HIGH IMPACT – Madrigal reported positive topline data from the double-blind portion of the its phase 3 MAESTRO-NAFLD study of resmetirom in NASH. Patients in the study were identified based on non-invasive imaging and biomarkers, and were treated with either 80mg, 100mg resmetirom once daily or placebo for 52 wks.
Safety (969 patients)
- Safe and well-tolerated at both 80 and 100mg doses
- Rates of diarrhea and nausea were higher with resmetirom vs placebo. Diarrhea was generally mild or involved increased stool frequency
Key secondary endpoints (943 patients)
- All key secondary endpoints were met with statistical significance
- Reductions in lipids were numerically lower in placebo controlled part vs open label part, likely due to COVID-related treatment interruptions which impacted the placebo-controlled part of the study to a greater extent
- MRI-PDFF reduction were similar between the placebo controlled and open label 100mg groups. Nearly half of patients in the double-blind study reached 50% MRI-PDFF reduction
High COVID related withdrawals and loss-to follow-up were reported in the double-blind study
- Withdrawals 9.8-15% between arms, 5-7.3% were lost to follow up
- Avg COVID-related dose or visit interruptions were 2 per patient
- Blister-pack manufacturing interruptions observed in the study
- In contrast, MAESTRO-NASH was not significantly impacted by COVID (5-6% withdrawal; as expected pre-COVID)
Q&A from investor call
- On other biomarkers: will analyze Fibroscan measurements and other fibrosis biomarkers over next few weeks. Have not analyzed DXA yet, but has not seen any changes in previous studies. Have not analyzed liver enzymes yet, they go in the normal range in open-label arm. Has not analyzed weight loss yet.
- On MAESTRO-NASH outlook: Data release still on track for 3Q 2022, believes both doses will achieve endpoint, data from MAESTRO-NAFLD increases confidence on 100mg dose.
- On diarrhea AE: diarrhea was mild, with single or few loose stools at the beginning of treatment. This was not observed in healthy volunteers. Overall AE rate is in line with open-label cohort and mild.
- On extrapolate MRI-PDFF results on NASH resolution and fibrosis improvement: Dr. Stephen Harrison noted good correlation with NASH resolution, but no clear correlation with fibrosis yet. Becky Taub noted that in Madrigal studies 30% reduction in MRI-PDFF was correlated with 1-stage reduction in fibrosis reduction in phase 2. Projecting that it will be validated by phase 3 studies.
- On next disclosures: Will include additional safety and imaging biomarker readouts, has not made a decision what will be shared yet in the disclosure but will focus on endpoints of greatest interest and outcomes such as DXA, PROs. Will likely present data at EASL 2022.
- On significance of liver volume corrected PDFF: Resmetirom causes 20% reduction in liver volume, mechanism is currently being investigated. Have not measured liver volume in current dataset.
MAESTRO-NAFLD was a unique pivotal study in NASH designed as a ‘real-life’ study utilizing non-invasive testing to select patients and monitor response to therapy, a practice more likely to be adopted in the clinical setting versus the more invasive and expensive liver biopsies. Data from the trial also helps build a large safety database which Madrigal believes now is consistent with ICH guidance (at least 1500 patients dosed for specific lengths at approved dose). The safety and biomarker results from the 52-wk MAESTRO-NAFLD study are largely consistent with the phase 2 data and the MAESTRO-NAFLD open label arm. The incidence of diarrhea and nausea, however, are higher than those previously reported and may be of concern, but Madrigal claims that they are mild and occur only at the initiation of treatment. We await further data from the trial (such as Fibroscan, MRE etc.) which will reinforce the positive results reported here, as well as results from the biopsy trial (MAESTRO-NASH) in Q3 2022 which will allow Madrigal to file resmetirom for accelerated approval.
Source: Madrigal Press Release