The Medicines and Healthcare products Regulatory Agency (MHRA) in the UK has approved Gilead Sciences' Livdelzi (seladelpar) for the treatment of primary biliary cholangitis (PBC) in adults. This approval marks a significant advancement for patients who have an inadequate response to ursodeoxycholic acid (UDCA), the standard first-line treatment, or cannot tolerate UDCA.
Livdelzi is approved for use in combination with UDCA for those with an inadequate response, or as a monotherapy for those who cannot tolerate UDCA. PBC is a rare, progressive autoimmune disease affecting the bile ducts, leading to inflammation and potential liver damage. It affects approximately 25,000 people in the UK, predominantly women, and currently has no cure.
Mechanism of Action
Livdelzi belongs to a class of drugs called peroxisome proliferator-activated receptor-delta (PPARδ) agonists. These therapies work by activating the PPAR-delta protein, which reduces the production of bile acid in the liver. By reducing bile acid production, Livdelzi aims to prevent further liver damage and reduce circulating bile acid levels, thereby alleviating symptoms such as pruritus (chronic itching).
Clinical Trial Data
The approval was primarily based on data from the Phase 3 RESPONSE trial (NCT04620733), a Gilead-sponsored study evaluating the efficacy and safety of Livdelzi versus placebo over one year. The trial enrolled 193 adults with PBC who had an inadequate response to UDCA or experienced unacceptable side effects. Results from the RESPONSE trial demonstrated that a significantly greater percentage of patients treated with Livdelzi achieved a composite biochemical response, defined as specific reductions in alkaline phosphatase (ALP) and total bilirubin levels, compared to placebo. Notably, 25% of patients on Livdelzi achieved normal ALP levels after one year, compared to none in the placebo group. Furthermore, Livdelzi-treated patients experienced a statistically significant reduction in pruritus compared to placebo.
In the RESPONSE study, 62% of patients receiving oral Livdelzi achieved the primary endpoint of composite biochemical response at one year, versus 20% of those on placebo.
Expert Commentary
"Keeping patients safe and enabling their access to high quality, safe and effective medical products are key priorities for us," said Julian Beach, MHRA's interim executive director of healthcare quality and access. "We're assured that the appropriate regulatory standards for the approval of this medicine have been met. As with all products, we will keep its safety under close review."
Current Landscape and Future Implications
UDCA, marketed as Actigall and Urso in the U.S., is the current standard first-line treatment for PBC, aiding in the flow of bile from the liver. However, it is not effective for all patients, and some cannot tolerate its side effects. Livdelzi offers a valuable alternative for these patients, addressing an unmet medical need in PBC management. The drug received accelerated approval in the U.S. last year and is under review in the European Union, where an advisory committee has recommended its approval in combination with UDCA or as a monotherapy. Gilead Sciences gained access to Livdelzi through its acquisition of CymaBay Therapeutics.
