Drugs, approval in the EU of 2 new therapies for rare cholestatic diseases

The European Commission has granted conditional marketing authorization for elafibranor in the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in patients who cannot tolerate the treatment. Elafibranor is ‘first in class’, the first of a new class of drugs, peroxisome proliferator-activated receptor (PPAR) agonists, which exert an effect on the PPARα and PPARδ receptors, which are believed to be regulatory key to bile acid homeostasis, inflammation and fibrosis. Odevixibat has also been approved in exceptional circumstances – explains a note released by Ipsen – for the treatment of cholestatic itching in children with Alagille Syndrome (Algs) starting from 6 months of age. It is a non-systemic ileal bile acid transporter (Ibat) inhibitor administered orally once daily. Odevixibat blocks Ibat, resulting in a decrease in serum bile acids that can accumulate in the liver.

“We are pleased – said Sandra Silvestri, Chief Medical Officer of Ipsen – that elafibranor and odevixibat have been approved in the European Union as new options for the treatment of two rare cholestatic diseases with disabling symptoms that significantly impact the quality of life of patients and their families. People living with PBC have not seen the introduction of any therapeutic innovation for almost a decade, despite up to half of patients not tolerating or responding to currently available therapies, and patients with Alagille Syndrome have to face an intolerable itching. We are proud to be able to offer these people two new effective treatment options.”

The approval of elafibranor is based on data from the Elative phase III clinical trial which demonstrated a statistically significant therapeutic benefit, in terms of biochemical response after treatment with elafibranor 80 mg (51%) compared to patients treated with placebo (4% ), with a placebo-adjusted difference of 47% (p<0.001). A greater reduction from baseline in the PBC Worst Itch-Nrs score was also observed in treated patients compared to placebo, but this reduction was not statistically significant. However, treatment with elafibranor was associated with an improvement in pruritus, as evidenced by a greater reduction in total PBC-40 Itch and 5-D Itch scores compared to placebo. Similar proportions of patients in the Treated and placebo arms experienced adverse events, adverse events that were treatment-related, serious or serious, or led to treatment discontinuation.

“For those who live with PBC – explained Marco Carbone, professor of Gastroenterology at the University of Milan-Bicocca and consultant hepatologist at the Transplant Center of the Niguarda hospital in Milan – being able to have an innovative, effective and well-tolerated solution represents a significant breakthrough in the treatment and management of this disease. PBC is a progressive cholestatic disease that can lead to liver failure and, in some people, even the need for a liver transplant. This new therapy not only allows us to effectively manage the progression of the disease, but also the debilitating itching that compromises patients’ quality of life.”

The approval of odevixibat is based on data from the Assert clinical trial, the first and only phase III study in the world to have been completed in patients with Algs. These data demonstrated statistically and clinically significant improvements in scratching tendency from baseline to month 6 for patients treated with odevixibat compared to placebo. These improvements were observed rapidly and were maintained throughout the study period. In treated patients, compared to placebo, a statistically significant reduction in serum bile acid concentration at the end of treatment was also demonstrated, with improvements in sleep parameters reported by several observers. The overall incidence of treatment-emergent adverse events was similar to that of placebo, with a low rate of drug-related diarrhea in ALGS patients.

It is “a painful and stressful disease, which often presents itself in the first months of life – underlined Henkjan Verkade, Gastroenterologist and pediatric hepatologist at the Department of Pediatrics of the University of Groningen, Beatrix Children’s Hospital and University Medical Center of Groningen , Netherlands – One of the most common symptoms is severe itching that causes sleep disturbances in both the child and his or her caregivers. Having a new treatment option that has been shown to reduce itching and improve sleep quality is a particularly positive development for the ALGS community.”