Nonalcoholic steatohepatitis (NASH) is described as a subgroup of nonalcoholic fatty liver disease (NAFLD), where excessive fat buildup is accompanied by liver cell injury and inflammation. Currently, the global prevalence of NAFLD ranges between 11.2–37.2%, while the prevalence of NASH ranges between 15.9–68.3% (Dufour et al., 2021; Riazi et al., 2022). As such, NASH has the potential to be a large and lucrative therapy market owing to the prevalence of the disease and the lack of approved agents. According to GlobalData forecasts, the NASH market will be worth $27.7 billion by 2031. This article will discuss the FDA’s recent acceptance of Intercept Pharmaceuticals’s obeticholic acid (OCA) new drug application (NDA) resubmission in NASH and how OCA’s likelihood of approval compares to other drugs in late-stage development.

Although there are currently no marketed products for NAFLD/NASH, the various stages of NASH pathophysiology have given rise to numerous strategies that companies employ to develop therapies acting on different molecular targets. Leading the race to commercialization is Intercept Pharmaceuticals, which, in December 2022, resubmitted its NDA for obeticholic acid (OCA), an FXR agonist, as a Class 2 resubmission (which has a six-month review period) for the treatment of patients with pre-cirrhotic liver fibrosis due to NASH. For context, in June 2020 the FDA rejected Intercept’s OCA NDA, with the federal agency issuing a complete response letter (CRL) requesting longer term post-interim analysis efficacy and safety data from the ongoing pivotal Phase III REGENERATE trial (NCT02548351).

The newly resubmitted NDA is supported by two positive, interim 18-month analyses from the REGENERATE trial and a detailed analysis of the largest safety database in NASH demonstrating a solid safety and tolerability profile for the long-term use of OCA. Specifically, after 18 and 48 months of treatment, 25mg of OCA demonstrated statistically significant improvement in liver fibrosis by at least one stage without worsening of NASH. While the co-primary endpoint of improvement in liver histology supports OCA’s bid for an accelerated approval, positive data from the second primary endpoint of all-cause death and liver-related clinical outcomes could help support a full approval. As of January 19, 2023, FDA has accepted the resubmitted NDA and set a PDUFA of June 22, 2023.

Although the resubmitted NDA has been accepted by FDA this time around, the acceptance of the resubmitted NDA comes after negative topline results from the company’s Phase III REVERSE trial (NCT03439254) evaluating OCA in patients with compensated cirrhosis due to NASH. According to the topline results, OCA failed to show superiority compared to placebo at improving liver scarring in patients with compensated NASH-related cirrhosis. While Intercept remains confident that the disappointing topline results from REVERSE will not affect its OCA NDA in pre-cirrhotic liver fibrosis due to NASH, it is possible that FDA may request an advisory committee meeting for the application closer to spring 2023 with requests to see additional data of OCA’s efficacy and safety data from REGENERATE and a more detailed review of the failed safety data from REVERSE. Therefore, according to GlobalData’s Pharmaceutical Intelligence Center, as of now, OCA has a 64% likelihood of approval (LOA), as shown in Table 1, which displays the drug-specific LOA of late-stage assets currently in development for NASH in the 7MM (US, France, Germany, Italy, Spain, UK, Japan). If approved, OCA will be the first drug to enter the market for the treatment of NAFLD/NASH in the US. However, given the FDA’s previous actions, it would not be surprising if the agency once again delays the approval of Intercept’s OCA to ensure the positive benefit-risk profile of OCA in the long-term.