Phase 3 drug pipelines in the treatment of non‐alcoholic steatohepatitis

Abstract

Non‐alcoholic steatohepatitis (NASH), which is a more severe form of non‐alcoholic fatty liver disease, can at least partly lead to cirrhosis, hepatocellular carcinoma, and hepatic failure. Liver transplantation is the only option for NASH cirrhosis at this time. By 2020, NASH is projected to overtake hepatitis C as the leading cause of liver transplants in the USA. There are still no approved drugs for treating NASH. Although there are approximately 196 agents of investigational NASH therapies in various stages of development, we here mainly review phase 3 drug candidates in the pipeline for NASH. The NASH space across the seven major markets of the USA, France, Germany, Italy, Spain, the UK, and Japan, is set to rise from $618 million in 2016 to approximately $25.3 billion by 2026. However, the fact that the race to develop an effective drug against NASH has reached the home stretch, with five drug candidates (obeticholic acid, elafibranor, selonsertib, cenicriviroc, and resmetirom) in phase 3 stage of the trial, is welcome news for patients. The very earliest a NASH drug could hit the market is 2021, assuming all goes well as planned.

Selonsertib, a Potential Drug for Liver Failure Therapy by Rescuing the Mitochondrial Dysfunction of Macrophage via ASK1-JNK-DRP1 Pathway

“…Thus, it is important to identify a potential drug and further clarify its treatment mechanism and determine its therapeutic window for ALF. In this study, we showed that selonsertib, a selective inhibitor of ASK1 and currently in a phase III clinical trial on NASH [20], could effectively protect against LPS/GalN-induced ALF by inhibiting the activation of hepatic ASK1-JNK-DRP1 pathway and alleviating mitochondrial damage of macrophages. Unfortunately, selonsertib is only effective early after LPS/GalN administration and the limited therapeutic window may be related to the time point of JNK and DRP1 mitochondrial translocation.…”

Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

“…Moreover, no approved treatments exist for NASH. Therefore, research is ongoing to identify new targets to develop safer and more effective anti-obesity and anti-NASH drugs by improving energy metabolism, insulin sensitivity and inflammation [53][54][55][56][72][73][74][75][76][77][78][79].…”

Making progress in nonalcoholic fatty liver disease (NAFLD) as we are transitioning from the era of NAFLD to dys-metabolism associated fatty liver disease (DAFLD)

“…diabetic retinopathy or nephropathy in patients with T2DM [35]. Being a highly prevalent disease without a standard noninvasive biomarker and an approved treatment renders ΝAFLD/MAFLD/DAFLD an attractive topic for researchers, clinicians, policymakers and industry [26]; it has been estimated that the drug market for NASH will reach $US 25 billion in the USA, Japan, and European Union-5 (England, France, Germany, Italy and Spain) in 2026 [36]. This has resulted in a race to develop the most appropriate medication(s) the soonest possible.…”