Molnupiravir Medical Presentation - 25th Jan'22.pptx

The Emerging Role Of Molnupiravir In
Treatment Of COVID 19

Management of COVID - 19
Molnupiravir, Favipiravir Remdesivir, Monoclonal antibody cocktail (Casirivimab-Imdevimab)

3
Molnupiravir
Molnupiravir (MK-4482 or EIDD 2801) prodrug
enters the cell and gets converted to β-d-N4-
hydroxycytidine (NHC) triphosphate (MTP).
MTP exists as 2 tautomers (mimics cytidine (C)
or uridine (U) inviral RNA) ----pair with
guanosine (G) or adenosine (A), respectively
Molnupiravir is a broad spectrum oral antiviral drug originally developed to treat influenza.
Molecular formula: C13H19N3O7
Alternative names: MK-4482, EIDD-2801
Class: Nucleoside analogues
Mode of action : Exerts antiviral action through introduction
of copying errors during viral RNA replication

Mechanism of action of Molnupiravir
Step 1: Incorporation
 RNA-dependent RNA polymerase (RdRp) enzyme incorporate
M (MTP) instead of C (CTP) or U (UTP) in the newly
synthesized RNA
Step 2: Copy Errors
 The presence of M in the RNA then leads to copy errors in
the RNA products, which do not support formation of intact
new viruses, as predicted by the ‘error catastrophe’ model
Molnupiravir inhibits replication by introducing copying errors during viral RNA replication
Copy Errors

Indications & Dosage
Therapeutic Indication
For the treatment of adult patients with COVID-19, with SpO2 >93% and who have high risk of
progression of the disease including hospitalization or death.
Dosage
Dosage is 800mg (4 capsules of 200 mg) twice a day for 5 days (10 doses total).
Prescribing information

Limitations of authorized use
Molnupiravir is not authorized:
 for use in patients less than 18 years of age
 for initiation of treatment in patients requiring immediate hospitalization due to COVID-
19 at that stage, (however, if it was initiated before hospitalization due to COVID 19, it may
be continued).
 for use for longer than 5 consecutive days.
 for pre-exposure or post-exposure prophylaxis for prevention of COVID-19
 for pregnant women
 Females of childbearing potential should use a reliable method of contraception correctly
and consistently, as applicable, for the duration of treatment and for 4 days after the last
dose of molnupiravir.
 Males of reproductive potential who are sexually active with females of child bearing
potential should use a reliable method of contraception correctly and consistently during
treatment and for at least 3 months after the last dose

Invitro susceptibility against VOC
Title Study design Key outcomes
Remdesivir, Molnupiravir and
Nirmatrelvir remain active against
SARS-CoV-2 Omicron and other
variants of concern
VeroE6-GFP cells were pre-
treated overnight with serial
dilutions of the compounds
before infection.
• Molnupiravir along with other drugs like remdesivir,
and nirmatrelvir retain their activity against the VOCs
Omicron, Alpha, Beta, Gamma, and Delta.
Reduced interferon antagonism
but similar drug sensitivity in
Omicron variant compared to
Delta variant SARS-CoV-2 isolates
Caco-2 and Calu-3 cells were
infected with SARS-CoV-2
variant Delta and Omicron
• Omicron isolates display similar sensitivity to eight of
the most important anti-SARS-CoV-2 drugs and drug
candidates (including remdesivir, molnupiravir, and
Paxlovid)
Preprints: https://doi.org/10.1101/2022.01.03.474773; https://doi.org/10.1101/2021.12.27.474275;

Evidence Summary: Preclinical Study
T. P. Sheahan et al., Sci. Transl. Med. 10.1126/scitranslmed.abb5883 (2020).
Cox RM, Wolf JD, Plemper RK. Therapeutic MK-4482/EIDD-2801 Blocks SARS-CoV-2 Transmission in Ferrets. Res Sq [Preprint]. 2020 Oct 12:rs.3.rs-89433. doi: 10.21203/rs.3.rs-89433/v1. Update in: Nat Microbiol. 2020 Dec 3;: PMID: 33052328;
PMCID: PMC7553152.
Title Study design Key outcomes
An orally bioavailable broad-
spectrum antiviral inhibits
SARS-CoV-2 in human airway
epithelial cell cultures and
multiple coronaviruses in mice
The primary goal of this study was to
determine the antiviral activity of the
nucleoside analog NHC (EIDD-1931)
against multiple emerging CoV in vitro
and antiviral efficacy of its prodrug,
EIDD-2801, in mouse models of CoV
pathogenesis.
 Molnupiravir potently inhibits SARS-CoV-2 replication.
 Also causes dose-dependent reduction in SARS-CoV-2 titers
 In mice, improved pulmonary function, and reduced virus
titer and body weight loss
Recent ferret model confirms
that molnupiravir is active
against SARS-CoV-2, even
reducing the risk of subsequent
transmission
Ferrets (Mustela putorius furo) were
used as an in vivo model to examine
the efficacy of therapeutically
administered oral MK-4482/EIDD-
2801against SARS-CoV-2 infection and
virus transmission to uninfected contact
animals.
• Suppressed SARS-CoV-2 infection spread to untreated
contact animals.
• Reduced nasal viral load. Infectious particles were
undetectable within 24-36 hours.
• These results suggest that treatment with molnupiravir may
quickly render patients noninfectious
Orally delivered MK-4482
inhibits SARS-CoV-2 replication
in the Syrian hamster model
Syrian hamster animal model
was established to assess the
inhibitory effect of the nucleoside
analog MK-4482 on SARS-CoV-2
replication in vivo
• inhibits SARS-CoV-2 replication in the Syrian hamster
model.
• Reduced virus replication was associated with reduced
lung pathology.

9
medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20235747
Study Design : Single and multiple doses of Molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind,
placebo-controlled study, which included evaluation of the effect of food on pharmacokinetics
• Molnupiravir appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00
to 1.75 hours,
• Mean maximum observed concentration and area under the concentration versus time curve increased in a
dose-proportional manner, and there was no accumulation following multiple doses.
• Molnupiravir was well tolerated.
• Only 1 moderate adverse event (headache. grade 2) was reported, which occurred at the 400-mg dose level.
• The most frequently reported adverse event was diarrhea, which was reported by 7.1% of subjects who
were administered Molnupiravir and 7.1% of subjects who were administered placebo.
• There were no serious adverse events and there were no clinically significant findings in clinical laboratory,
vital signs, or electrocardiography.
Phase 1
Trial

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Evidence Summary : Preliminary Findings from a Phase 2a
Trial of Investigational COVID-19 Therapeutic Molnupiravir
 Aim : To evaluate the safety, tolerability, and efficacy to eliminate SARS-CoV-2 viral RNA of molnupiravir (EIDD-2801/MK-
4482), an investigational oral antiviral agent.
 Study Design : randomized, double-blind, placebo-controlled trial
 N= 202 non-hospitalized adults who had signs or symptoms of COVID-19 within 7 days and confirmed active SARS-CoV-2
infection
 The primary efficacy objective : Reduction in time to viral negativity measured by reverse transcriptase polymerase chain
reaction (RT-PCR) analysis of nasopharyngeal swabs.
 The secondary objective : Reduction in time to negativity of infectious SARS-CoV-2 virus isolation from nasopharyngeal swabs
from participants with symptomatic COVID-19
 Recent findings:
 Of the 182 participants with an evaluable nasopharyngeal swab, 42% (78/182) showed detectable levels of cultured virus at
baseline.
 At day 5, there was a reduction ( p=0.001) in positive viral culture in subjects who received molnupiravir (all doses)
compared to placebo: 0% (0/47) for molnupiravir and 24% (6/25) for placebo.
 Of 202 treated participants, no safety signals have been identified and of the 4 serious adverse events reported, none were
considered to be study drug related
A quicker decrease in infectious virus among individuals with early COVID-19 treated with molnupiravir
https://www.precisionvaccinations.com/vaccines/molnupiravir-mk-4482-eidd-2801-antiviral

Evidence Summary: Phase 2/3
https://www.precisionvaccinations.com/vaccines/molnupiravir-mk-4482-eidd-2801-antiviral
• Patient Population: Symptomatic outpatient adults (≥18 years) with documented positive SARS-CoV-2 test result &
with ≤7 days of symptoms of COVID-19 at entry
• Design: Randomized, double-blind study of MK-4482 vs. placebo
• Dose/Duration: 200, 400, 800 mg vs. placebo BID for 5 days (Phase 2); final chosen dose vs. placebo (Phase 3)
• Endpoint: Hospitalization or death
• Sample Size: N=1450 (Phase 2: 300; Phase 3: 1150)
• Conduct: 170 sites in 17 countries
Results Phase 2 study:
• Maximum antiviral effect was observed in the 800 mg dose compared with the 200 and 400 mg doses.
• The percentage of patients who were hospitalized and/or died was lower in the combined molnupiravir-
treated groups versus the placebo arm.

Also called as MOVe-OUT trial, this was a randomized, double-blind, multi-site study; a phase-3 study
1443 patients were randomly assigned to molnupiravir treatment or placebo.
This study was conducted globally at more than 170 sites.
Exclusion criteria
• Need for hospitalization
• Dialysis or glomerular filtration rate <30,
• Pregnancy,
• Unwillingness to use contraception,
• SARS-CoV-2 vaccination
Inclusion criteria
• Non-hospitalised patients.
• Laboratory-confirmed COVID-19 infection.
• Onset of symptoms five days before study
randomization.
• At least one risk factor associated with poor
disease outcome.
New England Journal of Medicine. 2021 doi:10.1056/nejmoa2116044
Phase 3
Trial

Most common risk factors for poor disease
outcome:
 Obesity
 Age> 60 years
 Diabetes Mellitus
 Heart disease.
Primary outcome
• To evaluate the percentage of patients that are
hospitalized and/or die within 29 days of
randomization.
6.80%
6.30%
0.10%
9.70%
9.20%
1.30%
ALL CAUSE- HOSPITALIZATION OR
DEATH
COVID-19 RELATED
HOSPITALISATION OR DEATH
COVID-19 RELATED DEATH
Hospitalisation
or
death
through
day
29
Parameter
Results of MOVe-OUT study
Molnupiravir Placebo
30% reduction in rate of hospitalization
or death in molnupiravir group
Interim analysis (n=775) showed 50% reduction in rate of
hospitalization or death in molnupiravir group
Phase 3
Trial

Subgroup Analysis
Phase 3
Trial
In most prespecified
subgroups, the
percentage of
participants who were
hospitalized or died
was lower with
molnupiravir than
placebo

WHO clinical scale
Phase 3
Trial
A lower percentage of participants who received molnupiravir showed worse outcomes on the
WHO 11-point ordinal scale compared with those who received placebo; the largest observed
differences occurred at Days 10 and 15

Adverse Events
Phase 3
Trial
• The percentage of participants with at least one AE was similar in the two groups (30.40% in molnupiravir
and 33.0% in placebo group), as was the percentage of participants with adverse events considered by the
investigators to be related to the trial regimen (8.0% vs. 8.4%).
• Deaths resulting from adverse events, none of which were deemed by the investigators to be related to
the trial regimen, were reported less frequently in the Molnupiravir group than in the placebo group

Results
• A primary end-point event (hospitalization/death) occurred in 48 of 709 Molnupiravir
recipients (6.8%) and 68 of 699 placebo recipients (9.7%), a reduction in risk of
hospitalization by 30%.
• Greater improvement in WHO Clinical Progression Scale with molnupiravir over placebo.
• Consistent efficacy among subgroups including participants infected with SARS-CoV-2
variants (delta, gamma, and mu) was observed.
• One death occurred in the treatment group, and nine among placebo recipients.
• Adverse events were similar in the two groups.
Conclusion: MOVe-OUT trial showed that molnupiravir effectively reduced the hospitalization or
mortality risk in patients with mild-to-moderate COVID-19 infection.
Phase 3
Trial

Pharmacokinetic Properties
 Absorption: Following twice daily oral administration of 800 mg molnupiravir, the median time to peak
plasma NHC concentrations (Tmax) was 1.5 hours.
 Effect of Food on Oral Absorption: In healthy subjects, the administration of a single 200 mg dose of
molnupiravir with a high-fat meal resulted in a 35% reduction in NHC peak concentrations (Cmax), AUC
was not significantly affected..
 Metabolism/distribution: Molnupiravir is rapidly converted in the plasma to EIDD-1931 (NHC), which
after distribution into various tissues is converted by host kinases into EIDD-1931 59-triphosphate, the
active antiviral agent. No accumulation was observed in the multiple-ascending dose part of this study.
 Elimination: The effective half-life of NHC is approximately 3.3 hours. The fraction of dose excreted as
NHC in the urine was ≤3% in healthy participants.

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Drug-drug interactions
• No drug interactions have been identified based on the limited available data.
• No clinical interaction studies have been performed with molnupiravir.
• Based on in vitro studies, neither molnupiravir nor NHC are inhibitors or inducers of
major drug metabolising enzymes or inhibitors of major drug transporters.
• Therefore, the potential for molnupiravir or NHC to interact with concomitant
medications is considered unlikely.

Pregnant Women
 Molnupiravir should not be administered to a pregnant woman or a woman who may be pregnant.
Lactating Women
 Do not administer to lactating women.
 If administered to a nursing mother, stop the breastfeeding during 5 days of therapy 4 days after therapy.
Paediatric Patients
 The safety and efficacy of Molnupiravir in patients below 18 years of age have not been established. No data are available.
Males of reproductive potential
 Should use a reliable method of contraception correctly and consistently during treatment and for at least 3 months after the last dose
Females of childbearing age
 Should use a reliable method of contraception correctly and consistently, as applicable, for the duration of treatment and for 4 days after
the last dose of molnupiravir.
Geriatric Patients
 No dose adjustment of Molnupiravir is required based on age.
Renal/Hepatic impairment Patients
 No dose adjustment of Molnupiravir is required based on age
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Use In Special Populations
Prescribing Information

21
Safety & Tolerability – Preclinical Data
Mutagenicity
• In 2 distinct in vivo rodent mutagenicity models (Pig-a mutagenicity assay and Big Blue® (cII Locus) transgenic rodent
assay) molnupiravir did not induce increased mutation rates relative to untreated historical control animals, and
therefore is not mutagenic in vivo.
• Molnupiravir was negative for induction of chromosomal damage in in vitro micronucleus (with and without
metabolic activation) and in vivo rat micronucleus assays.
• Based on the totality of the genotoxicity data, molnupiravir is of low risk for genotoxicity or mutagenicity in clinical
use.
Bone and cartilage toxicity
• Bone and cartilage toxicity, consisting of an increase in the thickness of physeal and epiphyseal growth cartilage with
decreases in trabecular bone was observed in the femur and tibia of rapidly growing rats in a 3-month toxicity study at
≥ 500 mg/kg/day (5.4 times the human NHC exposure at the RHD).
• There was no bone or cartilage toxicity in a 1-month toxicity study in rapidly growing rats up to 500 mg/kg/day (4.2 and
7.8 times the human NHC exposure at the RHD in females and males, respectively), in dogs dosed for 14 days up to 50
mg/kg/day (1.6 times the human NHC exposure at the RHD), or in a 1-month toxicity study in mice up to 2,000
mg/kg/day (19 times the human NHC exposure at the RHD).
Growth cartilage is not present in mature skeletons; therefore the bone and cartilage findings are not relevant for adult
humans. The clinical significance of these findings for paediatric patients is unknown.

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Embryofoetal Development
In an embryofoetal development (EFD) study in rats, molnupiravir was administered orally to pregnant rats at 0, 100, 250,
or 500 mg/kg/day from gestation days (GDs) 6 to 17. Molnupiravir was also administered orally to pregnant rats at up to
1,000 mg/kg/day from GDs 6 to 17 in a preliminary EFD study. Developmental toxicities included post-implantation losses,
malformations of the eye, kidney, and axial skeleton, and rib variations at 1,000 mg/kg/day (8 times the human NHC
exposure at the RHD) and decreased foetal body weights and delayed ossification at ≥500 mg/kg/day (2.9 times the
human NHC exposure at the RHD). There were no developmental toxicities at ≤250 mg/kg/day (0.8 times the human NHC
exposure at the RHD). Maternal toxicities included decreased food consumption and body weight losses, resulting in the
early sacrifice of individual animals at 1,000 mg/kg/day, and decreased body weight gain at 500 mg/kg/day.
There are no available human data on the use of molnupiravir in pregnant individuals to evaluate the risk of major birth
defects, miscarriage or adverse maternal or fetal outcomes.
Safety & Tolerability – Preclinical Data
Conclusion:
• Not be used in paediatric patients and during pregnancy
• If administered to a nursing mother, stop the breastfeeding during 5 days of therapy 4 days after therapy

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Safety & Tolerability – Clinical trial data
• In MOVe-OUT study, 30.4% (216/710) of those receiving molnupiravir and 33.0%
(231/701) of those receiving placebo reported drug-related adverse events.
• The frequently reported adverse events (occurring in ≥1% of participants in either
group) were diarrhea (1.7% vs. 2.1%), nausea (1.4% vs. 0.7%), and dizziness (1.0%
vs. 0.7%).
• To date, safety and laboratory data from MOVe-OUT provide no evidence for
unexpected findings or trends observed at any of the doses studied.

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Positioning - Molnupiravir
Risk Factors
• Age >60 years;
• Active cancer;
• Chronic kidney disease;
• Chronic obstructive pulmonary disease;
• Obesity;
• Serious heart conditions [heart failure, coronary artery
disease, or cardiomyopathies]; or
• Diabetes mellitus.
For the treatment of adult patients with COVID-19, with SpO2 >93% and who have high risk of progression of the disease
including hospitalization or death.
Not to be used in
• Pregnancy
• Lactation
• Pediatric patients
Precautions
 Females of childbearing potential should use a reliable method of contraception correctly and consistently, as
applicable, for the duration of treatment and for 4 days after the last dose of molnupiravir.
 Males of reproductive potential who are sexually active with females of child bearing potential should use a reliable
method of contraception correctly and consistently during treatment and for at least 3 months after the last dose
Is Effective against
Covid-19 patients with RT-PCR confirmed
(Omicron/Delta)

Molnupiravir: Conclusion
• Molnupiravir is an oral antiviral with broad spectrum activity.
• Molnupiravir is now licensed (EUA) for use in the United Kingdom, United States, Japan, Denmark and Philippines
including India for SARSCoV-2 infected persons 18 years of age or older who have one risk factor for progression to
severe illness.
• It has good in-vitro activity against SARS CoV-2
• Phase 3 has shown:
• Relative risk reduction of hospitalization or death by 30%.
• Greater improvement in WHO Clinical Progression Scale
• Consistent efficacy among SARS-CoV-2 variants (delta, gamma, and mu)
• It is generally safe and well-tolerated. Most common adverse events reported were nausea, diarrhoea and headache.
• It should not be given to pregnant and lactating women and to pediatric patients
• Appears to be promising antiviral drug for the treatment of non-hospitalized adult patients (≥ 18 years if age) with mild
COVID 19

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