‘Unfavorable benefit-risk’: FDA panel votes against obeticholic acid approval for NASH
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Key takeaways:
- FDA panel voted 12-2 against approval for obeticholic acid for pre-cirrhotic patients with liver fibrosis due to nonalcoholic steatohepatitis.
- Advisors reported a “concerning” benefit-risk profile for obeticholic acid.
An FDA advisory committee voted against approval for obeticholic acid in pre-cirrhotic patients with liver fibrosis due to nonalcoholic steatohepatitis, citing a “concerning” benefit-risk profile.
The Gastrointestinal Drug Advisory Committee voted 12 to 2 with 2 abstentions that the benefits of 25 mg obeticholic acid (Ocaliva, Intercept Pharmaceuticals) do not outweigh its risks among patients with NASH and stage 2 or 3 fibrosis, most notably drug-induced liver injury and quality of life.
The committee also voted 15 to 1 to defer accelerated approval of obeticholic acid (OCA) until clinical outcome data is submitted, at which time the traditional approval pathway could be considered.
“We have a promising outcome with regard to a surrogate endpoint,” Benjamin Lebwohl, MD, MS, chairperson for the Gastrointestinal Drug Advisory Committee, said. “[However,] the degree to which that promising surrogate endpoint will ultimately yield benefits in terms of the primary endpoint of the study remains mired in uncertainty, particularly regarding the concerns related to drug induced liver injury. At this point, I do not believe that the benefits outweigh the risk.”
He added: “We are keeping in mind that this is a surrogate endpoint among people who are asymptomatic at baseline. This is a serious disease; the bar needs to be quite high when considering that fact.”
The panel based their decision on evidence presented by Intercept Pharmaceuticals representatives who reported on data from an ongoing phase 3 REGENERATE study (747-303) which was informed by histology and biochemical data from the phase 2, double-blind, placebo-controlled trials, FLINT and D8602001.
In trial D8602001, patients with NASH received either OCA 10 mg (n = 51), OCA 20 mg (n = 51), OCA 40 mg (n = 50) or placebo (n = 50). Researchers observed a 2-point or greater improvement in NASH with no worsening fibrosis among 22%, 28%, 38% and 20%, respectively, with a dose-dependent improvement among those in the 20 mg and 40 mg dosage groups. Results from the modified intention to treat population among patients in the FLINT trial showed a greater proportion of patients treated with OCA 25 mg (45% [50/110) compared with placebo (21% [23/109) had a 2-point or greater improvement in NASH with no worsening fibrosis following 72 weeks of treatment (RR = 2.2; 95% CI, 1.4-3.3).
“Our NASH clinical development program has shown treatment with OCA 25 mg results in clinically meaningful, anti-fibrotic effects,” Thomas Capozza, MD, FACP, executive director of clinical research at Intercept Pharmaceuticals, said. “The goal of therapy is to slow, halt or reverse disease progression. As such, the regulatory primary fibrosis endpoint underestimates benefit.”
He continued: “OCA 25 mg not only meets the primary fibrosis endpoint of reversal at 18 months, but also attenuates fibrosis progression, as well as improves noninvasive tests in patients with no change in fibrosis stage. This anti-fibrotic effect is highly likely to lead to clinical benefit.”
Both phase 2 trials demonstrated adverse effect profiles consistent with the observed dose-dependent increase in pruritis and drug-induced liver injury.
Interim analysis results among patients with NASH and stage 2 or 3 fibrosis from 747-303, which included 825 patients administered OCA 10 mg, 827 patients administered OCA 25 mg and 825 patients given placebo, showed a “modest treatment effect” on the surrogate endpoint of improved fibrosis without NASH worsening at 18 months. The estimated risk difference comparing OCA 25 mg to placebo ranged from 8.6% (95% CI, 4.2-13) to 12.8% (95% CI, 7-18.5).
Sangeeta Sawhney, MD, vice president of clinical development at Intercept Pharmaceuticals, noted that OCA demonstrates a “well characterized safety profile” based on long-term study data. Though, current resubmission data from 616 OCA 25 mg-treated patients and 667 placebo-treated patients showed more patients in the treatment group experienced severe and worse adverse events as well as adverse events leading to dose modification or permanent discontinuation (12.1% vs. 8.1%).
“The profile is consistent with OCA’s mechanism of action and background comorbidities in patients with NASH,” she said. “Most of the observed events are known and commonly managed by gastroenterologists and hepatologists. Rigorous comprehensive assessments have shown that safety can be managed with existing practice guidelines.”
Despite improved fibrosis without worsening of NASH, Ruby Mehta, MD, from the FDA Office of New Drugs, noted the FDA’s stance on OCA’s efficacy remains unchanged from their initial new drug application review from 2019 to 2020.
“The FDA initially concluded that OCA was associated with an unfavorable benefit-risk profile,” she said. “In this resubmission, our assessment of efficacy has remained unchanged. … Our concerns regarding the safety/risks also remain unchanged. Given these findings, FDA continues to believe that the benefit-risk profile of OCA 25 mg remains concerning.”
Frank A. Anania, MD, FACP, AGAF, FAASLD, acting director of the FDA, further reported that treating 1,000 patients with OCA 25 mg for 1 year would translate to 263 additional patients with pruritis, 198 with dyslipidemia, 22 with severe pruritis, 12 with gallbladder disease, 11 with drug-induced liver injury of mild severity, 8 with cholecystectomy and 2.4 with drug-induced liver injury of moderate severity. Treatment over 2 years would approximately double these additional outcomes.
References:
- FDA. Gastrointestinal Drug Advisory Committee (GIDAC) meeting FDA briefing document. Available at: https://www.fda.gov/media/168215/download. Accessed: May 19, 2023.
- FDA. Gastrointestinal Drug Advisory Committee (GIDAC) meeting draft questions. Available at: https://www.fda.gov/media/168212/download. Accessed: May 19, 2023.
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