The Covid-19 pandemic has resulted in significant global morbidity and mortality as well as disruption to the economies of virtually every country.1 Part of this tragedy could have been avoided with the development of deliverable, oral bioavailable and direct-acting antiviral treatments. Molnupiravir, the orally bioavailable prodrug of N4-hydroxycytidine (NHC), is beginning to meet this need. Synthesized at the Emory Institute for Drug Development (EIDD), molnupiravir is active against influenza as well as against several other RNA viruses, including SARS-CoV-2.2 When the coronavirus pandemic first emerged, EIDD developed molnupiravir for the treatment of pathogenic coronavirus infections rather than the flu. This decision was based on a large body of work done in cell culture and animal models of SARS, MERS, and ultimately SARS-CoV-2.3-5 NHC is intracellularly phosphorylated to its triphosphate derivative, which is incorporated into viral RNA, resulting in fatal replication errors. An additional advantage is a high genetic barrier to resistance.
Jayk Bernal and colleagues now report in the Newspaper the results of a phase 2 to 3 placebo-controlled trial of molnupiravir that may begin to tackle this global problem. The drug was administered orally (800 mg [four tablets] twice daily for 5 days) and compared to a corresponding placebo.6 Patients with mild to moderate disease and at least one risk factor for progression to serious disease (including age> 60 years, obesity, diabetes, or cardiovascular disease) were eligible for the recruitment. The primary endpoint was a composite endpoint of hospitalization or death at 29 days. In the planned interim analysis, 775 patients infected with SARS-CoV-2 and presenting symptoms lasting up to 5 days were recruited; 387 patients received molnupiravir and 388 received placebo. The pre-defined interim scan was completed at approximately 50% of expected enrollment. In the molnupiravir group, the risk of hospitalization or death was 7.3% (28 of 385 patients) compared to 14.1% (53 of 377) in the placebo group (P = 0.001); no deaths had occurred in the molnupiravir group at the time of this interim analysis. However, final analysis of this peer-reviewed data shows a more modest effect. In the final data, 1433 infected volunteers were randomized to receive molnupiravir (716 patients) or placebo (717 patients). A primary endpoint event occurred in 48 of 709 molnupiravir recipients (6.8%) and 68 of 699 placebo recipients (9.7%), an absolute difference of approximately 3 percentage points. One death occurred in the treatment group and nine among the placebo recipients. Many potential reasons for the decreased effect of the drug include pre-existing antibodies to the SARS-CoV-2 core and a lower viral load at the time of enrollment.
In patients for whom sequence data were available, molnupiravir was active against the three predominant circulating variants (delta, gamma and mu) and showed modest antiviral effect. Adverse events were similar in the two groups.
This clinical trial potentially provides a tool in the management of Covid-19, pending evaluation by the Food and Drug Administration (FDA), the European Medicines Agency and other regulatory bodies. Several points deserve to be underlined. First, treatment with molnupiravir was started within 72 hours of symptom onset in almost 50% of patients; however, we should aim to start treatment within 72 hours in all patients, as shown in influenza studies.seven Since SARS-CoV-2 infection needs to be confirmed, a companion point-of-care diagnostic test would be helpful. Molnupiravir is less beneficial when given late in the course of the disease, that is, after patients have had symptoms for more than 3 to 5 days or after hospitalization, as shown by reports of two phase 2 trials of molnupiravir.8.9 Second, the safety database is small and will require careful monitoring for the appearance of side effects. Third, potential mutagenic toxicity has been of concern, since the drug is mutagenic in Chinese hamster ovary cells.ten However, there is a body of data that addresses concerns related to the potential mutagenicity and genotoxicity of molnupiravir.11 Based on the data set, UK regulatory authorities have declared that the risk of mutagenicity or genotoxicity in clinical use of molnupiravir is low and its use was approved in the UK on November 4, 2021. .12 The UK Molnupiravir Summary Report recommends licensing for people with SARS-CoV-2 aged 18 years or older who have a risk factor for progression to serious disease – a population similar to that described in the article by Jayk Bernal et al. The report notes a low risk of genotoxicity, a concern for some doctors.ten Molnupiravir has not been recommended for women who are pregnant or breastfeeding or for those who could become pregnant during treatment. The FDA will review this data, most likely before the end of the year, when considering emergency use authorization. Fourth, the sponsor has indicated in the secular press that drug patents will be made available to the patent pool of the World Health Organization and to generic drug manufacturers so that molnupiravir can be produced for developing countries. , ideally at low cost.
Vaccines should be the primary form of protection against SARS-CoV-2; however, oral bioavailable drugs will become an essential tool for physicians in the management of this horrible disease. It should be noted that, although the data has not been peer reviewed, Pfizer has announced the efficacy of its oral bioavailable protease inhibitor, Paxlovid, and Gilead has reported a benefit of outpatient treatment with remdesivir. . Data for both drugs require peer review. The availability of drugs with different mechanisms of action offers the possibility of creating combination therapies that are potentially synergistic and less likely to lead to resistance.