Comparison of effectiveness and safety of molnupiravir versus sotrovimab for COVID-19: A systematic review and meta-analysis.

BACKGROUND AND AIM: This systematic review and meta-analysis aimed to compare the effectiveness and safety of molnupiravir and sotrovimab in the treatment of patients with coronavirus disease 2019 (COVID-19). METHODS: Cochrane Library, Web of Science, PubMed, medRxiv, and Google Scholar were systematically searched to identify relevant evidence up to December 2023. The risk of bias was assessed using the risk of bias in nonrandomized studies of interventions tool. Data were analyzed using Comprehensive Meta-Analysis (CMA). RESULTS: Our search identified and included 13 studies involving 16166 patients. The meta-analysis revealed a significant difference between the molnupiravir and sotrovimab groups in terms of the mortality rate (odds ratio [OR] = 2.07, 95% confidence interval [CI]: 1.16, 3.70). However, no significant difference was observed between the two groups in terms of hospitalization rate (OR = 0.71, 95% CI: 0.47, 1.06), death or hospitalization rate (OR = 1.51, 95% CI: 0.81, 2.83), and intensive care unit admission (OR = 0.59, 95% CI: 0.07, 4.84). In terms of safety, molnupiravir was associated with a higher incidence of adverse events (OR = 1.67, 95% CI: 1.21, 2.30). CONCLUSION: The current findings indicate that sotrovimab may be more effective than molnupiravir in reducing the mortality rate in COVID-19 patients. However, no statistical difference was observed between the two treatments for other effectiveness outcomes. The certainty of evidence for these findings was rated as low or moderate. Further research is required to provide a better comparison of these interventions in treating COVID-19 patients.

Virology and safety profile of Molnupiravir at three different doses for treatment of SARS-CoV-2: a systematic review and meta-analysis.

Molnupiravir is incorporated into the viral genome, thereby increasing errors, mismatching, and misdirecting the viral polymerase thereby, halting viral RNA replication of SARS-CoV-2. Following PRISMA guidelines, a thorough literature search was performed on electronic and medical databases from December 2022 till January 2023. Molnupiravir 800 mg showed significance in creating viral RNA error rate at Day 5 (WMD: 4.91; 95% CI; [1.19, 8.63] p = 0.01; I2 = 0%). Similarly, at 400 mg, Molnupiravir creates an RNA error rate (WMD: 2.27; 95% CI; 2.27 [0.50, 4.65] p = 0.02; I2 = 0%). Furthermore, exhibit a significant outcome for mean change in SARS-CoV-2 RNA viral load from baseline in nasopharyngeal sample at 800 mg Molnupiravir on Day 3 (WMD: -0.22; 95% CI; [-0.35, -0.08] p = 0.002; I2 = 0%), Day 5 (WMD: -0.32; 95% CI; [-0.53, -0.11] p = 0.003; I2 = 24%) and overall pooled analysis (WMD: -0.17; 95% CI; [-0.29, 0.33] p = 0.003; I2 = 32%). Moreover, Molnupiravir 400 mg significantly reduced the incidence of death compared to the placebo group (RR: 0.17; 95% CI; [0.07, 0.43] p = 0.0002; I2 = 0%). Molnupiravir effectively treats SARS-CoV-2 patients by eliminating the virus from the host.

A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes.

Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus and many will be lethal; thus, molnupiravir-induced elevated mutation rates reduce viral load1,2. However, if some patients treated with molnupiravir do not fully clear the SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, are found almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age groups with widespread use of the drug. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onward transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.

MYC-induced cytidine metabolism regulates survival and drug resistance via cGas-STING pathway in mantle cell lymphoma.

Lymphocyte proliferation and tumourigenesis are dependent on nucleotide synthesis to support DNA, RNA and phospholipid synthesis. Here, we identified that reprogramming of nucleotide metabolism as an important factor divides mantle cell lymphoma (MCL) into two groups with different transcriptional signalling pathways and varying prognoses. We establish a nucleotide metabolism-related prognostic model that includes six genes with different regression coefficients, which significantly predicts prognosis for MCL patients (p < 0.0001). Of these six genes, de novo CTP synthesis pathway enzyme CTPS1 whose inhibitor (STP938) is already in clinical trials for relapsed/refractory lymphomas (NCT05463263) has the highest regression coefficient. An increase in CTPS1 expression predicts adverse overall survival and progression-free survival with independent prognostic significance in 105 primary MCL samples and GEO database (GSE93291). CRISPR CTPS1 knockout causes DNA damage and proliferation defects in MCL. Additionally, MYC positively regulates CTPS1 expression, and TP53-aberrant and ibrutinib-resistant MCL cells also rely on cytidine metabolism. Furthermore, besides the obvious decreased CTP pool caused by CTPS1 deficiency, CTPS1 inhibition may also induce immune-related responses via activating dsDNA-cGAS-STING pathway, which plays a crucial role in impeding tumour growth in MCL patients.

Evaluation of molnupiravir (EIDD-2801) efficacy against SARS-CoV-2 in the rhesus macaque model.

Molnupiravir (EIDD-2801) is a prodrug of a ribonucleoside analogue that is currently being used under a US FDA emergency use authorization for the treatment of mild to moderate COVID-19. We evaluated molnupiravir for efficacy as an oral treatment in the rhesus macaque model of SARS-CoV-2 infection. Twenty non-human primates (NHPs) were challenged with SARS-CoV-2 and treated with 75 mg/kg (n = 8) or 250 mg/kg (n = 8) of molnupiravir twice daily by oral gavage for 7 days. The NHPs were observed for 14 days post-challenge and monitored for clinical signs of disease. After challenge, all groups showed a trend toward increased respiration rates. Treatment with molnupiravir significantly reduced viral RNA levels in bronchoalveolar lavage (BAL) samples at Days 7 and 10. Considering the mild to moderate nature of SARS-CoV-2 infection in the rhesus macaque model, this study highlights the importance of monitoring the viral load in the lung as an indicator of pharmaceutical efficacy for COVID-19 treatments. Additionally, this study provides evidence of the efficacy of molnupiravir which supplements the current ongoing clinical trials of this drug.

Trimethoxy Trityl Groups as a Potent Substituent for Anti-cancer Cytidine Analog Prodrugs.

Methoxy trityl groups are acid-responsive protecting groups that are routinely used in the process of nucleoside analog synthesis. This study investigated the potential of methoxy trityl groups, monomethoxy trityl (MMT), dimethoxy trityl (DMT), and trimethoxy trityl (TMT), as acid-responsive substituents for designing anti-cancer cytidine analog prodrugs. For this purpose, we synthesized six gemcitabine (GEM) derivatives, which were modified either 4-(N)- or 5'-(O)-sites with MMT, DMT, and TMT, as candidates for anti-cancer cytidine analog prodrugs. In vitro dissociation test of methoxy trityl groups clearly showed that the acid responsivity of the methoxy trityl moieties was in the order TMT>DMT>MMT. Furthermore, the rate of 5'-(O)-methoxy tritylation was higher than that of 4-(N)-methoxy tritylation. Along with high acid-responsivity, trimethoxy trityl-O-GEM (TMT-O-GEM) showed superior cytotoxicity against 2D cultured human breast cancer cells (MCF-7 and MDA-MB-231) and human pancreatic cancer cells (AsPC-1) compared to other methoxy-tritylated GEM derivatives. Moreover, TMT-O-GEM suppressed the growth of MCF-7 spheroids compared with trimethoxy trityl-N-GEM (TMT-N-GEM). Both TMT-O-GEM and TMT-N-GEM were negligibly deprotected and metabolized in mouse or human serum after 72 h, indicating that trimethoxy tritylation inhibits deamination by cytidine deaminase. These results indicate that 5'-(O)-trimethoxy tritylation is a potent approach for the development of anti-cancer cytidine analog prodrugs.

Lethal mutagenesis as an antiviral strategy.

[Figure: see text].

Molnupiravir: First Approval.

Molnupiravir (Lagevrio®) is an orally-administered antiviral prodrug that inhibits replication of RNA viruses through viral error induction. It is being developed by Merck and Ridgeback Biotherapeutics for the prevention and treatment of Coronavirus disease 2019 (COVID-19). Molnupiravir received its first approval on 4 November 2021 in the UK for the treatment of mild to moderate COVID-19 in adults with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) diagnostic test and who have at least one risk factor for developing severe illness. Molnupiravir is filed for approval and has emergency use authorization for the treatment of COVID-19 in several countries, including the USA, Japan and those in the EU. This article summarizes the milestones in the development of molnupiravir leading to this first approval for COVID-19.

Molnupiravir in unvaccinated patients with COVID-19.

Overview of: Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al Molnupiravir for oral treatment of COVID-19 in nonhospitalized patients. NEJM 2021;doi:10.1056/NEJMoa2116044 [Epub ahead of print 16 Dec 2021].

Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Patients.

On 4th November 2021, the first oral antiviral drug for COVID-19, molnupiravir (Lagevrio®), received full regulatory approval from the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. Molnupiravir is an orally bioavailable antiviral drug for use at home when a SARS-CoV-2 test is positive. On 22nd December 2022, the FDA granted emergency use authorization (EUA) for the oral antiviral drug, nirmatrelvir/ritonavir (Paxlovid®) for adults and children with mild and moderate COVID-19 at increased risk of progression to severe COVID-19. These regulatory drug approvals come at a crucial time when new variants of concern of the SARS-CoV-2 virus are spreading rapidly. Although the FDA approved remdesivir (Veklury®) on 22nd October 2020 for use in adults and children for the treatment of COVID-19 requiring hospitalization, its use has been limited by the requirement for intravenous administration in a healthcare facility. The four FDA-approved therapeutic neutralizing monoclonal antibodies, imdevimab, bamlanivimab, etesevimab, and casirivimab are costly and also require medically-supervised intravenous administration. The availability of effective, low-cost oral antiviral drugs available in a community setting that can be used at an early stage of SARS-CoV-2 infection is now a priority in controlling COVID-19. An increasing number of repurposed antiviral drugs are currently under investigation or in the early stages of regulatory approval. This Editorial aims to present an update on the current status of orally bioavailable antiviral drug treatments for SARS-CoV-2 infection.

Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern.

We assessed the in vitro antiviral activity of remdesivir and its parent nucleoside GS-441524, molnupiravir and its parent nucleoside EIDD-1931 and the viral protease inhibitor nirmatrelvir against the ancestral SARS-CoV2 strain and the five variants of concern including Omicron. VeroE6-GFP cells were pre-treated overnight with serial dilutions of the compounds before infection. The GFP signal was determined by high-content imaging on day 4 post-infection. All molecules have equipotent antiviral activity against the ancestral virus and the VOCs Alpha, Beta, Gamma, Delta and Omicron. These findings are in line with the observation that the target proteins of these antivirals (respectively the viral RNA dependent RNA polymerase and the viral main protease Mpro) are highly conserved.

An updated practical guideline on use of molnupiravir and comparison with agents having emergency use authorization for treatment of COVID-19.

BACKGROUND AND AIMS: Molnupiravir is a newer oral antiviral drug that has recently received emergency use authorization (EUA) in USA, UK and India. We aim to conduct an update on our previous systematic review to provide practical clinical guideline for using molnupiravir in patients with COVID-19. METHODS: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar until January 5, 2022, using key MeSH keywords. RESULTS: Final result of phase 3 study in 1433 non-hospitalized COVID-19 patients showed a significant reduction in composite risk of hospital admission or death (absolute risk difference, -3.0% [95% confidence interval {CI}, -5.9 to -0.1%]; 1-sided P = 0.02) although with a non-significant 31% relative risk reduction (RRR). RRR for death alone was 89% (95% CI, 14 to 99; P-value not reported). Number needed to treat to prevent 1 death or 1 hospitalization or death composite appears to be closely competitive to other agents having EUA in people with COVID-19. However, cost-wise molnupiravir is comparatively cheaper compared to all other agents. CONCLUSION: Molnupiravir could be a useful agent in non-pregnant unvaccinated adults with COVID-19 who are at increased risk of severity including hospitalization. However, it is effective only when used within 5-days of onset of symptoms. A 5-days course seems to be safe without any obvious short-term side effects.