How a change in FDA guidance might revolutionise MASH drug development

Transformative new shifts have taken place in the last month in the metabolic dysfunction-associated steatohepatitis (MASH) therapy space, with Madrigal’s Rezdiffra becoming the first approved drug in the EU for patients with MASH and moderate-to-advanced fibrosis (F2–3). Shortly after, Novo Nordisk’s Wegovy was approved in the US for MASH F2–3, providing the first direct competition to Rezdiffra, which until now had exclusive access to US patients since its approval in March 2024. However, these two assets may not be alone in the MASH market for long. A new decision by the FDA has paved the way for even further expansion of the MASH therapy landscape.

Last month, the FDA announced that it would accept Echosens’ letter of intent (LOI) for the qualification of a novel reasonably likely surrogate endpoint (RLSE)—Liver Stiffness Measurement (LSM) by Vibration-Controlled Transient Elastography (VCTE)—in future MASH F2–3 clinical trials. Echosens manufactures a device, the FibroScan, which measures LSM by VCTE.

The impact of this announcement could be transformational for future MASH clinical trials, driving a shift away from the use of liver biopsies in diagnosis and assessment of disease progression. This is particularly notable, given that many past MASH assets had struggled in reaching a biopsy-based fibrosis improvement trial endpoint. Until now, this posed an obstacle to approval, which typically required meeting this endpoint. However, now that LSM by VCTE is on the path to be formally recognised as an RLSE, it is likely that assets could instead focus on achieving improvements in this non-invasive parameter instead. Moreover, LSM by VCTE is far less subjective than pathologist-based biopsy assessment, potentially allowing for greater standardisation of patient outcomes.

As well as this, the ability to avoid biopsy altogether will likely drastically speed up trial recruitment times, given the difficulty of conducting biopsies as opposed to measuring LSM by VCTE. As Echosens noted in its press release, this could “accelerate drug development and also be easily translatable to clinical practice.”

It is important to note that the LOI is only the first step in the FDA’s complicated Drug Development Tool (DDT) qualification process. Next, Echosens must make a Qualification Plan (QP) submission with available relevant data, knowledge gaps, proposed data collection plans, and analysis plans, which the FDA will take up to six months to review. After that, the FDA will issue a Determination Letter that will make additional requests for data and include recommendations about data required for the third step, the Full Qualification Package (FQP). The FQP will include detailed descriptions of all studies, analyses, and results related to LSM by VCTE, which will require a comprehensive, up to ten-month review by the FDA. After this, the FDA issues another Determination Letter that decides whether it has qualified. Nevertheless, the fact that the FDA chose to issue a press release about the acceptance of the first step alone indicates a high level of confidence in LSM by VCTE’s future success in this process.

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Drug developers appear to have responded positively to the FDA decision. Echosens has noted that Novo Nordisk, one of its pharmaceutical partners, shares its ambition to double diagnostic rates for people living with advanced to severe MASH by 2027 and that the FDA’s recent announcement could help in achieving that goal. Moreover, Lilly recently announced plans for a Phase III trial for its assets tirzepatide and retatrutide in metabolic dysfunction-associated steatotic liver disease (MASLD) that eschewed biopsy altogether, instead relying purely on non-invasive assessment to accelerate trial timelines. Given that LSM by VCTE is set to be the first non-invasive test available as an RLSE, it appears likely that Lilly will embrace this endpoint, particularly given that it had joined Boehringer Ingelheim and Novo Nordisk in providing letters of support for Echosens’ Letter of Intent to the FDA.

The announcement could provide Echosens with a major edge over rival quantitative diagnostic developers, such as HepQuant, which created the cholate uptake-measuring HepQuant Duo test, and Siemens, with its assay-based ELF Test. So far, no other company has a non-invasive RLSE accepted by the FDA, though this announcement is likely to drive Echosens’ competitors to double down their efforts towards FDA acceptance.

Nevertheless, Echosens could also focus on expanding its LSM by VCTE’s RLSE portfolio, by potentially expanding LSM by VCTE beyond MASH F2–3 trials and submitting Letters of Intent in additional indications. LSM by VTE is often used as an outcome measure in MASH with compensated cirrhosis (MASH F4) trials, including Akero’s SYNCHRONY-Outcomes trial of efruxifermin and 89bio’s ENLIGHTEN-Cirrhosis trial of pegozafermin. In addition, LSM by VCTE is also being used in key alcohol-related liver disease (ALD) trials, such as GSK’s Phase II STARLIGHT trial of GSK4532990 and Altimmune’s Phase II RESTORE trial of pemvidutide. These two indications could offer LSM by VCTE further opportunities to achieve RLSE status.

With the FDA’s decision, Echosens has both consolidated its position as the leading non-invasive diagnostic manufacturer in the MASH space and opened the door for faster approval of a wider range of drugs to meet the unmet need in this growing disease. Coupled with the recent global launch of its Guided VCTE technology, which streamlines the VCTE process, and Echosens’ strategic partnerships with drug developers, the LSM by VCTE endpoint is set to play a major role in MASH drug development in the years to come.

Jay Patel is a Pharma analyst with GlobalData.

“How a change in FDA guidance might revolutionise MASH drug development” was originally created and published by Clinical Trials Arena, a GlobalData owned brand.

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