The NASH Cupboard, Now Bare, Has Two Candidates

Nonalcoholic steato-hepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD). It is considered the second phase of NAFLD and is characterized by hepatic inflammation and ballooning due to fat in liver cells. Severe cases can result in liver cirrhosis and complications from liver disease. Currently, the only effective therapy for NASH is weight loss, which is often difficult to achieve.

In a recent interview with Managed Healthcare Executive, Ray Tancredi, MBA, a divisional vice president at Walgreens, discussed the unmet need of NASH treatment. By Tancredi’s reckoning, the market for NASH drugs could reach
$3.2 billion by 2028.

Tancredi mentioned two drugs in late-stage development: Ocaliva (obeticholic acid), which is being developed by Intercept Pharmaceuticals Inc., a biotech company in Morristown, New Jersey; and resmetirom, which is being developed by Madrigal Pharmaceuticals Inc., a company headquartered in suburban Philadelphia. Both might be approved by the FDA this year.

Ocaliva is a first-in-class farnesoid X receptor agonist that received FDA accelerated approval for treating primary biliary cholangitis, a condition in which bile ducts are destroyed, leading to liver fibrosis and eventually cirrhosis.

Intercept Pharmaceuticals has had at least two setbacks while pursuing approval of Ocaliva for treating NASH. First, in 2020, the FDA turned down a request for accelerated approval of the drug in the treatment of fibrosis caused by NASH, requesting additional post-interim analysis of safety and efficacy data. Later, in 2022, the company announced that the phase 3 REVERSE trial of Ocaliva did not meet its primary end point.

Intercept soldiered on with a resubmission of an application for the use of Ocaliva in patients with pre-cirrhotic liver fibrosis due to NASH. In January 2023, the FDA accepted the application for accelerated approval based on positive results from the pivotal phase 3 REGENERATE trial. Findings from that study showed improvement in liver fibrosis without worsening of NASH. However, severe skin itching and a rise in low-density lipoprotein (LDL) cholesterol are side effects that may give prescribers and patients pause.

Resmetirom is a first-in-class thyroid hormone receptor beta-
selective agonist. The 52-week MAESTRO-NASH phase 3 trial demonstrated that resmetirom was effective in achieving NASH resolution without worsening of fibrosis and improving fibrosis by at least one stage without worsening of NAFLD. A key secondary end point of lowering LDL cholesterol was also met.

Based on the encouraging trial results and a favorable safety profile, the company plans to apply for accelerated FDA approval of resmetirom during the second quarter of 2023.

In the development and race to market, Ocaliva appears to be ahead of resmetirom despite its earlier setbacks.

But resmetirom surpasses Ocaliva in terms of cost-effectiveness, according to a report from the Institute for Clinical and Economic Review (ICER) earlier this year. Using placeholde prices, ICER, estimated that Ocaliva treatment would cost $676,000 over a lifetime compared with resmetirom’s cost of $416,000, a $260,00 difference.

Rosanna Sutherby, Pharm.D., an independent medical writer and community pharmacist in High Point, North Carolina, is a regular contributor to Managed Healthcare Executive.