EMA says it will consider conditional approval for NASH drugs using intermediate endpoints

The European Medicines Agency (EMA) said in a new reflection paper that it will consider granting conditional marketing approval to sponsors developing treatments for non-alcoholic steatohepatitis (NASH) based on the use of intermediate endpoints to address a high unmet need for these products.

The paper addresses non-cirrhotic NASH, fibrosis stage 2 and 3, and cirrhotic NASH (fibrosis stage 4).

EMA said the paper outlines a “preliminary” development strategy for these products, as their experience in this space is still evolving.

EMA said that NASH “is considered the progressive, necro-inflammatory phenotype of non-alcoholic fatty liver disease (NAFLD), which itself is the most prevalent chronic liver disease worldwide with an estimated prevalence in the Western world of around 25%, and it is estimated that about 20-50% of these suffer from NASH.”

Despite the prevalence of the disease, there are no approved treatments for NASH in the EU. In the US, the Food and Drug Administration (FDA) on 14 March approved Madrigal Pharmaceuticals Rezdiffra (resmetirom) for treating adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis).

EMA said that “due to the unmet medical need in the field, a strategy to obtain an early, conditional approval (conditional marketing authorisation; CMA) of new compounds based on these intermediate endpoints could be considered.”

This strategy will only be acceptable if an unmet need is still present, a positive benefit-risk ratio can be concluded, and the applicant can provide comprehensive data post-marketing.

For non-cirrhotic NASH, fibrosis stage 2 and 3, acceptable intermediate endpoints would be:

The resolution of NASH – with the presence of any grade of steatosis, and no ballooning, only minimal (grade 1) lobular inflammation and no worsening of the stage of fibrosis.

The improvement of fibrosis by at least 1 stage without any worsening of NASH, and no worsening of ballooning and lobular inflammation, and no more than 1 grade increase in steatosis.

For cirrhotic NASH, fibrosis stage 4, or compensated cirrhosis, the reversal of cirrhosis can be considered an intermediate endpoint. “The endpoint would need to exclude the occurrence of any decompensation event, an increase in MELD [Model for End-Stage Liver Disease] as well as a deterioration (or re-occurrence) of features of NASH activity (inflammation, ballooning, and fat) at the same time (Improvement of cirrhosis by at least one fibrosis grade without occurrence of a decompensation event and without deterioration of MELD and NAS-score).

The paper will go into effect on 1 October 2024.

Reflection paper

EMA says it will consider conditional approval for NASH drugs using intermediate endpoints

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