In a week in which the US FDA moved to restrict emergency use authorisations for new Covid-19 vaccines, developers will be heartened to see that the agency’s willingness to greenlight coronavirus treatments remains undiminished.
Witness the EUA granted yesterday to Vir/Glaxosmithkline’s late-to-the-game antibody sotrovimab (VIR-7831). And today Molecular Partners and Novartis started a 2,100-patient phase 2/3 study with ensovibep, a Darpin-based antiviral; if this trial reads out positively it will be used to put ensovibep on the expedited EUA path.
Ensovibep and another molecule, MP0423, are Darpins originated by Molecular Partners to which Novartis has opt-in rights under a deal struck last October. The latter molecule is thought to be better against variants – a hot issue currently – than ensovibep thanks to different targeting mechanisms, but it is further behind, still in preclinical development.
Ensovibep, meanwhile, has shown tolerability in a small volunteer study. The potentially pivotal trial, Empathy, will enrol 400 patients into its phase 2 portion and 1,700 into phase 3; there is no restriction by Covid-19 severity, and the co-primary endpoints are change in viral load and occurrence of hospitalisation, casualty visit or death.
Though Novartis has not exercised its global licence option it is clearly interested, and will conduct the trial. In a further sign of optimism, ensovibep has been included in the NIH’s phase 3 Activ-3 study in hospitalised Covid-19 patients.
Perhaps much of the enthusiasm has been driven by the scientific approach underlying Darpins, which are antibody mimetics around a tenth of the size of a MAb. Backing the promise is in vitro modelling suggesting that ensovibep retains potency against Covid-19’s South Africa, Brazil and Kent variants, as well as the strains emerging in India, according to Molecular Partners.
Still, beyond Gilead’s Veklury the development of antiviral approaches as an initial strategy against Covid-19 has met largely with failure, with Merck & Co recently discontinuing MK-7110 and narrowing focus with molnupiravir to non-hospitalised patients. The antiviral pipeline is rather thin.
|Antivirals in development for Covid-19|
|Veklury (IV)||Gilead||FDA-approved in Covid-19 patients requiring hospitalisation; Gilead discontinued ph3 study in high-risk outpatients (NCT04501952) on 12 Apr||Repurposed Ebola research project|
|NT-300||Romark||Failed ph3 mild-moderate study on 14 Apr; company to file for EUA based on 85% reduction in progression to severe illness||Reformulation of nitazoxanide|
|Molnupiravir (oral)||Merck & Co/Ridgeback||Ph3 in outpatients (Move-Out, NCT04575597); Merck discontinued ph2/3 trial in hospitalised pts (Move-In; NCT04575584) on 15 Apr||Repurposed flu antiviral|
|AT-527 (oral)||Roche/Atea||Ph2 in hospitalised pts (NCT04396106); ph3 in outpatients (NCT04889040)||Repurposed hep C antiviral|
|Ensovibep (IV)||Novartis/Molecular Partners||Ph2 in symptomatic pts (NCT04834856); ph2/3 in ambulatory pts (Empathy, NCT04828161); ph3 in hospitalised pts (Activ-3, NIH-sponsored)||Designed for Sars-Cov-2|
|PF-07304814 (IV)||Pfizer||Ph1 in hospitalised pts (NCT04535167, excludes severely ill or with certain pre-existing conditions)||Repurposed Sars research project|
|MP0423 (IV)||Novartis/Molecular Partners||Preclinical||Designed for Sars-Cov-2; different targeting mechanisms vs ensovibep|
|Source: Evaluate Pharma & clinicaltrials.gov.|
It seems that more precise antibody approaches have fared better, with Lilly’s bamlanivimab plus etesevimab, and Regeneron’s casirivimab and imdevimab, winning EUAs.
And there is a push for more, with Vir/Glaxo’s sotrovimab gaining an EUA yesterday for treating mild to moderate Covid-19 in high-risk adults and children. This was based on the Comet-Ice trial, which succeeded after Activ-3 investigators jettisoned the MAb over fears of lack of benefit (Roche and Vir add to the conflicting Covid-19 data, March 11, 2021).
Being a single agent could give sotrovimab an advantage over Lilly and Regeneron’s combo MAbs, and Vir also cites in vitro data backing activity against “all known variants of concern”. However, the group's stock has deflated since its January peak, and was unmoved this morning.
While it is obvious that the EUA pathway is wide open for Covid-19 treatments, for vaccines the FDA has narrowed its guidance. On Tuesday it cautioned that for the remainder of the current pandemic it might decline to review and process further EUA requests, except those whose developers have “already engaged with the agency”.
This exception would include Astrazeneca and Novavax’s delayed candidates, which are subject to the Warp Speed programme. It would apparently not cover a third delayed project, Curevac’s CVnCoV, which is to yield phase 2/3 data imminently; however, the point is moot, Curevac having deprioritised the US in favour of Europe.