Madrigal’s Maestro result puts the focus on Nash
Resmetirom’s first pivotal liver disease study reminds the markets about the third quarter’s Nash readout, but investors wanted more.
In May 2018 a phase 2 trial of Madrigal’s resmetirom spurred a resurgence in interest in the liver disease Nash. It has taken nearly four years for a phase 3 readout to show whether there is promise behind the hype, and today investors got the answer: maybe.
The answer is not more emphatic because of significant gaps in the data revealed today from the phase 3 study Maestro-NAFLD-1, including essential detail on resmetirom’s effect on fibrosis, its cardiac safety and other adverse events. On a topline basis Maestro-NAFLD-1 is positive, however, so some will take hope from it to a corresponding pivotal Nash study.
The Nash trial, Maestro-Nash, is due to yield data in the third quarter, and together these two studies are to back a US filing that Madrigal hopes will make resmetirom the first drug approved for treating Nash and liver fibrosis. This is an accolade that others, most famously Intercept’s Ocaliva and Genfit’s elafibranor, failed to achieve.
Real life
Importantly, only Maestro-Nash recruits biopsy-confirmed Nash patients; Maestro-NAFLD-1 uses non-invasive imaging and biomarkers to select patients, and allows patients considered for Maestro-Nash but who fail the biopsy confirmation. Thus Maestro-NAFLD-1 is said to be testing resmetirom in non-alcoholic fatty liver disease “presumed” to be Nash, and Madrigal calls it a “real-life Nash study”.
First the good news: Maestro-NAFLD-1’s primary endpoint, concerning safety, appears to have been met, with no additional concerns versus what Madrigal had seen in phase 2 back in 2018. The main adverse event outliers versus placebo were diarrhoea and nausea.
On the efficacy side Maestro-NAFLD-1 again backed up more robustly what resmetirom had earlier shown. Among important measures the randomised 80mg and 100mg resmetirom cohorts showed 52-week reductions in liver fat content by MRI-PDFF of 43% and 48% respectively, which was statistically significant versus an 8% reduction in the placebo arm.
The trial’s 100mg open-label cohort had already shown a 53% reduction in this measure, a level thought to correlate with the FDA-approvable endpoint of Nash resolution, but which at the time had no adjustment for a control group.
However, this is perhaps where the good news ended, with Madrigal stressing that the trial remained blinded at the patient level, and that detailed data were being held back for a conference.
As such, detail on several safety measures investors were looking for, namely unwanted effects on cartilage, bone and heart rate, were not provided. These are relevant given resmetirom’s activity as a thyroid hormone receptor beta agonist, and all management would do is cite earlier reassuring data.
And the other part of the FDA-approvable Nash endpoint is no fibrosis worsening, and here Madrigal again left investors unsatisfied. A key metric would be the Fibroscan data used to enrol patients into Maestro-NAFLD-1, and how this finding changed over 52 weeks, but the company said these data had not yet been analysed.
| Resmetirom's route to a Nash approval | ||
|---|---|---|
| Phase 3 trial | Maestro-NAFLD-1 | Maestro-Nash |
| Key enrolment criteria | Suspected or confirmed Nash/NAFLD by Fibroscan & MRI-PDFF | Biopsy-confirmed Nash |
| Primary endpoint(s) | Safety | 52-wk Nash resolution without fibrosis worsening, long-term outcome |
| Result | Grade ≥3 TEAEs balanced vs placebo; diarrhoea 23-31% vs 14% for placebo; nausea 12-18% vs 8% for placebo; no data on bone, heart rate etc | Due Q3 2022 |
| Key secondaries | 52-wk MRI-PDFF | 52-week improvement on fibrosis |
| Result | 43-48% reductions vs -8% for placebo; no data on Fibroscan analysis | Due Q3 2022 |
| Source: company statements & clinicaltrials.gov. | ||
Investors will note that Maestro-Nash has as co-primary endpoint the hard metric of 52-week Nash resolution with no worsening in fibrosis.
True, reducing fibrosis in Maestro-NAFLD-1 would have represented a home run, analysts reckon, but without seeing some data on this Madrigal remains open to the bears’ claim that resmetirom acts simply by reducing liver fat, and thus might not meet the FDA’s criteria for an approvable Nash drug. Resmetirom’s phase 2 trial did not measure fibrosis, and detailed preclinical safety data have never been published.
With such gaps it is little wonder that Madrigal stock was virtually unmoved this morning. Maestro-NAFLD-1 is encouraging in the sense that resmetirom has not drawn a blank, but in terms of handicapping Maestro-Nash’s chances of success many investors will be none the wiser.
