IQIRVO Shows Sustained Long-Term Benefits in Primary Biliary Cholangitis with Novel Fatigue Mechanism Insights
核心洞察
Interim data from the ELATIVE trial extension shows IQIRVO (elafibranor) maintains biochemical response in 72% of patients at week 182, with a 47% reduction in alkaline phosphatase from baseline over three years of treatment.
New proteomic analysis reveals IQIRVO's PPAR (搜索) α/δ agonist activity may modulate fatigue-associated pathways linked to mitochondrial function, offering mechanistic insights into symptom improvement.
The drug demonstrates sustained improvements in fatigue and pruritus symptoms alongside stabilization of fibrosis markers, with no new safety signals identified during long-term follow-up.
Ipsen announced new long-term efficacy and mechanistic data for IQIRVO (elafibranor) in primary biliary cholangitis (搜索) (PBC (搜索)) that will be presented at The Liver Meeting 2025, hosted by the American Association for the Study of Liver Diseases (AASLD). The interim results from the ELATIVE trial's open-label extension demonstrate sustained therapeutic benefits over more than three years of treatment while providing novel insights into the drug's mechanism of action against fatigue.
Sustained Long-Term Efficacy
The ELATIVE long-term extension trial, which includes over three years of follow-up in 115 patients with PBC (搜索), showed that IQIRVO delivers sustained improvements in biomarkers of cholestasis and stabilization in markers of fibrosis. At week 182, 72% of patients receiving IQIRVO maintained a biochemical response, with a 47% reduction in alkaline phosphatase (ALP) from baseline. The proportion of patients achieving normal ALP levels remained consistent with previously presented Phase III results from the ELATIVE trial.
"PBC (搜索) does not impact all patients in the same way. Therefore, it is important for us to have access to data associated with long-term treatment benefit on the disease biomarkers and liver tests, as well as a positive impact on symptoms," said Dr. Cynthia Levy, Professor of Medicine, Division of Digestive Health and Liver Diseases, University of Miami. "These preliminary results, which indicate a potential improvement not only in pruritus, but also in fatigue, are very encouraging."
Mechanistic Insights into Fatigue Management
A second analysis from the ELATIVE trial examined the relationship between changes in the expression of fatigue-associated proteins and reported outcomes of fatigue in patients on IQIRVO. The clinical findings are consistent with previously published mechanistic data, suggesting that PPAR (搜索) α/δ agonist activation may modulate key pathways involved in energy metabolism and mitochondrial function.
Fatigue remains one of the most common and burdensome symptoms for patients with PBC (搜索), with no currently approved therapies to address it. However, clinically meaningful improvements in fatigue have been observed with IQIRVO versus placebo in the ELATIVE trial, with around one in two patients reporting a significant reduction in fatigue severity.
Safety Profile and Treatment Implications
The long-term data confirmed a well-characterized safety profile with no new safety signals identified over the three-year follow-up period. Improvements in patients with moderate-to-severe fatigue were sustained, with similar results observed for pruritus symptoms.
"These findings underscore IQIRVO's potential as a long-term treatment option that not only manages the markers of disease progression and symptoms that impact the quality of life of people living with PBC (搜索), but also helps us better understand the mechanisms behind fatigue," said Sandra Silvestri, MD, PhD, Executive Vice President, Chief Medical Officer, Ipsen.
Clinical Trial Design and Patient Population
ELATIVE is a multi-center, randomized, double-blind, placebo-controlled Phase III clinical trial with an open-label long-term extension. The trial evaluated the efficacy and safety of elafibranor 80mg once daily versus placebo for the treatment of patients with PBC (搜索) with an inadequate response or intolerance to ursodeoxycholic acid (UDCA), the existing first-line therapy for PBC.
The trial enrolled 161 patients who were randomized 2:1 to receive elafibranor 80mg once daily or placebo. Patients with an inadequate response to UDCA continued to receive UDCA in combination with elafibranor or placebo, while patients unable to tolerate UDCA received only elafibranor or placebo.
Drug Mechanism and Regulatory Status
IQIRVO is an oral, once-daily, peroxisome proliferator-activated receptor (PPAR (搜索)) agonist that exerts effects on PPARα (搜索) and PPARδ (搜索). Activation of PPARα and PPARδ decreases bile toxicity and improves cholestasis by modulating bile acid synthesis, detoxification and transporters, while also providing anti-inflammatory effects through different pathways.
The drug received Breakthrough Therapy Designation from the U.S. FDA in 2019 and was granted accelerated approval in June 2024, conditional approval by the EMA in September 2024, and UK MHRA approval in October 2024. These approvals are contingent on further verification of clinical benefit.
Disease Background
PBC (搜索) is a rare, autoimmune liver disease where a build-up of bile and toxins and chronic inflammation cause irreversible fibrosis of the liver and destruction of the bile ducts. The condition impacts approximately 100,000 people in the US and 165,000 people in Europe, with the majority being women. PBC is a lifelong condition that can worsen over time if not effectively treated and may lead to liver transplant and in some cases, premature death.