FDA to review approval application for seladelpar as PBC treatment

Agency agreed to CymaBay's request for priority review

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by Steve Bryson, PhD |

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The U.S. Food and Drug Administration (FDA) will review CymaBay Therapeutics’ application for seladelpar, an oral investigational treatment for adults with primary biliary cholangitis (PBC).

The regulatory request covers seladelpar for itching, or pruritus, in PBC patients without cirrhosis or with well-compensated cirrhosis (Child-Pugh class A) whose disease fails to adequately respond to ursodeoxycholic acid (UDCA) or those who are intolerant. Cirrhosis is a serious complication of PBC, marked by permanent liver scarring. UDCA, also called ursodiol and marketed as Urso and Actigall, is the first-line PBC therapy.

“Acceptance of the seladelpar NDA [new drug application] for the treatment of PBC, is an important step forward in our ongoing mission to make this potential, novel, targeted treatment option available for people living with PBC,” Klara Dickinson, chief regulatory and compliance officer at CymaBay, said in a company press release.

The FDA also agreed to the company’s request for priority review, which shortens the review period from 10 months to six months. A decision is expected by Aug. 14.

“We are encouraged by the agency’s decision to grant priority review for seladelpar, and its recognition of the significant need for new treatment options for people living with PBC,” Dickinson said. “If approved, we believe seladelpar has the potential to raise the bar in second-line treatment of PBC by reducing markers of disease progression and improving pruritus, so we look forward to continued discussion with the agency throughout its review.”

 What does seladelpar do in PBC?

PBC is a rare autoimmune disease marked by chronic inflammation in the bile ducts, the tubes that transport the digestive fluid called bile from the liver to the intestines, which results in bile acids building up to toxic levels in the liver. Itchy skin, caused by bile acids leaking  into the bloodstream, is a common early sign of PBC.

Seladelpar is a first-in-class oral molecule that works by selectively activating PPAR-delta, a protein that regulates metabolic and liver disease pathways. Preclinical and clinical data support its ability to modulate genes involved in bile production, inflammation, and scarring.

The approval application includes data from previous Phase 2 clinical trials, two placebo-controlled Phase 3 clinical trials — RESPONSE (NCT04620733) and ENHANCE (NCT03602560) — and a long-term Phase 3 study called ASSURE (NCT03301506).

Results from the trials, which included more than 500 PBC patients, showed seladelpar could reduce disease biomarkers and ease patient-reported itching, with benefits sustained with long-term treatment.

Recently published ENHANCE data showed seladelpar significantly lowered blood levels of an itch-associated molecule called interleukin-31 (IL-31) in PBC patients. Lower IL-31 levels were significantly linked to less patient-reported itching.

Seladelpar was granted breakthrough therapy status in the U.S. for PBC, including pruritis in adults with cirrhosis or with compensated cirrhosis. It also received PRIority MEdicine (PRIME) and orphan drug status in the European Union for PBC. These designations are intended to support and advance the therapy’s development and regulatory review.

In light of the promising path of seladelpar, CymaBay is being acquired by Gilead Sciences in a deal worth $4.3 billion that will add seladelpar to the latter’s existing portfolio of therapeutics to treat liver disease.

“We are looking forward to advancing seladelpar by leveraging Gilead’s longstanding expertise in treating and curing liver diseases,” Daniel O’Day, chairman and CEO of Gilead, said in a joint press release. “Building on the strong research and development work by the CymaBay team to date, we have the potential to address a significant unmet need for people living with PBC and expand on our existing broad range of transformational therapies.”

“Today’s agreement with Gilead is the culmination of years of focus and determination at CymaBay to advance seladelpar and bring new hope to people living with PBC and their families, said Sujal Shah, CymaBay’s president and CEO.