Madrigal Pharmaceuticals has reported positive Phase 3 results for its non-alcoholic steatohepatitis (NASH) drug candidate resmetirom, potentially paving the way for the first approved treatment in a therapeutic area that has seen numerous high-profile failures.
The Massachusetts-based biotech announced that resmetirom, a once-daily oral thyroid hormone receptor (THR) β-selective agonist, met both primary endpoints in the pivotal MAESTRO-NASH trial, demonstrating both NASH resolution and improvement in liver fibrosis – a combination that has proven elusive in previous development efforts.
After 52 weeks of treatment, NASH resolution – defined as a two-point or greater reduction in NAFLD activity scores with no worsening of liver fibrosis – was achieved in 26% of patients receiving the 80mg dose and 30% of those on the 100mg dose, compared to just 10% in the placebo group. Additionally, one-stage or greater improvement in liver fibrosis was observed in 24% and 26% of the respective resmetirom groups, versus 14% of patients on placebo.
"These results suggest resmetirom can help patients achieve improvement in both the underlying steatohepatitis that drives this disease and the resulting fibrosis that is associated with progression to cirrhosis and its complications," said Becky Taub, Chief Medical Officer at Madrigal.
The drug also demonstrated metabolic benefits, reducing LDL-cholesterol by 12-16% across the two dosing groups while the placebo group saw a 1% increase. This aligns with resmetirom's proposed mechanism of action, which increases fat metabolism in the liver to reduce the toxic deposits that drive NASH progression.
NASH: A Growing Health Concern
NASH represents an advanced form of non-alcoholic fatty liver disease (NAFLD) that affects millions globally and is strongly associated with obesity, diabetes, and metabolic syndrome. As obesity rates continue to rise in industrialized nations, NASH prevalence is expected to increase substantially, creating what analysts project could be a multi-billion dollar market opportunity.
The condition is characterized by fat accumulation and inflammation in the liver, which can progress to fibrosis, cirrhosis, and potentially liver failure if left untreated. Currently, lifestyle modifications remain the only recommended intervention, with no FDA-approved pharmacological therapies available.
A Challenging Development Landscape
Madrigal's success comes against a backdrop of numerous failures in NASH drug development. Earlier this year, Gilead Sciences reported that its late-stage candidate selonsertib failed to meet the primary endpoint in the Phase 3 STELLAR-4 trial for patients with compensated cirrhosis due to NASH.
The apoptosis signal-regulating kinase 1 (ASK1) inhibitor showed no significant benefit over placebo, with only 14.4% of patients on the 18mg dose and 12.5% on the 6mg dose achieving the primary endpoint of fibrosis improvement without NASH worsening, compared to 12.8% on placebo.
"While we are disappointed that the STELLAR-4 study did not achieve its primary endpoint, we remain committed to advancing therapies for patients with advanced fibrosis due to NASH, where there is a significant unmet need for effective and well-tolerated treatments," said John Hutchison, Gilead's Chief Scientific Officer at the time of the announcement.
Gilead's setback followed similar disappointments from companies including Intercept Pharmaceuticals, Genfit, Albireo, CymaBay, Cirius, and NGM Biopharma. Intercept, once considered the frontrunner in NASH development, faced a significant setback when the FDA rejected its marketing application for obeticholic acid in 2020, and the company subsequently withdrew its European filing.
Market Implications
Madrigal's market capitalization has more than tripled following the positive data announcement, exceeding $4 billion – coincidentally matching what some analysts, including Andrea Tan of Goldman Sachs, project as potential peak annual sales for resmetirom.
Industry observers are already speculating about Madrigal becoming an acquisition target, with valuations potentially reaching $9 billion, given the significant unmet need in NASH and the scarcity of successful late-stage programs.
Looking Forward
All patients enrolled in MAESTRO-NASH – up to 2,000 in total – will continue on therapy beyond the initial 52-week treatment period. Madrigal plans to follow participants for up to 54 months to generate data on clinical outcomes, including progression to cirrhosis, hepatic decompensation events, and all-cause mortality.
These longer-term outcomes will be crucial for establishing resmetirom's clinical value proposition and could strengthen its position in what is expected to become a competitive market if multiple therapies eventually gain approval.
The company previously reported positive results in another Phase 3 trial called MAESTRO-NAFLD-1, which included some NASH patients. With both pivotal studies now showing favorable outcomes, Madrigal appears positioned to submit regulatory filings for resmetirom in non-cirrhotic NASH with liver fibrosis.
If approved, resmetirom would represent a significant advancement in NASH treatment and potentially establish Madrigal as a leader in this challenging but potentially lucrative therapeutic area.
