Lagevrio™ (Molnupiravir) Oral Antiviral 2023
Merck's Lagevrio™ (Molnupiravir) (Molxvir) (emorivir) is an investigational oral antiviral developed initially to treat influenza. Lagevrio is an orally bioavailable form of a potent ribonucleoside analog that inhibits replicating multiple RNA viruses, including SARS-CoV-2, the causative agent of COVID-19. Lagevrio is a mutagenic nucleotide analogue, the underlying biochemical mechanisms with the purified RdRp complex of SARS-CoV-2.
Initially developed at Emory University, Miami, Florida-based Ridgeback Biotherapeutics L.P. and its partner Merck conducted a comprehensive nonclinical program to characterize the safety profile of molnupiravir, including assays such as Big Blue and PIG-a, which are designed to provide a robust measure of a drug or chemical's ability to induce mutations in vivo. In addition, animals were administered molnupiravir for more extended and higher doses (mg/Kg) than those employed in human studies. These studies indicate that molnupiravir is not mutagenic or genotoxic in vivo mammalian systems.
Lagevrio consists of the nucleoside analog N4-hydroxycytidine. Lagevrio has been evaluated against coronaviruses, including SARS-1 and MERS-CoV. In addition, Lagevrio s active in several models of SARS-CoV-2, including for prophylaxis, treatment, and prevention of transmission.
The U.S. National Institutes of Health (NIH) highlighted a non-peer-reviewed phase 2 study on June 17, 2021, that concluded by saying, 'Molnupiravir is the first oral, direct-acting antiviral shown to be highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA and has a favorable safety and tolerability profile.' And on October 23, 2021, the NIH PubMed reported the phase 2/3 NCT04575597 study recently released that molnupiravir significantly reduced the risk of hospitalization or death in adults experiencing mild or moderate COVID-19. To benefit individual and public health, clinical applications of Lagevrio to promptly treat COVID-19 patients and prevent SARS-CoV-2 virus transmission may be expected.
On November 4, 2021, the U.K. Medicines and Healthcare Products Regulatory Agency granted authorization in the U.K. for molnupiravir, known locally as Lagevrio. In addition, the U.K. published a Summary of Product Characteristics for Lagevrio 200 mg hard capsules on November 4, 2021. Form: Swedish Orange, opaque, size 0 (approximately 21.7 mm x 7.6 mm) hard capsule, printed with MSD corporate logo on the cap and "82" on the body in white ink.
The U.S. Food and Drug Administration (FDA) Antimicrobial Drugs Advisory Committee met on November 30, 2021, and voted 13 to 10 to endorse Lagevrio. Merck's presentation and the meeting agenda were posted on November 26, 2021. And on December 16, 2021, Data from the MOVe-AHEAD phase 3 study demonstrated that early treatment with Lagevrio significantly reduced the risk of hospitalization or death in high-risk, unvaccinated adults with COVID-19.
On December 23, 2021, the U.S. FDA issued an emergency use authorization (EUA) to Merck Sharp & Dohme Corp. for molnupiravir for the treatment of mild-to-moderate COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate. It is not approved for the pre-exposure or post-exposure prevention of COVID-19. Under the EUA, fact sheets that provide essential information about using molnupiravir to treat COVID-19 as authorized must be made available to healthcare providers, patients, and caregivers. An updated FAQ was also published by the FDA.
On February 1, 2022, the U.S. NIH issued an updated version of the statement that the COVID-19 Treatment Guidelines Panel for non-hospitalized people released on December 23, 2021. The WHO's ninth update included a conditional recommendation on March 3, 2022, for the treatment with molnupiravir to those at the highest risk of hospitalization. In addition, it clarified who should not receive this investigational drug.
The peer-review journal NEJM published an Original Research funded by Merck on February 10, 2022, that concluded, 'Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19 about 50%. However, a related Correspondence published by the NEJM on March 16, 2022, stated the efficacy later decreased to approximately 30%.
A WHO published on March 11, 2022, a master study protocol: 'Safety monitoring of molnupiravir for treating mild to moderate COVID-19 infection in low and middle-income countries using cohort event monitoring.' The WHO has provided a conditional recommendation for molnupiravir for those at the highest risk of hospitalization. And a randomized, controlled clinical trial published in The Lancet on December 22, 2022, showed that molnupiravir did not reduce the frequency of COVID-19-associated hospitalizations or death among high-risk vaccinated adults in the U.K. community.
Merck announced on February 21, 2023, that LAGEVRIO did not demonstrate a statistically significant reduction in the risk of COVID-19 following household exposure to another individual with COVID-19. The Phase 3 MOVe-AHEAD trial evaluated people who did not have COVID-19 at baseline (confirmed by a negative baseline SARS-CoV-2 test and no signs and symptoms) but lived with someone who was recently diagnosed with COVID-19. In the primary endpoint of participants who did not have evidence of SARS-CoV-2 infection at baseline (confirmed by a negative SARS-CoV-2 test), the LAGEVRIO-treated group was observed to be 23.6% less likely than those who received a placebo to develop COVID-19 through Day 14 (a positive post-baseline SARS-CoV-2 test with evidence of signs and symptoms); the primary endpoint was not met. The safety profile of LAGEVRIO in this trial was generally consistent with that observed in previously reported clinical studies and post-authorization experience in the treatment of COVID-19. Merck intends to submit full results from this study for presentation at a scientific meeting or publication.
Lagevrio Molnupiravir [USAN] RN: 2349386-89-4. Lagevrio (PLGB 53095/0089); UNII: YA84KI1VEW, InChIKey: HTNPEHXGEKVIHG-QCNRFFRDSA-N; PubChem CID145996610; CAS Number 2349386-89-4; DrugBank DB15661; Chemical Formula: C13H19N3O7; Molecular Formula: C13H19N3O7; CHEBI: 180653.
New Jersey-based Merck (NYSE: MRK), known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world's most challenging diseases in pursuit of its mission to save and improve lives. Florida-based Ridgeback Biopharmaceuticals was co-founded by CEO Wendy Holman and Dr. Wayne Holman, a scientific advisor, focusing on developing antiviral medications for epidemic and pandemic risk diseases.
Lagevrio Availability 2023
LAGEVRIO is approved or authorized for use in more than 25 countries, including Australia, Japan, the United States, the United Kingdom, and China, for treating certain adults diagnosed with COVID-19. As of October 2023, 3,400,674 doses of LAGEVRIO were distributed in the U.S., and 1,480,725 had been administered.
However, Merck and Ridgeback Biotherapeutics announced on February 23, 2023, that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had recommended the refusal of the marketing authorization for LAGEVRIO for the treatment of certain adults. Merck and Ridgeback will appeal the decision and request a re-examination of the CHMP's opinion.
Merck entered into a procurement agreement with the U.S. Government in November 2021. The U.S. Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response (ASPR) oversees the allocations of Paxlovid to state and territorial health departments and select Health Resources & Services Administration-funded health clinics and pharmacies. AmerisourceBergen is the sole distributor of molnupiravir in the U.S.
On September 28, 2022, Sinopharm and Merck signed a cooperation framework agreement under which Sinopharm would be a dealer and exclusive commission agent of the antiviral COVID-19 medicine in China.
Molnupiravir is the original generic brand; in Europe and the U.K. (Lagevrio); in India (Molxvir) (Molnulup, Molulife, Molena).
On October 1, 2021, Merck and Ridgeback Biotherapeutics announced that molnupiravir significantly reduced the risk of hospitalization or death at a planned interim analysis of the Phase 3 MOVe-OUT trial in at-risk, non-hospitalized adult patients with mild-to-moderate COVID-19.
On June 19, 2020, Miami-based Ridgeback Biotherapeutics announced the launch of two Phase 2 clinical trials to test the efficacy of EIDD-2801 as an antiviral treatment for COVID-19. On July 1, 2020, Merck and Ridgeback Biotherapeutics L.P. announced that the U.S. Federal Trade Commission granted early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act. As a result, all closing requirements have been completed for the previously announced partnership transaction to advance the development of EIDD-2801, an investigational orally-available antiviral agent currently in early clinical development to treat patients with COVID-19.
This antiviral was developed at Emory University in Georgia by its drug innovation company, Drug Innovation Ventures at Emory. When the COVID-19 pandemic began, DRIVE quickly repurposed a broad-spectrum antiviral drug it had been developing for infectious diseases. The oral antiviral was later acquired by Ridgeback Biotherapeutics, which partnered with Merck & Co. to continue developing the antiviral.
In the U.S. and select markets outside the U.S., LAGEVRIO is the approved trademark for molnupiravir.
Molnupiravir oral antiviral is indicated to mitigate SARS-CoV-2 betacoronavirus infection and block transmission for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options authorized by the FDA are not accessible or clinically appropriate.
The WHO announced on March 3, 2022, that pregnant and breastfeeding women should not be given the drug. In addition, in the U.S., UK, and India, Lagevrio is not recommended during pregnancy. And there are limited data on the presence of molnupiravir or its metabolites in human milk. Therefore, whether molnupiravir affects the breastfed infant or milk production is unknown.
The recommended dose of Lagevrio is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days. The safety and efficacy of molnupiravir when administered for periods longer than five days have not been established. Therefore, Lagevrio should be administered as soon as possible after a diagnosis of COVID-19 has been made and within five days of symptom onset. If the patient misses a dose of Lagevrio within 10 hours of the time it is usually taken, the patient should take it as soon as possible and resume the regular dosing schedule. If a patient misses a dose by more than 10 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to compensate for a missed dose.
Pediatric population: The safety and efficacy of Lagevrio in patients below 18 years of age have not been established. No data are available.
Lagevrio Side Effects
There are limited clinical data available for molnupiravir. No contraindications have been identified based on the limited available data on the emergency use of molnupiravir authorized under its EUA. However, severe and unexpected adverse events not previously reported with molnupiravir use may occur. In an analysis of a phase 3 trial of subjects with mild to moderate COVID-19 treated with molnupiravir (n=386), the most common adverse reactions (≥1% of subjects) reported during treatment and during 14 days after the last dose were diarrhea (3%), nausea (2%), dizziness (1%) and headache (1%) all of which were Grade 1 (mild) or Grade 2 (moderate). Serious AEs occurred in 7% of subjects receiving molnupiravir and 10% receiving placebo; most serious AEs were COVID-19 related.
In July 2021, a study discussed decoding molnupiravir-induced mutagenesis in SARS-CoV-2 - Available evidence suggests that molnupiravir could become a paradigmatic example of using lethal mutagenesis as an antiviral strategy. However, there are inherent risks in this approach. NHC can be metabolized by the host cell to the 2′-deoxyribonucleoside form by the ribonucleotide reductase and then incorporated into the host cell DNA. The mutagenic effect of NHC has been shown in animal cell cultures, raising concerns about the potential risk of molnupiravir-induced tumorigenesis and the emergence of detrimental mutations in sperm precursor cell generation and embryo development.
On January 5, 2022, Indian Council for Medical Research (ICMR) Chief Dr. Balram Bhargava said 'that the antiviral drug Molnupiravir has major safety concerns. It can cause teratogenicity, mutagenicity, and cartilage damage and can also damage muscles. Contraception will have to be done for three months if this drug is given because the child born could have problems due to teratogenic influence," he told media in India.
VAERS is a passive reporting system, meaning it relies on individuals to send in reports of their experiences. However, anyone can submit information to VAERS, including parents and patients. And submit adverse event and medication error reports, using FDA Form 3500, to FDA MedWatch.
On August 1, 2023, Merck announced Lagevrio sales decreased by 83%. Merck reported on April 27, 2023, lower sales of LAGEVRIO, which decreased 88% to $392 million, mainly attributable to sales in the U.S. and U.K. markets in the first quarter of 2022 that did not recur in the first quarter of 2023. The LAGEVRIO sales decline was also attributable to lower sales in Japan and Australia.
Lagevrio News 2023
April 25, 2023 - The BMJ published a study based on VA data that concluded among people at high risk of progression to severe covid-19, molnupiravir use within five days of SARS-CoV-2 infection may be a viable approach to reduce the risk of PASC.
March 7, 2023 - The BMJ published Research: Molnupiravir and risk of hospital admission or death in adults with covid-19: emulation of a randomized target trial using electronic health records, that concluded this emulation of a randomized target trial suggest that molnupiravir might have reduced hospital admission or death at 30 days in adults with SARS-CoV-2 infection in the community during the recent omicron predominant era who were at high risk of progression to severe covid-19 and eligible for treatment with molnupiravir.
February 21, 2023 - Merck announced LAGEVRIO™ did not demonstrate a statistically significant reduction in the risk of COVID-19 following household exposure to another individual with COVID-19.
Molnupiravir COVID-19 Oral Antiviral Clinical Trials
Merck announced on April 1, 2022, a presentation that includes final analyses evaluating virologic outcomes throughout and following a five-day course of LAGEVRIO as part of the Phase 3 MOVe-OUT trial, which studied LAGEVRIO versus placebo for the treatment of COVID-19 in non-hospitalized adults with mild to moderate COVID-19 who were at high risk for progressing to severe disease. Among study participants for whom samples were available, viral infectivity was assessed via a plaque-forming assay in Vero cells. Prespecified exploratory virologic outcomes included changes from baseline in SARS-CoV-2 RNA levels and the percentage of study participants with viral clearance (i.e., undetectable SARS-CoV-2 RNA) and undetectable infectious SARS-CoV-2 through Day 29 in the modified intent-to-treat (mITT) population (≥1 dose of study intervention and not hospitalized before first dose). In participants with infectious virus isolated at baseline and for whom post-baseline infectivity data were available, molnupiravir was associated with more rapid elimination of infectious virus than placebo. At Day 3 of treatment, among patients with the infectious virus at baseline, infectious SARS-CoV-2 was detected in 0.0% (n=0/92) of patients who received LAGEVRIO, compared with 21.8% (n=20/96) of patients who received placebo. On Day 5, infectious virus was detected in 0.0% (n=0/91) of patients in the LAGEVRIO arm compared with 2.2% (n=2/89) in the placebo arm. On Day 10, no infectious virus was detected in either arm for patients with the infectious virus at baseline. Molnupiravir was also associated with more significant mean reductions from baseline in SARS-CoV-2 RNA than placebo from Days 3 through 10. However, molnupiravir and placebo were associated with comparable rates of viral RNA clearance through Day 29.
On January 24, 2022, the UK's RECOVERY Trial confirmed that Molnupiravir would be investigated as a potential treatment for patients hospitalized with COVID-19. RECOVERY will compare molnupiravir (800 mg twice daily for five days) with the usual standard of hospital care in adult patients hospitalized because of COVID-19. Molnupiravir is also being investigated as an at-home treatment by the PANORAMIC Trial, led by Oxford University's Nuffield Department of Primary Care Health Sciences.
The MOVe-AHEAD trial (MK-4482-002) (NCT04575597) found early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. Merck Sharp and Dohme funded the MOVe-OUT study. In addition, the companies announced on April 15, 2021, based on a planned interim analysis of data from Phase 2, the dose-finding portion (Part 1) of two ongoing placebo-controlled Phase 2/3 trials evaluating molnupiravir administered twice a day for five days in outpatients (MOVe-OUT) and hospitalized patients (MOVe-IN) with COVID-19, and from a previously completed Phase 2a dose-ranging study in outpatients, the decision has been made to proceed with the Phase 3 portion (Part 2) of MOVe-OUT in outpatients with COVID-19, evaluating the 800 mg dose of molnupiravir twice daily.
Aurobindo Pharma Limited is conducting a Phase 3, Prospective, Open-Label, Randomized, Multicenter, Parallel Study CTRI/2021/08/035424 in India to evaluate the efficacy and safety of Molnupiravir capsules when administered along with Standard of Care compared to Standard of Care alone in Indian patients with Moderate COVID-19 disease.
On June 17, 2021, a non-peer-reviewed study reported that Molnupiravir is the first oral, direct-acting antiviral that is highly effective at reducing nasopharyngeal SARS-CoV-2 infectious virus and viral RNA and has a favorable safety and tolerability profile. Eligible participants included outpatients with confirmed SARS-CoV-2 infection and symptom onset within seven days. Participants were randomized 1:1 to 200 mg molnupiravir or placebo, or 3:1 to molnupiravir (400 or 800 mg) or placebo, twice daily for five days. Antiviral activity was assessed as time to undetectable levels of viral RNA by a reverse transcriptase-polymerase chain reaction and time to eliminate infectious virus isolation from nasopharyngeal swabs. Among 202 treated participants, virus isolation was significantly lower in participants receiving 800 mg molnupiravir (1.9%) versus placebo (16.7%) on Day 3 (p = 0.02). On Day 5, the virus was not isolated from participants receiving 400 or 800 mg molnupiravir versus 11.1% of those receiving placebo (p = 0.03). In addition, time to viral RNA clearance was decreased, and a more significant proportion overall achieved clearance in participants administered 800 mg molnupiravir versus placebo (p = 0.01). Molnupiravir was generally well tolerated, with similar numbers of adverse events across all groups.
For more clinical study information, please visit http://merckcovidresearch.com.