By Brian Harvey, Managing Expert, YourEncore Regulatory Center of Excellence
Non-Alcoholic Steatohepatitis (NASH) is a specific metabolic disorder that manifests within the liver, possibly progressing to liver fibrosis and end-stage cirrhosis, as well as associating with an increased risk of cardiovascular (CV) morbidity & mortality and Type 2 Diabetes. Throughout the industrialized world today, the most common cause of chronic liver disease is Non-Alcoholic Fatty Liver Disease (NAFLD), the phenotypes of which extend from a Non-Alcoholic Fatty Liver (NAFL) to NASH. While NAFLD is a broad term that surrounds the spectrum of fatty liver disease, NASH is the most severe form and is closely related to the triple epidemic of obesity, pre-diabetes, and diabetes.1
Nearly 10-20% of those affected by NAFLD suffer from NASH. In the United States alone, NASH-associated cirrhosis is the third-most frequent cause for liver transplants, on track to become the leading cause by the end of 2020 (overtaking Hepatitis C in the process).2
Currently, the consequences of NASH are increasingly severe. For example, up to 38% of deaths in patients with NASH are directly related to CV events, showing a direct impact of this disorder on the entire body.3 Overall, the potential severity and lack of education around NASH represents a “substantial unmet medical need and a significant burden to healthcare systems.”2
Unfortunately, there are currently no FDA-approved drugs or biologics specifically indicated for the treatment of NASH patients, but change may soon be on the horizon. Multiple organizations have begun their pipeline development on drugs and treatments competing to be first to market. Phase III-IV clinical trials are also in progress, showing promising results in patients against a placebo.
During these Phase III endpoints, some patients have even achieved at least one stage of liver fibrosis improvement with no worsening of NASH at 72 weeks.4 Following these successes and a seamless rollover into Phase IV, the United States Food & Drug Administration (FDA) designated a “Priority Review” on this NDA, defining a goal to take on an application within six months, rather than the standard 10 months.5 This designation facilitates drug programs that address an unmet medical need in the treatment of serious or life-threatening conditions.6
Since this novel drug treatment is considered a “New Molecular Entity” (NME), meaning the drug has never before been approved,7 the FDA announced the need for review by external experts under the Advisory Committee (AdCom) meeting structure prior to the FDA action date.8 This AdCom meeting was originally scheduled for late April 2020, but unfortunately postponed the review due to the recent COVID-19 pandemic. The review deadline was extended for 3 months with the sponsor’s submission of additional data, deemed to be a major amendment by FDA.
The FDA staff decided to continue its review of the OCA NDA and rescheduled the April AdCom with the option of holding the newly envisioned concept of a Virtual AdCom in early June 2020, with the review action date pushed to later in the month.
On June 29, 2020, the novel drug’s parent company made the following announcement:
“The U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) regarding the New Drug Application (NDA) for obeticholic acid (OCA) for the treatment of fibrosis due to nonalcoholic steatohepatitis (NASH). The CRL indicated that, based on the data the FDA has reviewed to date, the Agency has determined that the predicted benefit of OCA based on a surrogate histopathologic endpoint remains uncertain and does not sufficiently outweigh the potential risks to support accelerated approval for the treatment of patients with liver fibrosis due to NASH. The FDA recommends that Intercept submit additional post-interim analysis efficacy and safety data from the ongoing REGENERATE study in support of potential accelerated approval and that the long-term outcomes phase of the study should continue.” 9
What we do know is that there is hope on the way for people living with NASH. With a greater emphasis on remote work, regulatory agencies will have to adapt to get these life-saving therapies to patients. With further testing and a final approval from the FDA, we could see a major breakthrough for treating this disorder, leading to happier, healthier, safer lives for people around the world.
1: European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol, 2016;64(6):1388-1402.
3: Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, associates with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149(2):389-397.