Factors Influencing COVID-19 Risk: Insights From Molnupiravir Exposure-Response Modeling of Clinical Outcomes.

Molnupiravir (MOV) is an oral antiviral for the treatment of coronavirus disease 2019 (COVID-19) in outpatient settings. This analysis investigated the relationship between ß-D-N4-hydroxycytidine (NHC) pharmacokinetics and clinical outcomes in patients with mild to moderate COVID-19 in the phase III part of the randomized, double-blind, placebo-controlled MOVe-OUT trial. Logistic regression models of the dependency of outcomes on exposures and covariates were constructed using a multistep process. Influential covariates were identified first using placebo arm data, followed by assessment of exposure-dependency in drug effect using data from both the placebo and MOV arms. The exposure-response (E-R) analysis included 1,313 participants; 630 received MOV and 683 received placebo. Baseline viral load, baseline disease severity, age, weight, viral clade, active cancer, and diabetes were identified as significant determinants of response using placebo data. Absolute measures of viral load on days 5 and 10 were strong on-treatment predictors of hospitalization. An additive area under the curve (AUC)-based maximum effect (Emax ) model with a fixed Hill coefficient of 1 best represented the exposure-dependency in drug effect and the AUC50 was estimated to be 19,900 nM hour. Patients at 800 mg achieved near maximal response, which was larger than for 200 or 400 mg. The final E-R model was externally validated and predicted that the relative reduction in hospitalization with MOV treatment would vary with patient characteristics and factors in the population. In conclusion, the E-R results support the MOV dose of 800 mg twice daily to treat COVID-19. Many patient characteristics and factors impacted outcomes beyond drug exposures.

Could a popular antiviral supercharge the pandemic?

Molnupiravir appears to be speeding SARS-CoV-2 evolution.

Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study.

BACKGROUND: Little is known about the real-world effectiveness of oral antivirals against the SARS-CoV-2 omicron (B.1.1.529) variant. We aimed to assess the clinical effectiveness of two oral antiviral drugs among community-dwelling COVID-19 outpatients in Hong Kong. METHODS: In this observational study, we used data from the Hong Kong Hospital Authority to identify an unselected, territory-wide cohort of non-hospitalised patients with an officially registered diagnosis of SARS-CoV-2 infection between Feb 26 and June 26, 2022, during the period in which the omicron subvariant BA.2.2 was dominant in Hong Kong. We used a retrospective cohort design as primary analysis, and a case-control design as sensitivity analysis. We identified patients with COVID-19 who received either molnupiravir (800 mg twice daily for 5 days) or nirmatrelvir plus ritonavir (nirmatrelvir 300 mg and ritonavir 100 mg twice daily for 5 days, or nirmatrelvir 150 mg and ritonavir 100 mg if estimated glomerular filtration rate was 30-59 mL/min per 1·73 m2). Outpatient oral antiviral users were matched with controls using propensity score (1:10) according to age, sex, date of SARS-CoV-2 infection diagnosis, Charlson Comorbidity Index score, and vaccination status. Study outcomes were death, COVID-19-related hospitalisation, and in-hospital disease progression (in-hospital death, invasive mechanical ventilation, or intensive care unit admission). Hazard ratios (HRs) were estimated by Cox regression for the primary analysis, and odds ratios in oral antiviral users compared with non-users by logistic regression for the sensitivity analysis. FINDINGS: Among 1 074 856 non-hospitalised patients with COVID-19, 5383 received molnupiravir and 6464 received nirmatrelvir plus ritonavir in the community setting. Patients were followed up for a median of 103 days in the molnupiravir group and 99 days in the nirmatrelvir plus ritonavir group. Compared with nirmatrelvir plus ritonavir users, those on molnupiravir were older (4758 [85·9%] vs 4418 [88.7%] aged >60 years) and less likely to have been fully vaccinated (1850 [33·4%] vs 800 [16·1%]). Molnupiravir use was associated with lower risks of death (HR 0·76 [95% CI 0·61-0·95]) and in-hospital disease progression (0·57 [0·43-0·76]) than non-use was, whereas risk of hospitalisation was similar in both groups (0·98 [0·89-1·06]). Nirmatrelvir plus ritonavir use was associated with lower risks of death (0·34 [0·22-0·52]), hospitalisation (0·76 [0·67-0·86]), and in-hospital disease progression (0·57 [0·38-0·87]) than non-use was. We consistently found reduced risks of mortality and hospitalisation associated with early oral antiviral use among older patients. The findings from the case-control analysis broadly supported those from the primary analysis. INTERPRETATION: During Hong Kong's wave of SARS-CoV-2 omicron subvariant BA.2.2, among non-hospitalised patients with COVID-19, early initiation of novel oral antivirals was associated with reduced risks of mortality and in-hospital disease progression. Nirmatrelvir plus ritonavir use was additionally associated with a reduced risk of hospitalisation. FUNDING: Health and Medical Research Fund, Health Bureau, Government of Hong Kong Special Administrative Region, China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19).

INTRODUCTION: Molnupiravir (MOV) is a broad-spectrum oral antiviral agent approved for the treatment of COVID-19. The results from in vitro and in vivo studies suggested MOV activity against many RNA viruses such as influenza virus and some alphaviruses agents of epidemic encephalitis. MOV is a prodrug metabolized into the ribonucleoside analog ß-D-N4-hydroxycytidine. It is incorporated into the viral RNA chain causing mutations impairing coding activity of the virus, thereby inhibiting viral replication. AREAS COVERED: This review analyzes the in vitro and in vivo studies that have highlighted the efficacy of MOV and the main pre-authorization randomized controlled trials evaluating its safety, tolerability, and pharmacokinetics, as well as its antiviral efficacy against SARS-COV-2 infection. EXPERT OPINION: MOV is an antiviral agent with an excellent tolerability profile with few drug-drug interactions. Treatment of mild-to-moderate COVID-19 can benefit from MOV administration in the precocious phases of the disease, prior to the trigger of an aberrant immune response responsible for the parenchymal damage to pulmonary and extrapulmonary tissues. However, its suspected mutagenic effect can be a factor limiting its use at least in selected populations and studies on its teratogen effects should be planned before it is authorized for use in the pediatric population or in pregnant women.

Editorial: Rebound COVID-19 and Cessation of Antiviral Treatment for SARS-CoV-2 with Paxlovid and Molnupiravir.

One of the most recently described clinical associations with SARS-CoV-2 infection is rebound COVID-19, which occurs between five and eight days following the cessation of antiviral treatment. Most case reports of rebound COVID-19 have been associated with cessation of treatment with the combined oral antiviral agent nirmatrelvir/ritonavir (Paxlovid). On 24 May 2022, the US Centers for Disease Control and Prevention (CDC) issued a Health Alert Network (HAN) Health Advisory update for patients, healthcare providers, and public health departments on COVID-19 rebound or recurrence of COVID-19. However, population data from the US showed no significant differences in the risk of developing rebound COVID-19 between patients treated with Paxlovid and Molnupiravir. The mechanisms of rebound COVID-19 remain unclear but may involve the development of resistance to the antiviral drug, impaired immunity to the virus, or insufficient drug dosing. A further explanation may be the persistence of a high viral load of SARS-CoV-2 in individuals who are no longer symptomatic. This Editorial aims to provide an update on what is known about rebound COVID-19 and the current public health implications.

Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial.

BACKGROUND: In the MOVe-OUT trial, molnupiravir showed a clinically meaningful reduction in the risk for hospitalization or death in adults with mild to moderate COVID-19 and risk factors for progression to severe disease. OBJECTIVE: To identify other potential clinical benefits of molnupiravir versus placebo. DESIGN: Secondary analysis of the randomized, double-blind, placebo-controlled phase 3 component of MOVe-OUT. (ClinicalTrials.gov: NCT04575597). SETTING: 107 sites globally. PARTICIPANTS: 1433 nonhospitalized adults aged 18 years or older with mild to moderate COVID-19. INTERVENTION: Molnupiravir, 800 mg, or placebo every 12 hours for 5 days. MEASUREMENTS: Changes from baseline in C-reactive protein (CRP) concentration and oxygen saturation (Spo 2), need for respiratory interventions (including invasive mechanical ventilation), and need for medical services in all randomly assigned participants through day 29, and need for respiratory interventions and time to discharge in the subgroup of participants who were hospitalized after randomization. RESULTS: Participants receiving molnupiravir showed faster normalization of CRP and Spo 2, with improvements observed on day 3 of therapy, compared with placebo. Molnupiravir-treated participants had a decreased need for respiratory interventions versus placebo-treated participants (relative risk reduction [RRR], 34.3% [95% CI, 4.3% to 54.9%]), with similar findings in participants who were hospitalized after randomization (RRR, 21.3% [CI, 0.2% to 38.0%]). Hospitalized participants who received molnupiravir were discharged a median of 3 days before those who received placebo. Acute care visits (7.2% vs. 10.6%; RRR, 32.1% [CI, 4.4% to 51.7%]) and COVID-19-related acute care visits (6.6% vs. 10.0%; RRR, 33.8% [CI, 5.6% to 53.6%]) were less frequent in molnupiravir- versus placebo-treated participants. LIMITATIONS: Some analyses were performed post hoc. Longer-term benefits of molnupiravir therapy were not evaluated. Participants were not immunized against SARS-CoV-2. CONCLUSION: The findings suggest there are additional important clinical benefits of molnupiravir beyond reduction in hospitalization or death. PRIMARY FUNDING SOURCE: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model.

SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was significant in males, but not females. The dwarf hamster model recapitulates mixed efficacy of molnupiravir in human trials and alerts that benefit must be reassessed in vivo as VOC evolve.

Repurposing Molnupiravir for COVID-19: The Mechanisms of Antiviral Activity.

Molnupiravir is a ß-d-N4-hydroxycytidine-5'-isopropyl ester (NHC) compound that exerts antiviral activity against various RNA viruses such as influenza, SARS, and Ebola viruses. Thus, the repurposing of Molnupiravir has gained significant attention for combatting infection with SARS-CoV-2, the etiological agent of COVID-19. Recently, Molnupiravir was granted authorization for the treatment of mild-to-moderate COVID-19 in adults. Findings from in vitro experiments, in vivo studies and clinical trials reveal that Molnupiravir is effective against SARS-CoV-2 by inducing viral RNA mutagenesis, thereby giving rise to mutated complementary RNA strands that generate non-functional viruses. To date, the data collectively suggest that Molnupiravir possesses promising antiviral activity as well as favorable prophylactic efficacy, attributed to its effective mutagenic property of disrupting viral replication. This review discusses the mechanisms of action of Molnupiravir and highlights its clinical utility by disabling SARS-CoV-2 replication, thereby ameliorating COVID-19 severity. Despite relatively few short-term adverse effects thus far, further detailed clinical studies and long-term pharmacovigilance are needed in view of its mutagenic effects.

Molnupiravir for the treatment of COVID-19.

Molnupiravir (MK-4482, EIDD-2801) is a promising broad-spectrum experimental antiviral developed by Merck & Co. It is a nucleoside analogue prodrug that undergoes rapid conversion into nucleoside triphosphate (NTP) by intracellular metabolic processes. NTP inhibits viral polymerase by acting as an alternative substrate. Molnupiravir was initially developed to treat influenza and Venezuelan equine encephalitis virus (VEEV) infection as it exerts its antiviral activity by inhibiting RNA-dependent RNA polymerase (RdRp). Currently, it is being developed for the treatment of SARS-CoV-2 infection. Molnupiravir has demonstrated potent in vitro antiviral activity against positive-sense RNA viruses including influenza viruses, SARS-CoV, SARS-CoV-2 and MERS-CoV with low cytotoxicity and a high resistance barrier. Molnupiravir has been evaluated in phase I, II and III trials where it has demonstrated good efficacy, dose-dependent pharmacokinetics and a sound safety profile. In an interim analysis of a phase III study, treatment with molnupiravir reduced the risk of hospitalization or death by 50% in patients with COVID-19; in the final analysis, the reduction was 30%. On the basis of positive results in clinical trials, molnupiravir has been authorized for emergency use by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) and the U.S. Food and Drug Administration (FDA) in adults with mild to moderate COVID-19.

New Perspectives on Antimicrobial Agents: Molnupiravir and Nirmatrelvir/Ritonavir for Treatment of COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged to cause pandemic respiratory disease in the past 2 years, leading to significant worldwide morbidity and mortality. At the beginning of the pandemic, only nonspecific treatments were available, but recently two oral antivirals have received emergency use authorization from the U.S. Food and Drug Administration for the treatment of mild to moderate coronavirus disease (COVID-19). Molnupiravir targets the viral polymerase and causes lethal mutations within the virus during replication. Nirmatrelvir targets SARS-CoV-2's main protease, and it is combined with ritonavir to delay its metabolism and allow nirmatrelvir to inhibit proteolytic cleavage of viral polyproteins during replication, preventing efficient virus production. Both drugs inhibit in vitro viral replication of all variants tested to date. Each is taken orally twice daily for 5 days. When started in the first 5 days of illness in persons at risk for complications due to COVID-19, molnupiravir and nirmatrelvir/ritonavir significantly decreased severe outcomes (hospitalizations and death) with adjusted relative risk reductions of 30% and 88%, respectively, for the two treatments. Molnupiravir should not be used in children or pregnant persons due to concerns about potential toxicity, and reliable contraception should be used in persons of childbearing potential. Nirmatrelvir/ritonavir may cause significant drug-to-drug interactions that limit its use in persons taking certain medications metabolized by certain cytochrome P450 enzymes. Both treatment regimens are important additions to the management of early COVID-19 in at-risk patients in the outpatient setting.

Safety and efficacy of molnupiravir in SARS-CoV-2-infected patients: A real-life experience.

Since the start of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, several treatments have been proposed to cure coronavirus disease 2019 (COVID-19) and prevent it. Molnupiravir is a ribonucleoside prodrug of N-hydroxycytidine with an in vitro and in vivo activity against SARS-CoV-2. We conducted a retrospective cohort study that included all people treated with molnupiravir between January 10, 2022, and March 31, 2022, at the University Hospital of Sassari. Molnupiravir was prescribed, according to the Italian Agency of Drug indications, to patients with recent symptom onset (≤5 days), no need for oxygen supplementation, and with a high risk of disease progression for the presence of chronic diseases. We included 192 people with a mean age of 70.4 ± 15.4 years, with 144 (75%) patients over 60 years. During the follow-up, 20 (10.4%) patients showed a disease progression. At the multivariate analysis, older age, having neurological disease, having dyspnea at the onset of the symptoms, and acquiring SARS-CoV-2 infection during hospital admission were associated with an increased risk of progression. In contrast, an early start of treatment was associated with a reduced risk of disease progression. Molnupiravir was also extremely safe since 13 (6.8%) adverse events were reported, with only one interruption. Our study shows that monlupiravir confirmed its efficacy and safety in a real-life cohort that included a high percentage of elderly people with a high comorbidity burden.

The COVID-19 Oral Drug Molnupiravir Is a CES2 Substrate: Potential Drug-Drug Interactions and Impact of CES2 Genetic Polymorphism In Vitro.

Molnupiravir is one of the two coronavirus disease 2019 (COVID-19) oral drugs that were recently granted the emergency use authorization by the Food and Drug Administration (FDA). Molnupiravir is an ester and requires hydrolysis to exert antiviral activity. Carboxylesterases constitute a class of hydrolases with high catalytic efficiency. Humans express two major carboxylesterases (CES1 and CES2) that differ in substrate specificity. Based on the structural characteristics of molnupiravir, this study was performed to test the hypothesis that molnupiravir is preferably hydrolyzed by CES2. Several complementary approaches were used to test this hypothesis. As many as 24 individual human liver samples were tested and the hydrolysis of molnupiravir was significantly correlated with the level of CES2 but not CES1. Microsomes from the intestine, kidney, and liver, but not lung, all rapidly hydrolyzed molnupiravir and the magnitude of hydrolysis was related closely to the level of CES2 expression among these organs. Importantly, recombinant CES2 but not CES1 hydrolyzed molnupiravir, collectively establishing that molnupiravir is a CES2-selective substrate. In addition, several CES2 polymorphic variants (e.g., R180H) differed from the wild-type CES2 in the hydrolysis of molnupiravir. Molecular docking revealed that wild-type CES2 and its variant R180H used different sets of amino acids to interact with molnupiravir. Furthermore, molnupiravir hydrolysis was significantly inhibited by remdesivir, the first COVID-19 drug granted the full approval by the FDA. The results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation. SIGNIFICANCE STATEMENT: COVID-19 remains a global health crisis, and molnupiravir is one of the two recently approved oral COVID-19 therapeutics. In this study, we have shown that molnupiravir is hydrolytically activated by CES2, a major hydrolase whose activity is impacted by genetic polymorphic variants, disease mediators, and many potentially coadministered medicines. These results presented raise the possibility that CES2 expression and genetic variation may impact therapeutic efficacy in clinical situations and warrants further investigation.

Using Twitter data to understand public perceptions of approved versus off-label use for COVID-19-related medications.

OBJECTIVE: Understanding public discourse on emergency use of unproven therapeutics is essential to monitor safe use and combat misinformation. We developed a natural language processing-based pipeline to understand public perceptions of and stances on coronavirus disease 2019 (COVID-19)-related drugs on Twitter across time. METHODS: This retrospective study included 609 189 US-based tweets between January 29, 2020 and November 30, 2021 on 4 drugs that gained wide public attention during the COVID-19 pandemic: (1) Hydroxychloroquine and Ivermectin, drug therapies with anecdotal evidence; and (2) Molnupiravir and Remdesivir, FDA-approved treatment options for eligible patients. Time-trend analysis was used to understand the popularity and related events. Content and demographic analyses were conducted to explore potential rationales of people's stances on each drug. RESULTS: Time-trend analysis revealed that Hydroxychloroquine and Ivermectin received much more discussion than Molnupiravir and Remdesivir, particularly during COVID-19 surges. Hydroxychloroquine and Ivermectin were highly politicized, related to conspiracy theories, hearsay, celebrity effects, etc. The distribution of stance between the 2 major US political parties was significantly different (P < .001); Republicans were much more likely to support Hydroxychloroquine (+55%) and Ivermectin (+30%) than Democrats. People with healthcare backgrounds tended to oppose Hydroxychloroquine (+7%) more than the general population; in contrast, the general population was more likely to support Ivermectin (+14%). CONCLUSION: Our study found that social media users with have different perceptions and stances on off-label versus FDA-authorized drug use across different stages of COVID-19, indicating that health systems, regulatory agencies, and policymakers should design tailored strategies to monitor and reduce misinformation for promoting safe drug use. Our analysis pipeline and stance detection models are made public at https://github.com/ningkko/COVID-drug.