines (PRIME) status and plans to file with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA).

About PBC

PBC is a rare, chronic inflammatory liver disease primarily affecting women (1 in 1,000 women over the age of 40 or about 130,000 total people in the U.S.). PBC 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 pruritus and fatigue, which can be debilitating for some patients. Progression of PBC is associated with an increased risk of liver-related mortality.

About Seladelpar

Seladelpar, an investigational treatment for people with PBC, is a first-in-class oral, selective PPARδ agonist, or delpar, shown to regulate critical metabolic and liver disease pathways in indications with high unmet medical need. Preclinical and clinical data support its ability to regulate genes involved in bile acid synthesis, inflammation, fibrosis and lipid metabolism, storage, and transport.

About CymaBay

CymaBay Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on improving the lives of people with liver and other chronic diseases that have high unmet medical need. Our deep understanding of the underlying mechanisms of liver inflammation and fibrosis, and the unique targets that play a role in their progression, have helped us receive breakthrough therapy designation (FDA), PRIME status (EMA), and orphan drug status (U.S. and Europe) for seladelpar, a first-in-class investigational treatment for people with PBC. A new drug application for seladelpar was submitted to the FDA in December 2023. Our evidence-based decision-making and commitment to the highest quality standards reflect our relentless dedication to the people, families, and communities we serve. To learn more, visit www.cymabay.com and follow us on X (formerly Twitter) and LinkedIn.

Cautionary Statements

Any statements made in this press release regarding potential FDA acceptance of the seladelpar NDA, the potential for seladelpar to treat PBC and potentially improve ALP levels, clinical symptoms or outcomes of the disease, the future EMA and MHRA filing plans of CymaBay and the timing thereof are forward-looking statements that are subject to risks and uncertainties. Actual results and the timing of events regarding the further development of seladelpar could differ materially from those anticipated in such forward-looking statements as a result of risks and uncertainties, which include, without limitation, risks related to: the success, cost and timing of any of CymaBay's product development activities, including clinical trials; and effects observed in trials to date that may not be repeated in the future. Additional risks relating to CymaBay are contained in CymaBay's filings with the Securities and Exchange Commission, including without limitation its most recent Annual Report on Form 10-K, its Quarterly Reports on Form 10-Q and other documents subsequently filed with or furnished to the Securities and Exchange Commission. CymaBay disclaims any obligation to update these forward-looking statements except as required by law.

For additional information about CymaBay visit www.cymabay.com.

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