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Primary biliary cholangitis (PBC)

Primary biliary cholangitis (PBC) is a cholestatic liver disease in which bile ducts in the liver are gradually destroyed. The damage to bile ducts can inhibit the liver’s ability to rid the body of toxins, and can lead to scarring of liver tissue known as cirrhosis. Although genetic or environmental factors are associated with the risk of PBC, the causes are still unknown, and most experts consider PBC as an autoimmune disease. Our proprietary compound, elafibranor (GFT505), has shown highly significant preliminary results in its phase 2 study in PBC, and has recently been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) as well as Orphan Drug Designation by the FDA and EMA (European Medicines Agency) for the treatment of PBC in adults with inadequate response to ursodeoxycholic acid (UDCA).

A serious chronic liver disease

PBC is a serious chronic, progressive hepatic disease that leads to inflammation and scarring of the small bile ducts in the liver which, if left untreated, can lead to cirrhosis, liver failure and ultimately liver transplantation. Although PBC is a relatively uncommon disease, its prevalence has drastically expanded in the United States in the last decade, with an increase of 80% of cases between 2006 and 2014. Women are 10 times more likely to be affected by PBC than men, and the incidence increases after the age of 50.¹

The initial symptoms of PBC are general fatigue and pruritus (itching); other potentially associated symptoms including dry eyes, dry mouth and jaundice. However, approximately 60% of patients are asymptomatic when the disease is diagnosed.²PBC is diagnosed based on blood tests revealing the presence of anti-mitochondrial antibodies (or AMAs) and high levels of the liver enzyme ALP.

In the absence of treatment, the 10-year survival of asymptomatic patients is estimated to be between 50 and 70%, with a median survival of 16 years. Among symptomatic patients, median survival in the absence of treatment is only 7 to 8 years. PBC is believed to be responsible for 2-3% of deaths by cirrhosis.³

With significant unmet medical needs

Today, there is no cure for primary biliary cholangitis. Although there are medications that work to slow its progression, a substantial number of patients can’t benefit from these therapies, either because of lack of response or intolerable side effects.

For many years the only medication available for the treatment of PBC was ursodeoxycholic acid (UDCA), a compound designed to help move bile through the liver and into the intestines. However, UDCA is efficient in only 50% of patients, 40% responding weakly or not at all to the treatment, and an additional 5-10% being unable to tolerate the drug.⁴

In May 2016, the FDA approved obeticholic acid (OCA) for the treatment of PBC in adults, in combination with UDCA – for patients with inadequate response to UDCA alone – and as monotherapy – for patients unable to tolerate UDCA. However, since then, the FDA had a Boxed Warning added to the Ocaliva label following concerns about increased risk of serious liver injury and death in certain patients.

Accordingly, there is still a significant medical need for new safe therapies to treat patients suffering from PBC.

Elafibranor for the treatment of PBC

The scientific literature has shown that targeting PPAR receptors has demonstrated multiple beneficial activities, including the reduction of bile acid synthesis, improved detoxification of bile in the bile duct and anti-inflammatory activity. In third party clinical trials, the use of drugs targeting PPAR receptors resulted in a significant decrease in ALP and improved biochemical profiles and pruritus in PBC patients.

Given elafibranor’s dual PPARα/δ agonist action, we believed its profile was ideal to target ALP reduction while maintaining a favorable tolerability profile and lack of demonstrated safety concerns. We therefore decided to conduct a Phase 2 clinical trial to evaluate elafibranor for the treatment of PBC, that has shown highly significant preliminary results.

In April 2019, the FDA decided to grant elafibranor the Breakthrough Therapy Designation based on our compelling Phase 2 data. A few months later, in July 2019, the FDA and the European Medicines Agency (EMA) have both granted Orphan Drug Designation to elafibranor, a PPAR alpha/delta agonist, for the treatment of PBC.

Positive top line data from the Phase 2 trial was published in December 2018 and has provided support to advance elafibranor into further clinical development in primary biliary cholangitis. Detailed results from our positive Phase 2 clinical trial evaluating elafibranor in PBC were presented in April 2019 at Association for the Study of the Liver (EASL) annual International Liver Congress™ (ILC).

¹ Lu et al 2018;
²Lindor et al. 2009; EASL PBC guidelines 2017;
³Lindor et al. 2009;
⁴ Nadya Al-Harthy et al. 2012