FDA Approves Gilead's Livdelzi (Seladelpar) for Primary Biliary Cholangitis
Key Insights
The FDA granted accelerated approval to Livdelzi (seladelpar) for treating primary biliary cholangitis (search) (PBC) in adults with inadequate response or intolerance to UDCA.
Approval was based on the Phase III RESPONSE trial, where Livdelzi significantly improved biochemical markers and reduced pruritus (search) compared to placebo.
Livdelzi is a PPARδ (search) agonist, administered orally, and represents a new treatment option for PBC, a chronic autoimmune liver disease affecting primarily women.
The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Livdelzi (seladelpar), a treatment developed by Gilead Sciences, for primary biliary cholangitis (search) (PBC) in adults who have an inadequate response to ursodeoxycholic acid (UDCA) or cannot tolerate it. This approval marks a significant advancement in the treatment landscape for PBC, a chronic autoimmune disease affecting primarily women. The accelerated approval was based on positive results from the Phase III RESPONSE study.
Clinical Efficacy and Trial Data
The approval of Livdelzi was primarily based on data from the pivotal Phase III RESPONSE study, a 12-month, double-blind, placebo-controlled trial. The study involved 193 patients who were either unresponsive to or had experienced serious adverse effects from UDCA treatment. Participants were randomized to receive either 10mg of Livdelzi or a placebo orally once daily for 12 months.
The primary endpoint was a composite biochemical response at month 12. Key secondary endpoints included normalization of alkaline phosphatase (ALP) levels and changes in the pruritus (search) numerical rating scale score from baseline at six months. Results indicated that 62% of participants receiving Livdelzi reached the primary endpoint, compared to 20% of those on placebo. Additionally, 25% of participants treated with Livdelzi achieved normalized ALP levels by month 12, a result not observed in the placebo group. Livdelzi also significantly reduced pruritus in patients compared to placebo.
Carol Roberts, president of The PBCers Organization, noted, "The availability of a new treatment option that can help reduce this intense itching while also improving biomarkers of active liver disease is a milestone for our community."
Mechanism of Action and Disease Context
Seladelpar is a selective peroxisome proliferator-activated receptor delta (PPARδ (search)) agonist. PPARδ is crucial for controlling glucose, fat, and cholesterol metabolism and is found in many tissues, including the liver. By activating PPARδ, seladelpar reduces bile acid production by lowering the activity of cholesterol 7 alpha-hydroxylase-1 (CYP7A1 (search)), an enzyme that converts cholesterol into bile acids.
PBC is characterized by impaired bile flow, leading to the accumulation of toxic bile acids in the liver. This condition affects approximately 130,000 individuals in the U.S., predominantly women. Without treatment, PBC can lead to severe liver damage and eventual failure.
Safety and Tolerability
In the RESPONSE study, the most frequently reported adverse events in patients treated with Livdelzi were headache, abdominal pain and swelling, nausea, and dizziness. Gilead warned that fractures have occurred in 4% of patients treated with Livdelzi compared to none in the placebo group and that patients should avoid Livdelzi if they have complete biliary obstruction.
Regulatory and Future Outlook
The FDA granted Livdelzi accelerated approval based on the reduction of ALP levels. Continued approval may depend on verifying clinical benefits in confirmatory trials. Gilead has initiated the Phase III AFFIRM study to analyze the impact of Livdelzi on clinical outcomes in individuals with compensated cirrhosis (search) due to PBC.
Daniel O’Day, Chairman and Chief Executive Officer, Gilead Sciences, stated, "Today’s approval of Livdelzi, with its distinct profile, provides them with an important new option. We look forward to leveraging Gilead’s long-standing expertise in liver disease to bring this promising new treatment to all those who could benefit."
Livdelzi is available as 10mg hard gelatine capsules for oral administration. It has also received Orphan Drug status in the U.S. and Europe, and is under review by the UK Medicines and Healthcare Products Regulatory Agency and the European Medicines Agency.