Easl 2023 – Madrigal denies pivotal endpoint change

The primary analysis of Maestro-Nash had always relied on Nafld activity score, with a controversial trial entry change just a “typo”, the company says.

Last December positive topline data with Madrigal’s Nash project resmetirom raised hopes that there might soon be an approved drug for Nash. But days later doubts crept in about an apparent change to the way Nash resolution was defined in the phase 3 Maestro-Nash trial and what this might mean for the project’s chances of approval.

Today Madrigal’s chief medical officer, Becky Taub, dismissed the criticism as "spin and buzz”, speaking to Evaluate Vantage during the Easl meeting. In fact, she said the co-primary endpoints had “never changed” – and that amendments to the study’s clinicaltrials.gov entry had been due to a typo in the original entry.

This was echoed by the trial's primary investigator, Dr Stephen Harrison of Pinnacle Clinical Research in San Antonio, who this morning told an Easl press conference: "We didn't change [the endpoint] during the course of the trial."

Still, it is not clear why Madrigal did not telegraph this mistake at the time. Investor concern is understandable, because changing a pivotal trial's endpoint, particularly without the FDA’s go-ahead, would make for a tough regulatory review. 

In any case, it should become clear fairly soon whether the US agency and Madrigal are aligned; the company is set to file the thyroid hormone receptor agonist for accelerated approval by the end of this month – a timeline confirmed today by Taub.

Easl picture

The data from the first part of Maestro-Nash were presented today in full at Easl. The study had two co-primary endpoints: Nash resolution – defined as a two-point reduction in the Nafld activity score (NAS) – with no worsening of fibrosis; and improvement in fibrosis without worsening NAS.

The confusion in December arose when eagle-eyed investors noticed that the trial’s clinicaltrials.gov entry had previously referred to “Nash activity score”, before being amended.

When asked about this today, Taub replied: “Nash is measured by NAS. No worsening of Nash is the same as no worsening of NAS.

“We defined NAS as Nash activity score, and that was a typo,” she added, putting this down to “whoever entered that term on clinical trials.gov”.

A Madrigal spokesperson later told Vantage: “NAS is the measure of Nash as defined by the NASH-CRN as sum of the components of ballooning, inflammation and steatosis. The typo didn’t signify any changes to the design of the trial itself.”

Fibrosis change

At Easl today, Dr Harrison presented data on these components of the NAS score.

There was also an analysis of fibrosis change among patients whose baseline fibrosis was graded as F1B or F2. Those with later-stage F3 fibrosis at baseline, who made up around 60% of trial participants, were excluded because progression among these patients is an event in the outcomes-driven portion of Maestro-Nash.

“The agency did not want any public data on that, because it could influence the trial,” Taub said. The outcomes data are due in 2026 or 2027; this part of the trial is designed to support full approval.

Taub believes that the data presented today bode well for this future readout, but the outcomes result remains a big unknown for Madrigal.

Another outcomes trial, Maestro-Nash Outcomes, in patients with cirrhosis, could also be used to support full approval, and to back a separate indication of Nash cirrhosis.

Source: Easl & Dr Stephen Harrison.

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