Novartis-partnered DARPin flames out in COVID-19 study, sending Molecular Partners' stock into nosedive

Shares in Molecular Partners fell 37% in Switzerland. (Maksim Tkachenko/iStock/Getty Images Plus)

ACTIV-3 has claimed yet another victim. Molecular Partners and Novartis are the latest companies to fail to clear the efficacy bar in the COVID-19 study, sponsored by the National Institutes of Health (NIH), leaving their hopes for ensovibep resting on a separate trial in non-hospitalized patients.

The NIH set up ACTIV-3 to evaluate anti-SARS-CoV-2 monoclonal antibodies and other therapies in patients hospitalized with COVID-19. Sub-studies of antibodies from Brii Biosciences, Eli Lilly and the GlaxoSmithKline-Vir Biotechnology collaboration all failed, cementing the impression that drugs that act on the virus itself are ineffective in hospitalized COVID-19 patients.

Molecular Partners moved ensovibep into the phase 3 study in the hope its differences to antibody therapeutics would help it deliver a better result. Ensovibep is a DARPin, protein scaffolds that are much smaller than monoclonal antibodies. The molecule is designed to bind to three parts of the virus’s receptor-binding domain, potentially making it less vulnerable to escape mutations that can limit the effectiveness of single-target antibodies. 

Whatever advantages ensovibep may have, they made no difference to the outcome in ACTIV-3. Like other molecules before it, ensovibep failed a planned futility analysis, leading to a recommendation to stop enrollment in the sub-study. Shares in Molecular Partners fell 37% in Switzerland.  

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In a statement, Molecular Partners CEO Patrick Amstutz said the failure of a series of drugs in ACTIV-3 is “potentially due to the multi-systemic inflammatory component of late-stage COVID-19 disease.” By the time a patient is hospitalized, that inflammatory component may be more significant than the virus itself, causing drugs such as Actemra to fare better than anti-SARS-CoV-2 antibodies.

Molecular Partners and Novartis, which paid $22 million for an option to in-license ensovibep last year, still have a shot at showing the DARPin works in non-hospitalized patients. The phase 2b part of the trial is set to deliver top-line data early next year. Molecular Partners split the trial in two, with the phase 2 aiming to show a fall in viral load and the phase 3 assessing hospitalization and death.