Early Response to MASH Drug Linked to Resolution, Fibrosis Improvement

In patients treated with resmetirom (Rezdiffra), early responses in blood and imaging biomarkers were associated with resolution of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis improvement, according to an exploratory analysis of the phase III MAESTRO-NASH trial.
Pooled data across treatment and placebo arms showed that these markers at weeks 12 to 16 correlated with MASH resolution and fibrosis improvement responses at week 52. Odds ratios ranged from 2.03 to 8.83 for alanine aminotransferase (ALT), magnetic resonance elastography liver stiffness measurement (MRE LSM), and MRI-proton density fat fraction (PDFF; all P≤0.001).
Responses in PRO-C3 — a biomarker of active fibrogenesis regularly used in clinical trials — also were associated with week-52 MASH resolution and fibrosis improvement, reported Rohit Loomba, MD, of the University of California San Diego, at the annual Liver Meeting in Denver, sponsored by the American Association for the Study of Liver Diseases.
Not surprisingly, the odds of achieving biomarker responses increased with resmetirom versus placebo.
With these biomarkers that are clinically available today, “these associations remain significant even after adjusting for weight loss,” Loomba said.
He observed that these early changes in blood and imaging biomarkers could give clinicians a noninvasive signal of response to resmetirom without an invasive biopsy.
During a Q&A session after the presentation, David Goldberg, MD, of the Miller School of Medicine at the University of Miami, said that while the data are impressive, “we can’t ignore the elephant in the room about the data integrity concerns” — a reference to a whistleblower lawsuit from Michael Charlton, MD, a former senior vice president and head of clinical development at Madrigal Pharmaceuticals, that recently became public. Charlton claims that the company, which developed resmetirom, forced him to resign after he raised safety concerns about the drug. Madrigal disputes the allegations.
In explaining the rationale behind the exploratory analysis, Loomba noted that the FDA granted accelerated approval to resmetirom — a liver-directed thyroid hormone receptor-β selective agonist — for the treatment of patients with noncirrhotic MASH with stages F2 and F3 fibrosis, in conjunction with diet and exercise.
The approval was based on results from MAESTRO-NASH, which showed treatment with the drug increased rates of MASH resolution and improvement in fibrosis versus placebo at week 52.
“Treatment response was confirmed by liver biopsy in the trial, but in clinical practice we typically do not perform liver biopsy to assess treatment response,” Loomba pointed out. “So the key question we are trying to understand here is, in a patient taking resmetirom, what early treatment-related changes in biomarkers or imaging are associated with histologic response at week 52?”
The researchers found that compared with placebo, resmetirom increased the odds of:

• ALT response (≥20% reduction) by week 12 (OR 2.17, 95% CI 1.52-3.13, P<0.001)
• MRI-PDFF response (≥30% reduction) by week 16 (OR 12.38, 95% CI 7.99-19.79, P<0.001)
• PRO-C3 response (≥10% reduction) by week 12 (OR 1.84, 95% CI 1.18-2.86, P=0.005)
• MRE LSM response (≥15% reduction) at week 52 (OR 1.71, 95% CI 1.04-2.88, P=0.038)

Loomba and his colleagues also found that patients on resmetirom had a shortened time to sustained response across all four of these tests.