factors include obesity , older age (> 60 years ), diabetes mellitus , or heart disease . Dr June Raine , MHRA Chief Executive , said : “ Following a rigorous review of the data by our expert scientists and clinicians , we are satisfied that Lagevrio ( molnupiravir ) is safe and effective for those at risk of developing severe COVID-19 disease and have granted its approval .
“ Lagevrio is another therapeutic to add to our armoury against COVID-19 . It is also the world ’ s first approved antiviral for this disease that can be taken by mouth rather than administered intravenously . This is important , because it means it can be administered outside of a hospital setting , before COVID-19 has progressed to a severe stage .”
This was an interesting development because the trial data were limited . It is useful to consider the mechanism of action of molnupiravir and what the trial results actually showed .
Mechanism of action Molnupiravir is an orally-active prodrug for N4-hydroxycytidine ( NHC ) – an antiviral ribonucleoside analogue that acts as a competitive substrate for virally encoded RNA-dependent RNA polymerase ( RdRp ). The ribonucleoside form of NHC ( rNHC ) has the ability to pair as either cytidine or uridine , thereby introducing mutations .
Basically , this means that when RNA is being assembled NHC is substituted in place of cytidine . This is sufficiently close to the correct nucleoside that the viral proof-reading enzyme does not remove it , but it results in a nonsense version of the RNA and slows or stops viral replication . This process is described as ‘ lethal mutagenesis ’ or ‘ error catastrophe ’.
NHC has powerful in vitro and in vivo activity against a number of RNA viruses . It is more than 100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ), with antiviral activity correlated to the level of mutagenesis in virion RNA . 10
Commentators have pointed out that there could be risks attached to the use of molnupiravir . First , mutagenic ribonucleoside analogues could be metabolised by the host cell and then incorporated into DNA , leading to mutagenesis of the host . This could pose a risk for reproductive toxicity . Second , ‘ supercharged ’ variants – viable , mutated viruses – could emerge , particularly if patients neglect to take a full course of treatment .
Molnupiravir trial On 1 October 2021 , Merck ( MSD ) and Ridgeback Biotherapeutics announced that early treatment with molnupiravir reduced the relative risk of hospitalisation or death by approximately 50 % in at-risk , non-hospitalised adult patients with mild-to-moderate
8 | Issue 100 | hospitalpharmacyeurope . com
References 1 Kadioglu O et al . Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning . [ Preprint ]. Bull World Health Organ . E-pub : 21 March 2020 . 2 Gordon De et al . A SARS-CoV-2 protein interaction map reveals targets for drug repurposing . Nature 2020 ; 583:459 – 68 . 3 Mc Cullough P et al . Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection ( COVID-19 ). Rev Cardiovasc Med 2020 ; 21 ( 4 ): 517 – 30 . 4 Bryant A et al . Ivermectin for Prevention and Treatment of COVID-19 Infection : A Systematic Review , Metaanalysis , and Trial Sequential Analysis to Inform Clinical Guidelines . Am J Ther 2021 ; 28 ( 4 ): e434 – e460 5 Ravichandran R et al . Indomethacin Use for Mild & Moderate hospitalised Covid-19 patients : An open label randomised clinical trial . medRxiv 2021 ; 07.24.21261007 . 6 Facente SN et al . Fluvoxamine for the Early Treatment of SARS-CoV-2 Infection : A Review of Current Evidence . Drugs 2021 ; 81:2081 – 9 . 7 Merino J et al . Ivermectin and the Odds of Hospitalization Due to COVID-19 : Evidence from a Quasi-experimental Analysis Based on a Public Intervention in Mexico City . SocArXiv ; 4 May 2021 . 8 Chamie-Quintero J et al . Sharp Reductions in COVID-19 Case Fatalities and Excess Deaths in Peru in Close Time Conjunction , State-By- State , with Ivermectin Treatments ( January 12 , 2021 ). https :// ssrn . com / abstract = 3765018 ( accessed January 2022 ). 9 Kerr L et al . Ivermectin Prophylaxis Used for COVID-19 : A Citywide , Prospective , Observational Study of 223,128 Subjects Using Propensity Score Matching . Cureus 2022 ; 14 ( 1 ): e21272 . 10 Zhou S et al . ß-d-N4-hydroxycytidine Inhibits SARS-CoV-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells . J Infect Dis 2021 ; 224 ( 3 ): 415 – 19 . 11 Bernal AJ et al . Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients . N Engl J Med 2021 ; December 16 : dOI : 10.1056 / NEJMoa2116044 . 12 OrthoEvidence Overestimation the treatment effects of molnupiravir against covid-19 : A deep look from the perspective of stopping-trial-early-forbenefits . OE Original 2021 ; 4 ( 10 ): 3 https :// myorthoevidence . com / Blog / Show / 153 ( accessed January 2022 )
Christine Clark PhD FRPharmS FCPP ( Hon )
COVID-19 , according to the interim analysis of the Phase III MOVe-OUT trial ( NCT04575597 ). 11 The results showed that 7.3 % of patients who received molnupiravir ( 800mg , 12-hourly for five days ) were either hospitalised or died by day 29 following randomisation ( 28 / 385 ), compared with 14.1 % of placebo-treated patients ( 53 / 377 ); p = 0.0012 . There were no deaths in the molnupiravir group compared with eight deaths in the placebo group . At this stage recruitment into the study was stopped on the recommendation of an independent Data Monitoring Committee and the US Food and Drug Administration ( FDA ).
Women who were pregnant , breastfeeding , or anticipating becoming pregnant were excluded from the trial . Men who enrolled in the trial were instructed not to have unprotected sex with women for at least four days after the last dose of drug .
Some commentators noted that , “ From a methodological perspective , a trial with a small number of events that is stopped early for apparent treatment effects might be prone to the risk of overestimation ”. 12 In this trial , the total number of outcome events was 81 .
On 26 November 2021 , the manufacturers announced the updated results on all 1433 patients enrolled in the trial . They showed that molnupiravir reduced the risk of hospitalisation or death from 9.7 % in the placebo group ( 68 / 699 ) to 6.8 % ( 48 / 709 ) in the molnupiravir group , giving an absolute risk reduction of 3.0 % ( 95 % CI 0.1 , 5.9 ; nominal p-value = 0.0218 ) and a relative risk reduction of 30 % ( relative risk 0.70 ; 95 % CI : 0.49 , 0.99 ). Moreover , the results of the trial clearly show ( in the appendix , figure S3 ) that the activity of molnupiravir was exclusively against the gamma variant and not against the delta , mu or other variants .
Early treatment choice The options available to health policy decision-makers boil down to – on the one hand – a tried and tested , cheap , generic drug whose use is associated with a 62 % reduction in mortality 86 % reduction in the risk of infection and is likely to retain activity against all variants – and , on the other hand – a new drug whose use is associated with a 30 % reduction in hospitalisation or death . Molnupiravir is estimated to cost about $ 700 per treatment in the US and there remain concerns about toxicity . The fact that it was only active against the gamma variant in the MOVe-OUT trial also gives cause for concern .
The UK has approved molnupiravir and the FDA has granted the drug emergency use authorisation . Meanwhile France has cancelled its order for molnupiravir .
It seems that some of the decision-makers could be in need of some guidance on the science so that it can be followed in such a way as to provide effective relief of human suffering within the resources available .