Gilead announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval for Livdelzi (seladelpar) as a treatment for primary biliary cholangitis (PBC). This approval is for use in adults who either do not respond adequately to ursodeoxycholic acid (UDCA) or cannot tolerate it.
Livdelzi can be used in combination with UDCA or as a monotherapy, though it is not recommended for patients with or who develop decompensated cirrhosis.
The FDA’s decision was primarily based on results from the pivotal Phase 3 RESPONSE study, a placebo-controlled trial.
In this study, 62% of participants treated with Livdelzi met the primary endpoint, achieving a composite biochemical response at 12 months, compared to 20% of those receiving a placebo. Additionally, 25% of the participants on Livdelzi experienced normalization of alkaline phosphatase (ALP) levels, a key marker for liver health, which was not observed in any of the placebo group.
A significant reduction in pruritus, a common and debilitating symptom of PBC, was also noted at six months for those on Livdelzi compared to the placebo group.
It’s important to note that while Livdelzi’s approval was granted based on ALP reduction, improvements in survival or prevention of liver decompensation events have not yet been confirmed. The continued approval of Livdelzi may depend on the results of further confirmatory trials.
Primary biliary cholangitis is a chronic autoimmune condition that damages the bile ducts, affecting about 130,000 Americans, primarily women. Without treatment, it can lead to liver failure. There is currently no cure for PBC.
Livdelzi, an oral PPAR delta agonist (delpar), represents a new option in PBC treatment, particularly for those who have not responded well to existing therapies. It has demonstrated effectiveness in normalizing ALP levels, an important marker of disease progression in PBC. The RESPONSE study, along with other studies such as the long-term ASSURE study and earlier phase trials, collectively represent the experiences of over 500 participants with PBC treated with Livdelzi. The ongoing Phase 3 AFFIRM study, a randomized, placebo-controlled trial, is evaluating Livdelzi’s effect on clinical outcomes in people with compensated cirrhosis due to PBC.
In the RESPONSE study, Livdelzi, administered either alone or with UDCA as a daily oral medication, showed significant reductions in key biomarkers of PBC and alleviated pruritus, a symptom that severely impacts the quality of life for those with the disease.
Livdelzi is the only treatment to show statistically significant and lasting improvements in both pruritus and cholestasis markers related to disease progression in a Phase 3 trial. The study’s primary endpoint was achieving a composite biochemical response at 12 months, which included ALP levels below 1.67 times the upper limit of normal (ULN), a reduction in ALP of at least 15% from baseline, and total bilirubin levels within the normal range. Secondary endpoints included ALP normalization and reduction in pruritus score.
Common side effects reported in the Livdelzi group, occurring in at least 5% of participants and more frequently than in the placebo group, included headache, abdominal pain, nausea, abdominal distension, and dizziness. No serious adverse events related to the treatment were reported.
Livdelzi’s mechanism as a PPAR-delta agonist plays a role in regulating key metabolic and liver disease pathways. Preclinical and clinical studies support its ability to influence genes involved in bile acid synthesis, inflammation, lipid metabolism, and fibrosis.
Livdelzi stands out as the first and only treatment for PBC that has achieved statistically significant improvements in biochemical response, ALP normalization, and pruritus when compared to placebo, addressing a critical unmet need for people living with this condition.
As part of the FDA's accelerated approval, Gilead has initiated the AFFIRM study, a confirmatory long-term outcomes trial involving individuals with compensated cirrhosis. The ongoing approval of Livdelzi may be dependent on the confirmation of its clinical benefits in these studies.
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