Ipsen and Genfit Report Positive Phase 3 Results in PBC

Rare Daily Staff

Ipsen and Genfit reported positive full results from the pivotal phase 3 ELATIVE trial of their experimental therapy elafibranor in patients with the rare, autoimmune liver disease primary biliary cholangitis.

The companies reported the results at the American Association for the Study of Liver Disease and published them in the New England Journal of Medicine.

Primary biliary cholangitis (PBC) is a rare, autoimmune, cholestatic liver disease, affecting approximately nine women for every one man. A build-up of bile and toxins and chronic inflammation causes irreversible fibrosis of the liver and destruction of the bile ducts. It is a life-long condition that can worsen over time if not effectively treated, leading to liver transplant and in some cases, premature death. PBC impacts patients’ daily lives through debilitating symptoms including most commonly pruritus and fatigue. Currently, there are no approved treatments available that can effectively manage both disease progression and life-impacting symptoms.

Elafibranor is a novel, oral, once-daily, dual peroxisome activated receptor (PPAR) alpha/delta agonist, currently under investigation as a treatment for patients with PBC. Concurrent alpha/delta activation targets inflammation, cholestasis, and fibrosis in PBC. In 2019, elafibranor was granted a Breakthrough Therapy Designation by the FDA in adults with PBC who have an inadequate response to UDCA. Elafibranor has not received approval by regulatory authorities anywhere in the world.

This trial evaluated the efficacy and safety of investigational elafibranor, an oral, dual PPAR alpha/delta agonist, as a potential novel class of treatment for patients with PBC.

Results show statistically significant improvements in biomarkers of disease progression across key endpoints with a significant treatment benefit achieved in the primary composite endpoint, demonstrating a 47 percent placebo-adjusted difference between patients on elafibranor 80 mg (51 percent) compared with patients on placebo (4 percent) achieving a biochemical response. In the trial, a biochemical response is defined as alkaline phosphatase (ALP) <1.67 x upper limit of normal, an ALP decrease of 15 percent or more, and total bilirubin ULN at 52 weeks. ALP and bilirubin are important predictors of PBC disease progression. Reductions in levels of both can indicate reduced cholestatic injury and improved liver function.

Only patients receiving elafibranor achieved normalization of ALP at Week 52 (15 percent vs none for placebo), a key secondary endpoint of the trial. The significant biochemical effect of elafibranor measured by ALP reduction was further supported by data demonstrating reductions from baseline in ALP levels were rapid, seen as early as Week 4 in the elafibranor group, and were sustained through Week 52, with a decrease in ALP of 41 percent on elafibranor compared with placebo.

ELATIVE investigated the effect of treatment with elafibranor on pruritus (severe itch) across three separate patient-reported outcome measures. On the key secondary endpoint using the PBC Worst Itch NRS score, the reduction of pruritus observed for elafibranor versus placebo was not statistically significant. Two other secondary patient-reported outcome measures were used to assess itch, and greater reductions in pruritus were observed with elafibranor compared with placebo at Week 52, according to the itch domain of PBC-40 quality of life questionnaire.

Elafibranor was well tolerated in the trial. Similar percentages of patients in the treatment group and the placebo group experienced adverse events, treatment-related adverse events, severe or serious adverse events, or adverse events leading to discontinuation. Adverse events occurring in >10 percent of patients and more frequently on elafibranor versus placebo included abdominal pain, diarrhea, nausea, and vomiting. Elafibranor has a well-documented safety profile across a broad patient population that is consistent with cumulative safety data from past elafibranor trials in other indications, including NASH.

“We believe these data suggest that elafibranor could be a paradigm-changing treatment meeting the unmet need for an effective second-line option,” said Christelle Huguet, executive vice president and head of Research and Development, Ipsen. “These data from ELATIVE have provided a better understanding of how we can effectively manage both disease progression and the symptom burden still experienced by many people living with PBC.”

Photo: Christelle Huguet, executive vice president and head of Research and Development for Ipsen