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While citing obeticholic acid's (Ocaliva) modest effect on a single surrogate endpoint for nonalcoholic steatohepatitis (NASH), FDA staff members raised "substantial concerns" over the frequency of drug-induced liver injury, along with a litany of other safety concerns.

The assessment dims the prospect of regulatory approval as the oral drug makes an iffy second bid to become the first-ever treatment for the severe form of nonalcoholic fatty liver disease (NAFLD).

On Friday, the will meet and vote on whether the benefits of obeticholic acid at a 25-mg dose outweigh the risks for NASH patients with advanced fibrosis (stages F2 and F3), a growing population that represents roughly a third of the estimated 17 million NASH patients in the U.S. Panelists will also vote on whether to recommend the FDA use the accelerated approval pathway or await clinical outcomes data from the pivotal supporting the application.

The phase III trial met one of the two prespecified primary endpoints, with 21% of participants receiving the 25-mg dose showing at least a 1-stage improvement in fibrosis and no worsening of NASH at 18 months versus 12.3% in the placebo arm, an 8.6% risk difference (95% CI 4.2-13.0).

For the second primary endpoint -- NASH resolution with no worsening of fibrosis at this time point -- no significant difference was seen (6.5% vs 3.5%, respectively). A third arm of the study testing a 10-mg dose of obeticholic acid showed no benefit over placebo for either endpoint.

NASH patients are at increased risk of progressive fibrosis and cirrhosis, and the condition represents the second leading cause of liver transplant. Weight loss is considered the most effective intervention for the roughly 5% of Americans with NASH. While bariatric surgery has shown benefit in trials, it is not a recommended treatment due to the high-risk nature of the procedure. As such, according to the FDA, pharmacological treatment remains an unmet need.

But in released ahead of Friday's meeting, FDA reviewers said their risk-benefit analysis "identified modest benefits and serious risks of OCA [obeticholic acid] for treatment of NASH."

Agency staff noted a "serious signal" for drug-induced liver injury among trial participants treated with the 25-mg dose, and the agency plans to ask its advisors if liver enzyme monitoring could adequately mitigate the risk, and what that monitoring might look like in terms of frequency and criteria for treatment discontinuation.

As assessed by a blinded hepatic safety adjudication committee, possible cases of drug-induced liver injury were seen in 57 patients treated at the 25-mg dose compared with 11 in the placebo group, while imbalances were also seen for probable cases (7 vs 1) and highly likely cases (1 vs 0).

Reviewers also said that adverse events in the 25-mg group "suggest that treatment with this dose exacerbates comorbidities or creates new ones for a patient population at risk for metabolic syndrome and its manifestations."

Specifically, they cited excess risk for cholecystitis and bile duct stones or sludge, along with the "related life-threatening complications and surgical interventions"; new-onset prediabetes/diabetes and need for additional anti-diabetic therapies in patients with diabetes; dyslipidemia requiring new treatment with statins or dose intensification; and acute kidney injury.

And that's not all, as a "substantial" excess risk of severe pruritus was seen with obeticholic acid, causing treatment interruptions or discontinuations, along with the administration of various strategies to address the issue.

"To take OCA 25 mg, that has modest efficacy on a single surrogate endpoint with unknown clinical benefit for NASH, patients will require careful monitoring of glucose, LDL cholesterol, and gallstone formation along with potential polypharmacy to mitigate the to-be-marketed OCA-related adverse events," wrote agency staff. "These newly added medications will expose subjects to potentially other adverse events as well as drug-drug interactions."

As a second phase III trial of obeticholic acid in NASH -- REVERSE -- for subjects with compensated cirrhosis, patients who progress to this level of disease would require treatment discontinuation, agency staff noted.

Reviewers further went on to cite a numerical imbalance in deaths with obeticholic acid across the development program: 17 were recorded among the 1,009 patients who received the 25-mg dose versus 10 of the 1,017 patients receiving placebo.

Obeticholic acid is currently indicated for treating primary biliary cholangitis, but in 2021 the FDA required a boxed warning over the risk of serious liver injury, and restricted it in primary biliary cholangitis patients with advanced cirrhosis.

This is the second go-around for the drug in NASH, after the FDA in 2020, though the agency told sponsor Intercept to continue following patients to conduct additional histopathology evaluations and gather more long-term safety data. Following discussions with the agency, the company increased the number of histopathology readers in an effort to eliminate potential bias.

Adverse events (AEs) and severe AEs in the NASH development program both occurred at a higher rate for subjects treated with the 25-mg dose compared with placebo. In addition, 12.1% and 8.1%, respectively, needed dose modifications or discontinued therapy.

Currently there are no tests that can accurately diagnose and stage NASH. REGENERATE enrolled patients with biopsy-proven NASH and established stage F2 or F3 fibrosis, meaning that prior to treatment, patients in clinical practice would need to undergo a biopsy, which carries its own risks.

While the FDA is not required to follow the advice of its advisory committees, it typically does.

Correction: This article has been updated to reflect that obeticholic acid in 2021 was restricted in primary biliary cholangitis patients with advanced cirrhosis.

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