The 1st Breakthrough Therapy Designation from the FDA for NASH Therapy
On October 13, French biopharmaceutical company Inventiva announced that the FDA has granted its leading drug candidate lanifibranor a "breakthrough therapy designation" for the treatment of non-alcoholic steatohepatitis (NASH). Since January 2015, Lanifibranor is considered the first NASH treatment drug to receive this title.
The complex pathogenesis of NASH
NASH is a severe type of non-alcoholic fatty liver disease (NAFLD), caused by excessive accumulation of fat in the liver. NASH is related to chronic liver inflammation and liver cell damage, which can lead to fibrosis, cirrhosis, and ultimately liver failure and even liver cancer. The global incidence of NAFLD and NASH is rising rapidly. According to statistics, there are more than 100 million people with NASH patients in the world, and the number is expected to exceed 350 million by 2030.
Since NASH was defined as a new disease in 1980, Elizabeth Powell et al. found that obesity and diabetes were the main risk factors, suggesting that NASH may be a metabolic-related disease. Animal studies showed that high-fat food or knock-out of the receptor can induce fatty liver, and fatty liver cells are more sensitive to damage from inflammatory factors and lipid oxides. Based on these studies, Day and James of the British Liver Research Center proposed the "double strike" theory of the pathogenesis of NASH in 1998 that fat accumulation and degeneration are the first blow and exposure to inflammatory factors and metabolic by-products is the second blow, which eventually lead to cell death, inflammation and fibrosis. With the deepening of clinical and basic research, researchers found that the hypothesis of Day and James is too simplistic. Nash is actually the result of multiple risk factors, multiple cell types, and multiple tissues and organs interacting in parallel, which is the so-called "multiple parallel strikes" theory. Risk factors include insulin resistance, oxidative stress, hormonal imbalance, chronic inflammation, fibrosis, immune and intestinal bacterial disorders, etc., involving various cells in the liver, intestine, and adipose tissue.
Statistics of high-stage drugs and targets in global R&D of NASH therapy
At present, NASH is predicted to be one of the largest drug markets in the field of liver disease after hepatitis C. It is estimated that the global NASH therapeutic drug market will reach US$40 billion in 2025.
On a global scale, the targets that have entered the development phase for NASH indications are FXR, PXR, NRF2, PPARs, GLP-1, SGLT-2, ASK-1, ACC, miR-33a, DGAT1/2, FGF21, AMPK, mTORC, CCR, AnxA1, RvD1, Galectin3, LOXL2, CYR61, etc. Among them, the rapid progress of clinical research includes GENFIT's PPAR receptor agonist Elafibranor, Intercept's farnesol receptor (FXR) agonist obeticholic acid (OCA), Allergan's CCR2/CCR5 chemokine receptor blocker Cenicriviroc (CVC), and Gilead's anti-apoptotic signal-regulated kinase 1 (ASK1) inhibitor Selonsertib. The phase III clinical trial of OCA reached a primary endpoint and is expected to become the first NASH drug to be marketed.
It is reported that this FDA breakthrough therapy designation is based on the positive results of Phase 2b clinical trials in patients with NASH. Lanifibranor is an oral small-molecule pan-PPAR agonist, which produces balanced activation of PPAR? and PPAR?, and can partially activate PPAR? to induce anti-fibrosis, anti-inflammatory, and beneficial metabolic changes in the body.
According to Mr. Frédéric Cren, Chairman, CEO and Co-founder of Inventiva, "Lanifibranor’s designation by the FDA is a remarkable achievement and recognition that lanifibranor can provide significant clinical benefits for patients with NASH. We look forward to continuing to work with the FDA closely to bring safe and effective therapies to NASH patients as soon as possible."