Phase-II study proves the efficacy of the dual PPARα/δ agonist elafibranor as additional therapy to ursodeoxycholic acid in the treatment of primary biliary cholangitis (PBC).
Primary biliary cholangitis (PCB) is an autoimmune disease in the course of which inflammation of the bile ducts, including intrahepatic bile ducts and channels, occurs, which can lead to cirrhosis and ultimately to liver failure. The disease can initially cause symptoms such as pruritus, fatigue and sometimes icterus, but often remains asymptomatic and is discovered by chance through conspicuous transaminases (see sources 1, 2). Standard therapy is ursodeoxycholic acid (UDCA), which, however, does not produce the desired results in all patients. Obeticholic acid, a semi-synthetic bile acid, is currently the only second-line therapy approved (see source 3).
Data from a Phase II study with the dual PPARα/δ agonist elafibranor in this indication were presented at the ILC 2019. Elafibranor is currently not approved in any indication, has anti-inflammatory properties and reduces the synthesis and toxicity of bile acids. The substance is investigated, for example, in the treatment of type 2 diabetes or non-alcoholic fatty liver disease. "The development of new therapies for PBC is important because many patients do not achieve the desired effect with the therapies available or do not tolerate the therapies," says Dr. Velimir Luketic of the Virginia Commonwealth University School of Medicine in Richmond, USA, who presented the latest data on elafibranor at the ILC.
The Phase II study included 45 patients with PBC without cirrhosis who did not respond adequately to UDCA. Patients were randomized into three groups, continued to take UDCA, and additionally received elafibranor in doses of 80mg/d or 120mg/d or placebo. The primary endpoint was the ALP alteration over 12 weeks compared to placebo. Both doses of elafibranor were shown to be significantly effective compared to placebo (p<0.001). Specifically, the ALP reduction was 48% in the 80mg group and 41% in the 120mg group compared to the baseline. In the placebo group, however, ALP increased by 3%. At week 12, 67% of subjects in the elafibranor 80mg/d group and 79% of patients in the elafibranor 120mg/d group had achieved ALP <1.67 x ULN, ALP reduction >15% and normal bilirubin. This was achieved in the placebo group in 6.7% of patients. In addition, there were significant improvements in lipid and inflammation markers and a trend towards a decrease in pruritus. Elafibranor was well tolerated. "These results suggest a substantial anticholestatic effect of elafibranor, which we hope can be translated into long-term therapeutic success for our patients," Dr. Luketic commented (see source 4).
Sources:
1. Fricker ZP, Lichtenstein DR: Primary sclerosing cholangitis: a concise review of diagnosis and management. Dig Dis Sci 2019; 64(3): 632-42
2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017; 67(1): 145-72
3. Novel strategies and therapeutic options for the management of primary biliary cholangitis. Therap Adv Gastroenterol 2017; 10(10): 791-803
4. Luketic V et al: Elafibranor, a peroxisome proliferator-activated receptor alpha, and delta agonist demonstrate favorable efficacy and safety in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid treatment. ILC 2019, LB-02
5. International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL), 13 April 2019, Vienna