By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration has approved an oral dual peroxisome proliferator-activated alpha and delta receptor agonist for the treatment of primary biliary cholangitis, formerly known as primary biliary cirrhosis. Elafibranor was granted an accelerated approval and an orphan designation.
It is distributed by Ipsen Biopharmaceuticals Inc. as Iqirvo.
Indications
Elafibranor is indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults who have an inadequate response to or as monotherapy in those unable to tolerate UDCA.1
The accelerated approval was based on reduction of a biochemical marker (alkaline phosphatase). Continued approval may be contingent on demonstration of clinical benefit (i.e., improved survival, prevention of liver decompensation events).1 It is not recommended for patients who have or develop decompensated cirrhosis (e.g., ascites, variceal bleeding, and hepatic encephalopathy) or biliary obstruction.1
Dosage
The recommended dose is 80 mg orally once daily without regard to food.1 Myalgia and myopathy should be assessed prior to treatment initiation and periodic assessment during treatment especially in patients with signs and symptoms of new onset or worsening muscle pain or myopathy.1 Similarly, liver function tests should be assessed for potential drug-induced liver injury. Elafibranor is available as 80-mg tablets.
Potential Advantages
Elafibranor improves a biochemical indicator of cholestasis (alkaline phosphatase) compared to placebo in patients with PBC.1,2
Potential Disadvantages
Elafibranor has not been proven to improve clinical outcome in PBC.1 It did not significantly improve pruritus in study participants with moderate-to-severe pruritus.3 Fractures occurred in 6% of elafibranor-treated individuals compared to 0% for placebo-treated individuals.1
Myalgia or myopathy with or without creatine phosphokinase elevation have occurred in patients treated with elafibranor alone or concomitantly with a statin. Animal reproductive studies indicate that elafibranor may cause fetal harm. Adverse events include abdominal pain, diarrhea, nausea, and vomiting.
Comments
Elafibranor and its main active metabolite are believed to inhibit bile acid synthesis. It was evaluated in a randomized, double-blind, placebo-controlled study in adults (96% female and 91% white) with PBC who had an inadequate response or intolerance to UDCA.
Inclusion criteria included alkaline phosphate (ALP) levels at least 1.67 times the upper limit of the normal range (ULN) (174 U/L for women and 215 U/L for men) and total bilirubin level no more than two times the ULN (41 µmol/L).
Subjects were randomized to elafibranor (n = 108) or placebo (n = 53) once daily for at least 52 weeks. Those on a stable dose of UDCA were permitted to continue this treatment throughout the study.
The primary endpoint was a composite biochemical response defined as achieving ALP less than 1.67 times ULN (129 U/L for males, 104 U/L for females), with a reduction of ≥ 15% from baseline, and normal total bilirubin levels (at or below ULN [1.20 mg/dL]) at week 52.
One of the secondary endpoints was change in pruritus intensity based on Worst Itch Numeric Rating Scale (WI-NRS). Composite biochemical response rates were 51% for elafibranor and 4% for placebo. Seventy-five percent had a decrease of 15% compared to 17% for the placebo group.
There was a trend of lower ALP in the elafibranor group compared to the placebo group by Week 4.
There was no difference in total bilirubin less than or equal to ULN (85% vs. 83%). Among subjects with moderate-to-severe pruritis (41%), there was no difference in mean change from baseline through week 52 based on WI-NRS.
Clinical Implications
Primary biliary cholangitis (PBC) is a rare autoimmune-mediated chronic disease in which small bile ducts in the liver are inflamed and eventually destroyed due to accumulation of bile acids.3
The condition affects mostly women (9 to 1 ratio) with an estimated prevalence of 65 out of every 100,000 women.
Treatment usually is initiated with ursodeoycholic acid (UDCA) to slow disease progression (cirrhosis, end-stage liver disease, hepatocellular carcinoma) and transplant-free survival.
However, about 40% of patients do not achieve adequate response and 5% to 10% are unable to tolerate UDCA.3 Non-responders tend to be male and diagnosed at a younger age (< 30 years of age).4
Obetcholic acid is an FDA approved option for these individuals; however, in 2021, the FDA issued a Safety Communication on the risk of serious liver injury in patients with advanced cirrhosis.5 In addition, in a randomized controlled trial, the frequency of pruritus was higher with obetcholic acid (56% to 68%) compared to placebo (38%).6
Other options, off-label, include fenofibrate and bezafibrate. Elafibranor provides an option for those not responding or intolerant of UDCA and when obetcholic acid is not appropriate. The cost of elafibranor is expected to be $11,460 per 30-day supply or $139,430 per year.
A recent publication of a Phase III trial of seladelpar (peroxisome proliferator-activated delta agonist) reported that it provides biochemical response and reduced pruritus among study participants with moderate-to-severe pruritus.7 This could be the next drug on the horizon for PBC.
References
- Iqirvo prescribing information. Ipsen Biopharmaceutical Inc. Published June 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218860s000lbl.pdf
- Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and safety of elafibranor in primary biliary cholangitis. N Engl J Med 2024;390:795-805.
- American Liver Foundation. Primary biliary cholangitis. Updated March 22, 2024. https://liverfoundation.org/liver-diseases/autoimmune-liver-diseases/primary-biliary-cholangitis-pbc/
- Carbone M, Mells GF, Pells G, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 2013;144:560-569.
- U.S. Food and Drug Administration. FDA Drug safety communication: Due to risk of serious liver injury, FDA restricts use of Ocaliva (obeticholic acid) in primary biliary cholangitis (PBC) patients with advanced cirrhosis: Adding and updating warnings. https://www.fda.gov/media/149516/download?attachment
- Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016;375:631-643.
- Hirchfield GM, Bowlus CL, Mayo MJ, et al. A phase 3 trial of seladelpar in primary biliary cholangitis. N Engl J Med 2024;390:783-894.
The U.S. Food and Drug Administration has approved an oral dual peroxisome proliferator-activated alpha and delta receptor agonist for the treatment of primary biliary cholangitis, formerly known as primary biliary cirrhosis. Elafibranor was granted an accelerated approval and an orphan designation.
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