Coronavirus disease 2019 (COVID-19) pandemic has a catastrophic impact on human health.1 They cause the severe acute respiratory syndrome, leading to a significant increase in morbidity and mortality worldwide.2 In addition to ample vaccine availability for mitigating COVID-19, there is an urgency for an effective, easily compatible antiviral drug. Although antivirals like Ramdesivir and Favipiravir was tried in the early pandemic, yet it failed to exhibit the expected potency.2,3 Basics of Molnupiravir: It is an isopropyl ester prodrug initially developed by Emory inventory. Later the same was acquired by Merck and Ridgeback partnership.4 So far, the antivirals terminated the elongation of RNA-chain by targeting the viral polymerase, which was not a promising treatment of SARS-CoV-2 infections. They also had a limitation in their administration. Whereas molnupiravir, the so-called magic pill, is an exceptional drug with a unique error catastrophic mechanism that advances in increasing the rate of mutation in the viral genome, outweighing the

1. Molnupiravir - A Magic Pill for COVID-19 Pandemic
Zainabath Mahnoora* and Joyceline Dsouza*
Coronavirus disease 2019 (COVID-19) pandemic has a catastrophic impact on human
health.1 They cause the severe acute respiratory syndrome, leading to a significant
increase in morbidity and mortality worldwide.
2
In addition to ample vaccine
availability for mitigating COVID-19, there is an urgency for an effective, easily
compatible antiviral drug. Although antivirals like Ramdesivir and Favipiravir was
tried in the early pandemic, yet it failed to exhibit the expected potency.2,3
Basics of Molnupiravir:
It is an isopropyl ester prodrug initially developed by Emory inventory. Later the
same was acquired by Merck and Ridgeback partnership.4 So far, the antivirals
terminated the elongation of RNA-chain by targeting the viral polymerase, which was
not a promising treatment of SARS-CoV-2 infections. They also had a limitation in
their administration. Whereas molnupiravir, the so-called magic pill, is an exceptional
drug with a unique error catastrophic mechanism that advances in increasing the rate
of mutation in the viral genome, outweighing the tolerable biological threshold
leading to lethality and, finally the viral extinction.2
The drug has broad-spectrum antiviral activity involving a 2-step mutagenic
mechanism2. Initially, the ester prodrug is rapidly and extensively cleaved into the
plasma by host esterase to an active ribonucleoside analog b-D-N4-hydroxycytidine
(NHC; EIDD- 1931).
2,3
The active ribonucleoside analog form of the drug is distributed
to various tissues and converted to its corresponding NHC triphosphate or MTP.
Subsequently, they target the RdRp, which is virally encoded, inhibits the cytidine and
uridine triphosphates, and incorporates M instead. They use this NHC triphosphate
as a substrate instead of the cytidine and uridine triphosphates and then incorporate
either A or G in the RdRp active centers forming stable analog complexes and thus
leading the synthesis to a mutated RNA. Hence, the formation of the M-G and M-A base
pair does not impair the RdRp progression. Consequently, the 2-step mutagenesis can
be outlined as follows, +gRNA or subgenomic RNA is synthesized using M-containing
RNA as a template. The M containing RNA in the -gRNA causes a mutation in +gRNA
and sub-genomic RNA, subsequently resulting in the formation of mutagenesis, which
is lethal to the virus1,2.
Details of Clinical Trials:
Analyzing the articles, an in-vivo study was done on ferrets to examine the efficacy of
therapeutically administered oral molnupiravir against SARS-CoV-2 infection and
virus transmission to uninfected contact animals. Ferret models were used because

2. they resembled the human population. The study showed that the dose of 15 mg/kg
twice a day reduces the SARS-CoV-2 load in the upper respiratory tract and
completely suppresses spread to untreated contact animals. This study identified the
oral molnupiravir as a promising antiviral remedy to break SARS-CoV-2 community
transmission chains1. Administration of 800mg of molnupiravir among 202
participants showed that the drug is highly effective at reducing nasopharyngeal
SARS-CoV-2 infectious virus and viral RNA
3
.
Phase 1:
It is a double-blind, randomized controlled trial on healthy volunteers of 130
participants. They were administered with a dose range from 50 to 800 mg twice
daily for 5.5 days. The maximum observed concentration reaching the peak value was
at 1-1.75 h, and the half-life was found to be nearly one hr. with an apparent slower
elimination. The most commonly observed ADR was diarrhea and is most frequently
reported in multiple-dose studies. With a dose of 800mg twice daily, a participant had
a mild truncal maculopapular pruritic rash. The maximum tolerated dose by the
subject in a day is 1600mg. The primary outcome was Dose Limiting Toxicity (DLT),
while the secondary outcome included evaluation of safety and clinical progression.
2,6
Phase 2:
A double-blind, randomized-controlled, multicentric trial was conducted to evaluate
the safety and tolerability in patients with mild to moderate COVID-19. Molnupiravir
of 200mg, 400mg, and 800mg was administered to the test and placebo arm twice
daily for five days. The primary outcome is clearance of viral RNA in nasopharyngeal
swabs. The same was observed with 800mg BID of molnupiravir. The trial's
secondary outcome was evaluating time to infectious viral elimination from
nasopharyngeal swabs. Four of the participants were observed with ADR's such as
headache, insomnia, and increased alanine aminotransferase (ALT) levels. Only one
of the participants with 400 mg molnupiravir had decreased oxygen saturation and
cerebrovascular accident, and one patient from 800 mg molnupiravir had acute
respiratory failure.
2,5
Phase 3:
It is a double-blind, randomized study that was planned to assess the efficacy and
safety of molnupiravir in 1850 of non-hospitalized adult participants with COVID- 19.
Theinclusion criteria of thisstudy were confirmed cases of SARS-CoV-2 infection with
the sample collected 3 five days before the day of randomization with at least one sign
of the onset of initial symptoms of COVID-19. And they had at least one characteristic
that can increase the severity of illness, such as obesity, diabetes, heart disease, and

3. age above 60years. Exclusion criteria were currently hospitalized or expected to need
hospitalization for COVID- 19 within 48hours of randomization, on dialysis, or having
reduced estimated glomerular filtration rate, liver cirrhosis, hepatocellular
carcinoma, HIV, or hepatitis. The interim analysis of this phase 3 study showed a
significant reduction in hospital admission or death risk by 50%. Moreover, the
efficacy of molnupiravir was unaffected by the SARS-CoV-2 variant (gamma, delta, or
mu). Meanwhile, a few interim results of phase 3 trials conducted with molnupiravir
in mild and moderate COVID-19 in Indian patients conducted in Hetero Labs Limited,
Hyderabad, India are i) Earlier clinical improvement, ii) faster time to clinical
improvement in molnupiravir iii) higher RT-PCR negativity. iv) significantly fewer
hospital admissions. Collectively, this interim report tells about a faster clinical and
viral recovery. Several other ongoing studies of molnupiravir in mild COVID-19
patients was also done by other Indian pharmaceutical companies such as Aurobindo
pharma, Telangana, India (CTRI/2021/07/ 034588); NATCO pharma, Hyderabad,
India (CTRI/2021/05/ 033693); MSN Laboratories, Hyderabad, India
(CTRI/2021/05/ 033904); BDR Pharmaceuticals, Mumbai, India.2,5
Conclusion:
Molnupiravir mutates the virus to kill itself; since the mutations occur randomly, it's
difficult for the virus to evolve resistance. The drug required has to be given only for
a short term (5 days) via the oral route, easier to administer, and better compliance.
The advantage of a drug like molnupiravir is that it can be produced at a larger scale.
It doesn't require cold transportation, nor it requires in-hospital settings for its
administration, unlike other approved drugs for COVID-19.1,6 Data available so far
suggests that molnupiravir has been well-tolerated and found safe without any major
adverse events in phase 1, 2, and 3 clinical trials, at least in short-terms. Given to mild
and moderate (SpO2 >93% on room air as per US-based definition) COVID-19
patients within five days of symptoms, it can drastically decrease the disease
progression by reducing hospitalization and/or death as observed in the interim
report of the study. These emerging findings may hint that molnupiravir may prove
to be a global game-changer in the battle against SARS-CoV-2. As an oral antiviral
drug, it would be an incredible asset.
2,3
References:
1. Fischer WA, Eron JJ, Holman W, et al. Molnupiravir, an Oral Antiviral Treatment
for COVID-19. medRxiv. 2021;2021.06.17.21258639.
2. Singh AK, Singh A, Singh R, et al. Molnupiravir in COVID-19: A systematic
review of literature. Diabetes & Metabolic Syndrome: Clinical Research &
Reviews. 2021:15(6):102329.

4. 3. Khoo SH, Fitzgerald R, Fletcher T, Ewings S, Jaki T, Lyon R, Downs N, Walker L,
Tansley-Hancock O, Greenhalf W, Woods C. Optimal dose and safety of
molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-
escalating, randomized controlled study. Journal of Antimicrobial
Chemotherapy. 2021;76(12):3286-95.
4. Mahase E. Covid-19: Molnupiravir reduces risk of hospital admission or death
by 50% in patients at risk, MSD reports. BMJ. 2021;375:n2422.
5. Lee CC, Hsieh CC, Ko WC. Molnupiravir—A Novel Oral Anti-SARS-CoV-2 Agent.
Antibiotics. 2021;10(11):1294.
6. Painter GR, Natchus MG, Cohen O, et al. Developing a Direct Acting, Orally
Available Antiviral Agent in a Pandemic: The Evolution of Molnupiravir as a
Potential Treatment for COVID-19. Curr Opin Virol.2021;50:17-22.
*M.Pharm Student, Department of Pharmacy Practice, NGSM Institute of Pharmaceutical
Sciences, Nitte (Deemed to be University), Deralakatte, Mangaluru, Karnataka- 575018
Pharmacy Practice Communicator 4