On 19 May, the FDA’s Gastrointestinal Drugs Advisory Committee (GDAC), by a vote of 12 to two, with two abstentions, voted against the FDA’s approval of Intercept Pharmaceuticals’s new drug application (NDA) for obeticholic acid (OCA) 25mg oral tablets, for the treatment of pre-cirrhotic liver fibrosis due to nonalcoholic steatohepatitis (NASH). Additionally, when asked whether the FDA should consider a potential accelerated approval, panellists voted 15 to one against that regulatory pathway for the drug. For context, in January 2023, the FDA accepted Intercept’s resubmission of its NDA for OCA as a Class 2 resubmission (which has a six-month review period in NASH) and set a Prescription Drug User Fee Act (PDUFA) date of 22 June 2023. In addition, the FDA previously 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) in June 2020.

While extremely disappointing for Intercept and the NASH community, this vote is not entirely surprising, as the FDA had released briefing documents prior to the AdCom meeting, showing that the agency had concerns over potential risks of liver injury and diabetes from the drug, especially given its “modest” efficacy (8.6% risk reduction compared with placebo). Panellists were especially apprehensive about the drug-induced liver injury as a serious problem for OCA 25mg, in addition to several other side effects including gall bladder inflammation, bile duct stones, the onset of diabetes, lipid dysregulation, severe pruritus, and acute kidney injury. Additionally, panellists expressed doubts regarding Intercept’s use of a surrogate endpoint in its clinical trial. Specifically, the FDA questioned “how the magnitude of changes in these surrogate endpoints may translate to meaningful changes in clinical outcomes”.

Moreover, the FDA continued to show its lack of confidence in OCA following its failure to meet the other primary endpoint of showing significant NASH resolution with no worsening fibrosis with 25mg of OCA in the Phase III REGENERATE trial. Lastly, the agency stated that to qualify for the medication, patients would have to undergo a liver biopsy given that the NDA was submitted for pre-cirrhotic NASH patients with F2/F3 cirrhosis. To this point, the FDA argued that a liver biopsy creates the risk of severe bleeding and a very low chance of death, which could influence patients to forgo the procedure due to its painful and invasive nature. As such, the FDA concluded that the “modest” efficacy that OCA offers is not enough to “justify OCA use in NASH subjects with stage 2 or 3 fibrosis”, as well as in terms of a biopsy perspective in regard to the general NASH population. Although this vote has narrowed OCA’s chances to get FDA approval by the target PDUFA date of June 2023 it has left the door open for OCA to potentially present more robust data in the near future.

However, as it currently stands, with the Phase III REGENERATE trial scheduled to reach completion in September 2025, Intercept’s OCA will not be taking the title of first-to-market therapy in NASH. Recall, Madrigal Pharmaceuticals recently announced plans to submit an NDA seeking accelerated approval of resmetirom (selective thyroid hormone receptor-β agonist; THR-Beta agonist) for the treatment of non-cirrhotic NASH with liver fibrosis by June 2023. The company’s announcement to file for an NDA follows positive topline results from its pivotal Phase III MAESTRO-NASH clinical trial (NCT03900429). For context, the Phase III MAESTRO-NASH trial evaluated resmetirom (80mg or 100mg) in patients with NASH and fibrosis in resolving NASH and reducing progression to cirrhosis and/or hepatic decompensation. Topline results demonstrated that both daily oral doses of resmetirom achieved both primary endpoints (improvements in NASH and liver fibrosis on liver biopsies) and potentially clinically meaningful effects compared to placebo. Additionally, in January 2023, Madrigal presented data from a supportive analysis, conducted by central pathologists, that replicated the positive primary endpoint results using consensus reads of digitised biopsy images. Following such positive data, the unique mechanism of action (MOA), and the superior tolerability profile of Madrigal’s resmetirom, it is likely that resmetirom will be the first therapy approved in NASH.  

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