Molnupiravir

Therapeutic treatment significantly reduced SARS-CoV-2 viral load in upper respiratory tract and suppressed infection spread in a ferret model.

Human lung tissue was implanted into the back of immune deficient mice, where it grew into a formation with human lung tissue cell types and structures naturally found in lungs (therefore “human lung-only mice” (LoM)). LoM model was verified for further use – ACE2 and TMPRSS2 expression was observed and LoM were susceptible to SARS-CoV-2 (among others) infection. EIDD-2801 rapidly and dramatically decreased the number of infectious particles in LoM human lung tissue. It was efficacious both when administered as a prophylactic and as a therapeutical (especially when the treatment started 24 hours post viral challenge).

Inhibited SARS-CoV-2 RNA-dependent RNA polymerase in a cell-based assay with an EC50 of 0.22 μM.

The treatment had clinical benefit in patients who received it by day 5 after the onset of symptoms. 800 mg dosing was selected as optimal. It did not display dose-limiting side-effects. Sample size: 71 (200 mg) + 75 (400 mg) + 71 (800 mg) + 72 placebo. Dosage: 200 mg or 400 ,g or 800 mg twice dayly for 5 days Main outcome: Death of hospitalization through day 29.

The treatment had statistically significant clinical benefit in patients who received it by day 5 after the onset of symptoms. The profile of adverse events was similar in the placebo and the treatment group. Sample size: 680 (completed trial) + 672 placebo(completed trial). Dosage: 800 mg twice a day for 5 days. Main outcome: Death of hospitalization through day 29.

Triphosphate of derivative of β-D-N4-hydroxycytidine, which is the active metabolite of molnupiravir, was shown to be used by SARS-CoV-2 RNA-dependent RNA polymerase as a substrate instead of CTP or UTP. As a template, it stably base-paired either with G or A in the enzyme’s active centre, thus introducing mutations and evading proofreading activity. 

The drug displayed dose-proportional pharmacokinetics and was generally well tolerated. Reached plasma levels suggested plausible prophylactic and therapeutic benefit. Sample size: 48 (in different dosing subgroups) + 16 placebo. Dosage: 50 mg up to 1,600 mg doses (single or twice a day (800 mg)) in a dose escalation scheme. Main outcome: The safety and tolerability; pharmacokinetics.

The treatment was safe. The highest dosing was suggested for further evaluation. Sample size: 4 (300 mg) + 4 (600 mg) + 4 (800 mg) + 6 control. Dosage: 300, 600, or 800 mg up to twice a day for up to 6 days (a dose-escalation scheme). Main outcome: Dose-limiting toxicity.

Inhibited SARS-CoV-2 RNA-dependent RNA polymerase in an enzyme assay and also in a cell-based assay with an EC50 of 0.22 μM. 

The drug reduced lung viral titres and reduced lung pathology for all of the strains tested. 

When combined with favipiravir, a reduction in lung viral titres was observed in a hamster model. The combinational treatment also prevented infection transmission among co-housed animals. 

In unvaccinated individuals with COVID-19 symptom onset <7 days prior to treatment initiation, time to viral clearance was statistically significantly shorter in 800 mg-dosing group compared to placebo. Significantly less drug-treated participants had detectable infectious virus from nasopharyngeal swabs at day 3 of treatment, as well. No patient in 400 mg or 800 mg-dosing groups had infectious virus identified by day 5. The treatment was safe. Sample size: 23 (200 mg) + 58 (400 mg) + 52 (800 mg) + 61 placebo. Dosage: 200 mg, 400 mg, or 800 mg twice a day for 5 days. Main outcome: Time to viral clearance.

The compound retains its anti-SARS-CoV-2 activity in vitro against strains Alpha and Omicron. 

The compound inhibited SARS-CoV-2 Omicron variant in Calu-3 cells in a dose-dependent manner with an IC50 of 0.7556 μM. Molnupiravir displayed synergy with nirmatrelvir against the Omicron strain. Molnupiravir was also active against the Delta variant. 

The compound did not display significant inter-variant difference in its in vitro anti-SARS-CoV-2 activity – it was active. 

The drug significantly decreased viral replication (BA.1 strain) in lower respiratory tract of Syrian hamsters upon a viral challenge.

The drug significantly decreased viral replication (BA.2 strain) in lungs (but not nasal turbinates) of Syrian hamsters upon a viral challenge.