The UK pharmaceuticals authority said on Thursday that it has authorised the first oral antiviral for the treatment of Covid-19. Merck and Ridgeback collaborated to develop molnupiravir. “Molnupiravir has been approved for treatment in patients with mild to moderate COVID-19 and at least one risk factor for developing severe disease,” according to the UK Medicines and Healthcare products Regulatory Agency.
The next day, Pfizer reported trial findings for Paxlovid, their experimental Covid-19 oral antiviral candidate, claiming that it dramatically decreased hospitalisation and mortality.
In India, molnupiravir is undergoing trials. In the US, it is being evaluated by the Food and Drug Administration (FDA).
Why are these developments significant?
Other treatments had not given the results hoped for. The most important of these were four drugs or drug combinations in Solidarity — the world’s largest ever multi-clinical trials — conducted by the World Health Organization (WHO) last year.
The trials were on remdesivir, hydroxychloroquine, ritonavir and lopinavir, and interferon beta 1a. Eventually, the WHO concluded that the four repurposed drugs have little or no effect on hospitalised Covid-19 patients.
Now, the UK clearance to molnupiravir, and the promise shown by Pfizer’s drug, could pave the way for more effective management of Covid-19.
The UK regulator said molnupiravir has been found to be “safe and effective” following a “stringent review of the available evidence”. On October 27, the WHO said molnupiravir is being evaluated for inclusion in the WHO guidelines on Covid-19 therapeutics — and “is pending authorization for its use from regulatory bodies”.
For Paxlovid, Pfizer plans to submit its trial data to the US FDA for emergency use authorisation as soon as possible.
What is molnupiravir?
Molnupiravir (MK-4482, EIDD-2801), developed initially to treat influenza, has been repurposed to treat Covid patients. It interferes with the replication of SARS-CoV-2, thereby reducing severity of disease.
It is most effective when used early; the UK has recommended its use as soon as possible following a positive test and within five days of symptoms onset.
Merck expects to produce 10 million courses by the end of 2021. Merck, which already struck advance purchase agreements, will supply approximately 1.7 million courses to the US government; and 4,80,000 courses to the UK government. According to an article in Nature magazine, based on the US purchase, the cost of a five-day course works out to $700.
What is Paxlovid?
It is an investigational SARS-CoV-2 “protease inhibitor antiviral therapy”: It inhibits viral replication at proteolysis, a stage that occurs before viral replication. It is “… designed to be administered orally so that it can be prescribed at the first sign of infection or at first awareness of an exposure, potentially helping patients avoid severe illness,” Pfizer says.
Pfizer said it has entered into advance purchase agreements with “multiple countries and is in negotiations with several others”.
What have global trials shown?
On October 1, Merck announced the interim analysis of a global phase 3 study: 7.3% of patients who received molnupiravir were hospitalised through day 29 — compared to 14.1% of placebo-treated patients who were hospitalized or died.
Molnupiravir reduced the risk of hospitalisation or death by approximately 50%; and through day 29, no deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo. On participants with available sequencing data (40% ), molnupiravir demonstrated “consistent efficacy” across variants Gamma, Delta, and Mu.
Pfizer’s phase 2-3 study is being conducted across several countries. On Friday, it said an interim analysis found that Paxlovid reduces the risk of hospitalisation or death by 89% compared to placebo in non-hospitalized high-risk adults with Covid-19. Through Day 28, no deaths were reported in patients who received Paxlovid as compared to 10 deaths in patients who received placebo. Third, 0.8% of patients who received Paxlovid were hospitalised through Day 28 following randomization — compared to 7% of patients who received placebo and were hospitalised or died.
What is the status of the trials in India?
Merck has been in talks with multiple Indian drug manufacturers for voluntary licensing for molnupiravir. On June 29, five Indian pharma companies including Cipla Ltd, Dr Reddy’s Laboratories Ltd (DRL), Emcure Pharmaceuticals Ltd, Sun Pharmaceutical Industries Ltd, and Torrent Pharmaceuticals Ltd announced that they are collaborating for a trial of molnupiravir for the treatment of mild Covid in an outpatient setting.
“Interim data has been shared with the Drugs Controller General of India (DCGI). For now, the trial is in progress. We are also following approval-related developments in other countries, as well as the Covid-19 situation in various countries,” a DRL spokesperson said.
On September 9, the Subject Expert Committee of the Central Drugs Standard Control Organisation (CDSCO) said Hetero Labs Ltd had presented interim clinical data in moderate Covid-19 patients.
Last week, Hyderabad-based Optimus Group announced the completion of its phase 3 trial: On the fifth day, 78.4% in the treatment group tested RT-PCR negative compared to 48.2% in the placebo group; on the 10th day, 91.5% of the patients in the treatment group tested negative compared to 43% in the placebo group.