ArticlePDF AvailableLiterature Review

Molnupiravir in COVID-19: A systematic review of literature

Authors:
  • G.D Hospital and Diabetes Institute, Kolkata, India
  • GD Hospital & Diabetes Institute
  • Fortisc CDOC Hosopital

Abstract and Figures

Background and aims Molnupiravir is a newer oral antiviral drug that has recently been tested in COVID-19. We aim to conduct a systematic review of literature to find out the efficacy and safety of molnupiravir in patients with COVID-19. Methods We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar from inception until October 15, 2021, using MeSH keywords. Ongoing trials of molnupiravir in COVID-19 were additionally searched from the ClinicalTrials.Gov and ctri.nic.in/Clinicaltrials. We retrieved all the available granular details of phase 1 to 3 studies of molnupiravir in COVID-19. Subsequently we reviewed the results narratively. Results Two phase 1 double-blind, randomized, placebo-controlled (DBRPC) studies of molnupiravir showed that 1600 mg daily dose is safe and tolerable, without any serious adverse events up to 5.5 days. One phase 2 DBPRC study found significantly lower time to clearance (RNA negativity) with molnupiravir 800 mg twice daily compared to the placebo (log-rank p value = 0.013) in mild to moderate COVID-19. Interim report of one phase 3 DBRPC study in non-hospitalized COVID-19 found a significant reduction in the risk of hospital admission or death by 50% (p = 0.0012). However, no significant benefit was observed with molnupiravir in the later stage of moderate to severe COVID-19. Conclusion Molnupiravir is first oral antiviral drug to demonstrate a significant benefit in reducing hospitalization or death in mild COVID-19 and could be an important weapon in the battle against SARS-CoV-2. However, its role in moderate to severe COVID-19 is questionable and more studies are needed.
Content may be subject to copyright.
Since January 2020 Elsevier has created a COVID-19 resource centre with
free information in English and Mandarin on the novel coronavirus COVID-
19. The COVID-19 resource centre is hosted on Elsevier Connect, the
company's public news and information website.
Elsevier hereby grants permission to make all its COVID-19-related
research that is available on the COVID-19 resource centre - including this
research content - immediately available in PubMed Central and other
publicly funded repositories, such as the WHO COVID database with rights
for unrestricted research re-use and analyses in any form or by any means
with acknowledgement of the original source. These permissions are
granted for free by Elsevier for as long as the COVID-19 resource centre
remains active.
Review Article
Molnupiravir in COVID-19: A systematic review of literature
Awadhesh Kumar Singh
a
,
*
, Akriti Singh
b
, Ritu Singh
a
, Anoop Misra
c
,
d
,
e
a
G. D Hospital &Diabetes Institute, Kolkata, West Bengal, India
b
Jawaharlal Nehru Medical College &Hospital, Kalyani, West Bengal, India
c
Fortis C-DOC Hospital for Diabetes &Allied Sciences, New Delhi, India
d
National Diabetes, Obesity and Cholesterol Foundation, New Delhi, India
e
Diabetes Foundation (India), New Delhi, India
article info
Article history:
Received 23 October 2021
Received in revised form
25 October 2021
Accepted 27 October 2021
Keywords:
Molnupiravir
EIDD-2801
MK-4482
COVID-19
SARS-CoV-2
abstract
Background and aims: Molnupiravir is a newer oral antiviral drug that has recently been tested in COVID-
19. We aim to conduct a systematic review of literature to nd out the efcacy and safety of molnupiravir
in patients with COVID-19.
Methods: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar
from inception until October 15, 2021, using MeSH keywords. Ongoing trials of molnupiravir in COVID-19
were additionally searched from the ClinicalTrials.Gov and ctri.nic.in/Clinicaltrials. We retrieved all the
available granular details of phase 1 to 3 studies of molnupiravir in COVID-19. Subsequently we reviewed
the results narratively.
Results: Two phase 1 double-blind, randomized, placebo-controlled (DBRPC) studies of molnupiravir
showed that 1600 mg daily dose is safe and tolerable, without any serious adverse events up to 5.5 days.
One phase 2 DBPRC study found signicantly lower time to clearance (RNA negativity) with molnupiravir
800 mg twice daily compared to the placebo (log-rank p value ¼0.013) in mild to moderate COVID-19.
Interim report of one phase 3 DBRPC study in non-hospitalized COVID-19 found a signicant reduction in
the risk of hospital admission or death by 50% (p ¼0.0012). However, no signicant benet was observed
with molnupiravir in the later stage of moderate to severe COVID-19.
Conclusion: Molnupiravir is rst oral antiviral drug to demonstrate a signicant benet in reducing
hospitalization or death in mild COVID-19 and could be an important weapon in the battle against SARS-
CoV-2. However, its role in moderate to severe COVID-19 is questionable and more studies are needed.
©2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction
Coronavirus disease 2019 (COVID-19) caused by severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a
substantial increase in morbidity and mortality worldwide. Even
though adequate vaccines are now available and newer ones are
also under development for the prevention of severe COVID-19,
effective antiviral drugs to combat this disease are currently lack-
ing. While some of the drugs have recently been given an emer-
gency use authorization (EUA) for COVID-19, all of these
pharmaceutical agents have to be administered in hospital settings.
Therefore, the development of a simple oral antiviral agent has
been an elusive goal since the beginning of this pandemic.
Molnupiravir (Emory Institute of Drug Development-2801
[EIDD-2801]/MK-4482) is one upcoming oral drug which seems
promising. This oral agent was developed by Drug Innovation
Ventures at Emory University, later was acquired by Ridgeback
therapeutics in partnership with Merck &Co, USA. In general,
antiviral drugs tested so far usually terminate the elongation of
RNA-chain by targeting the viral polymerases but such antivirals
have not shown a very promising role in treatment of SARS-CoV-2
infections because of exonucleolytic proof-reading activity that can
remove mis-incorporated nucleotides from the nascent RNA. Both
molnupiravir and remdesivir (GS-5734) targets RNA-dependent
RNA-Polymerase (RdRp) enzyme used by the corona virus for
transcription and replication of its viral RNA genome [1,2]. While
remdesivir a nucleoside analog that stalls the RdRp and thus cir-
cumvents proof reading, molnupiravir has a unique mechanism of
action pretty similar to favipiravir. Notably, favipiravir was tried in
*Corresponding author. G. D Hospital &Diabetes Institute, Kolkata, 700013,
India.
E-mail address: drawadheshkumarsingh@gmail.com (A.K. Singh).
Contents lists available at ScienceDirect
Diabetes &Metabolic Syndrome: Clinical Research &Reviews
journal homepage: www.elsevier.com/locate/dsx
https://doi.org/10.1016/j.dsx.2021.102329
1871-4021/©2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
the early part of pandemic without much success. Remdesivir was
granted an EUA by the US Food Drug Administration (FDA), how-
ever in some studies it failed to show the expected efcacy, the
reason as to why WHO did not recommend it. Moreover, it can only
be administered via intravenous route in in-hospital settings which
has its own limitations.
Molnupiravir initially emerged as a possible treatment of
inuenza viruses, encephalitic alphaviruses like Venezuelan,
Eastern and Western equine encephalitic viruses due to its signif-
icant inhibitory effect in cell cultures [3,4]. It appears to work by the
mechanism of error catastrophewhich is essentially based on the
concept that by increasing the rate of mutation in the viral genome
beyond a biologically tolerable threshold it will become lethal to
the virus and lead to its extinction [5,6]. The broad-spectrum
antiviral activity of this drug is attributed to its 2-step mutagen-
esis mechanism. Molnupiravir is an isopropyl ester prodrug, which
is cleaved in plasma by host esterases to an active nucleoside analog
b
-D-N4-hydroxycytidine (NHC) or EIDD-1931 [5]. This active form
of the drug is distributed to various tissues and subsequently
converted to its corresponding 5
0
-triphosphate (NHC triphosphate
or MTP). This then targets the RdRp which is virally encoded and
competitively inhibits the cytidine and uridine triphosphates and
incorporates M instead. The RdRp uses the NHC triphosphate as a
substrate instead of the cytidine and uridine triphosphates and
then incorporates either A or G in the RdRp active centers forming
stable complexes and thus escaping proof reading by the synthesis
of a mutated RNA [7,8]. Kabinger et al. [7] conrmed with structural
studies about the formation of M-G and M-A base pairs in the active
center of RdRp and after cryo-EM density interpretation assumed
that one stable tautomer predominates in each case, that is, amino-
M tautomer forms a base pair with G and the imino-M tautomer
forms a base pair with A and do not impair the RdRp progression
[6]. Thus, the 2-step mutagenesis can be summarized as follows- in
the rst step, RdRp synthesizes negative strand genomic RNA(-
gRNA) by using positive strand genomic RNA(þgRNA) as a tem-
plate. Following this, in the second step, þgRNA or sub genomic
RNA is synthesized using M-containing RNA as template. The M
containing RNA in the -gRNA causes mutation in þgRNA and sub-
genomic RNA subsequently formed resulting in mutagenesis
which is lethal to the virus [5,6]. Fig. 1 illustrates the mechanism of
action (schematic representation) of molnupiravir against SARS-
CoV-2 and its comparison with remdesivir and favipiravir. These
mutations are also produced in the host cell (mammalian DNA)
which raises concerns regarding its interference with vaccination,
and its potential carcinogenic and teratogenic effects which are
theoretically possible with mutagenic drugs [9]. However, it might
be less likely because of its proposed short-term use etwice daily
for 5 days. It is also interesting to note that RNA synthesis in hep-
atitis C polymerase or RNA polymerase of respiratory syncytial vi-
rus is not seen with NHC triphosphate [10].
Earlier, molnupiravir had illustrated in vitro activity in human
airway epithelial cell culture against SARS-CoV-2. Improvement in
pulmonary function and decline in viral titer were noted in mice
infected with SARS-CoV-2 that were administered molnupiravir
[6]. Wahl et al. [11] demonstrated via in vivo studies on human
lung-only mice (LoM) that EIDD 2801 dramatically inhibited the
replication of SARS-CoV-2. Also, the drug demonstrated reduced
viral shedding and inammatory inltrates in nasal lavages and
adequate humoral antiviral response in ferret model of inuenza
[12]. Additionally, molnupiravir demonstrated an inhibitory effect
on the replication of SARS-CoV-2 in Syrian hamster model when it
was commenced 12 h before or after experimental infection [13].
Thus, further trials in humans were conducted for SARS-COV-2
infections. In this systematic review, we aimed to provide clinical
data with molnupiravir through phase 1 to 3 studies conducted in
patients with COVID-19.
2. Methods
A systematic literature search was conducted in the electronic
database of PubMed, MedRxiv and Google Scholar from inception
until October 15, 2021, using MeSH keyword COVID-19,SARS-
CoV-2, AND Molnupiravir,EIDD-2801,MK-4482. Details of
all the studies that reported outcomes with molnupiravir in people
with COVID-19 so far, were retrieved. Cross references related to
this topic were also retrieved. An additional search was made in the
data base of ClinicalTrials.gov and ctri.nic.in/Clinicaltrials for
ongoing study of molnupiravir in COVID-19 in USA and India,
respectively. Data available in grey literature as a top-line or interim
result were also retrieved. Two authors independently checked the
veracity of data. Here, we report the synthesis from the results of
studies conducted with molnupiravir in COVID-19.
3. Results
Overall, 48, 11 and 436 articles were found in the database of
PubMed, MedRxiv, and Google Scholar, respectively. Atotal of 7 and
12 studies on molnupiravir were found on ClinicalTrials.gov and
ctri.nic.in/Clinicaltrials, respectively. After exclusion of repetitions,
review articles, commentaries, perspectives and experimental
studies, we found following human studies that have reported the
results from phase 1 to 3 studies including completed, incomplete,
and several ongoing trials.
3.1. Phase 1 studies
First double-blind, randomized-controlled Phase 1 trial
(NCT04392219) on healthy volunteers (n ¼130) showed that
molnupiravir was well tolerated and there was a dose proportional
pharmacokinetics following administration. After oral administra-
tion, the prodrug molnupiravir is rapidly cleaved to its active form
EIDD-1931 with a median time of maximum observed concentra-
tion of 1e1.75 h. The geometric half-life was found to be nearly 1 h
with an apparent slower elimination phase following high single
dose or multiple doses, however no accumulation was noted after
multiple dosing. No decrease in overall absorption was noted in the
fed state although there was some decrease in the rate of absorp-
tion during fed state. A range of 50e800 mg twice daily dosing for
5.5 days and a single dose up to 1600 mg was found to be safe and
well tolerated. Unlike other nucleoside analogs and natural nucle-
osides that are generally actively secreted by the kidney, very little
EIDD-1931 was detected in urine which might be attributed to the
metabolism of EIDD-1931 to cytidine and uridine. Regarding
formulation, in all parts of the study, capsules of molnupiravir were
used except for single ascending doses where an oral solution was
used for exibility in dose escalation. For tolerability, a greater
proportion of patients in placebo arm had higher adverse events
compared to molnupiravir in both single (43.8% vs. 35.4%, respec-
tively) and multiple ascending doses (50.0% vs. 42.9%, respectively)
arm. While headache was the most frequently reported adverse
event in single ascending doses study (placebo arm had propor-
tionately higher headache compared to molnupiravir [18.8% vs.
12.5%, respectively]), diarrhea was the most frequently reported
adverse event noted in multiple ascending dose study (7.1% each in
placebo and molnupiravir). No clinically signicant abnormality in
either laboratory or vital signs or electrocardiography were seen,
and neither were any serious adverse events noted. Only one
subject discontinued because of mild truncal maculopapular pru-
ritic rash following 800 mg twice daily doses of molnupiravir which
the investigator thought was related to the drug [14].
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
2
Fig. 1. Mechanism of action (schematic representation) of molnupiravir against SARS-CoV-2 (works by inducing mutagenesis in viral RNA) as compared with remdesivir (works by
stalling RdRp in turn causing chain termination of newly formed RNA strand) and favipiravir (works by slowing/stalling RdRp causing chain termination or inducing mutagenesis or
both).
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
3
An open label randomized controlled but a small (n ¼18) phase
Ib/IIa trial- AGILE (NCT04746183) was conducted at the Royal Liv-
erpool and Broadgreen Clinical Research Facility using Bayesian
approach. Adult patients with RT-PCR conrmed SARS-CoV-2
infection within 5 days of symptom onset were included and ran-
domized to either standard of care (SOC, n ¼6) or 300, 600 and
800 mg doses of molnupiravir twice daily for 5 days by oral route
(n ¼4 in each arm). The primary outcome was to study the dose
limiting toxicity (DLT) while secondary outcome included evalua-
tion of safety and clinical progression. The primary outcome of DLT
up to 7-days was modelled on Bayesian dose-toxicity Mozgunov-
model with a priori assumed toxicity risk of 10% in SOC arm. A dose
was judged unsafe or unacceptably toxic if the probability of DLT is
30% or greater over the controls. All (4/4, 100%) patients receiving
300 and 600 mg, 1/4 (25%) patients receiving 800 mg, and 5/6
patients (83%) receiving SOC were found to have mild adverse
events. This nds highest dose of 800 mg twice daily had a 0.9%
probability of having 30% excess toxicity over the controls, and
therefore molnupiravir was considered safe and well tolerated,
with a plasma concentration within the target range [15].
3.2. Phase 2 studies
A double-blind, randomized-controlled, multicentric, phase 2a
trial (MK-4482-006) was conducted (NCT04405570, n ¼202) to
evaluate the safety and tolerability in patients with mild to mod-
erate COVID-19. Twice daily oral doses of 200 mg, 400 mg and
800 mg molnupiravir for 5 days were administered in the test arm
vs. placebo, after the randomization. While time to clearance of
viral RNA in nasopharyngeal swabs (tested by RT-PCR) was the
primary endpoint, secondary outcomes of the trial included eval-
uation of time to infectious viral elimination from nasopharyngeal
swabs and median RNA change from baseline on days 3, 5 and 7.
Assessment of activity, safety and tolerability was made for 28 days
after initiation of the study. Collection of nasopharyngeal swabs
was done on day 1 (baseline) and days 3,5,7,14 and day 28, and
antiviral activity (both quantitative and qualitative) was evaluated
using RT-PCR as well as after viral isolation method using Vero
C1008 cell culture method on days 2 and 5 post inoculation. Time to
clearance (RNA negativity) - the primary outcome - was signi-
cantly reduced in the molnupiravir 800 mg arm twice daily
compared to the placebo (log-rank p value ¼0.013, median: 14
days). Moreover, reduction in time to clearance of viral RNA was
also greater and signicant when compared to placebo (median: 14
days vs. 27 days; p value ¼0.01). It was noted that viral isolation
was signicantly lower in participants receiving 800 mg twice daily
molnupiravir compared to placebo (1.9% vs. 16.5% viral isolation,
respectively; p ¼0.02) on Day 3. On Day 5 no viral isolation was
noted from patients receiving 400 or 800 mg twice daily molnu-
piravir versus 11.1% viral isolation in participants receiving placebo
(p ¼0.03). Proportion of subjects who achieved SARS-CoV-2
negativity by the end of the study was 92.5%, 78.7%, 91.3% for
800 mg, 400 mg, 200 mg twice daily molnupiravir, respectively and
80.3% for placebo. Regarding tolerability, overall, very few, low
grade adverse events were noted in this study and was found to be
lowest in molnupiravir 800 mg twice daily group. Headache,
insomnia and increased levels of alanine aminotransferase (ALT)
were the only adverse events reported by more than 4 participants
and, 5% and 8.1% of molnupiravir and placebo groups, respectively
showed grade 3 level of adverse events. Two (2/140, 1.4%) as
compared to one (1/62, 1.6%) adverse event led to discontinuation
in molnupiravir and placebo groups respectively. No hematological
or dose related trend in clinical chemistry data was found. Treat-
ment was discontinued in 4 patients due to serious adverse events.
This includes one placebo administered patient who had hypoxia,
two patients from 400 mg molnupiravir group who had decreased
oxygen saturation and cerebrovascular accident, and one patient
from 800 mg molnupiravir group who had acute respiratory failure.
One death was reported in a patient from placebo group suffering
from hypoxia due to COVID-19 outside the 28-day time window
[16]. Another double-blind phase 2 trial (NCT04405739, n ¼96)
evaluating The Safety of EIDD-2801 and Its Effect on Viral Shedding
of SARS-CoV-2 (END-COVID Study) is currently under progress [17].
3.3. Phase 3 studies
The phase 3 double-blind, randomized study (MOVe-OUT) that
was planned to assess efcacy and safety of molnupiravir in 1850
non-hospitalized adult (18 years or older) participants with COVID-
19 (NCT04575597, MK-4482-002) has recently been stopped by the
independent data safety monitoring board due to excessive benet
in active treatment arm compared to the placebo. The inclusion
criteria of this study included a conrmed SARS-CoV-2 infection
with sample collection 5 days prior to the day of randomization
having negative serological tests in response to recent or prior
infection, having initial onset of signs/symptoms attributable to
COVID-19 for 5 days prior to the day of randomization and at least
1 of the following sign/symptom attributable to COVID-19 on the
day of randomization - having mild or moderate COVID-19 and
having at least 1 characteristic or underlying medical condition
associated with an increased risk of severe illness (obesity, an age of
over 60 years, diabetes, and heart disease) from COVID-19. Addi-
tionally, males either agreed to abstain from heterosexual inter-
course or to use contraception during the intervention period and
for at least 4 days after the last dose of study intervention. Females
must be having negative pregnancy test or not breastfeeding, and
either agree to abstain from heterosexual intercourse or must agree
to use contraception during the intervention period and for at least
4 days after the last dose of study intervention. Exclusion criteria
included currently hospitalized or expected to need hospitalization
for COVID-19 within 48 h of randomization, on dialysis, or having
reduced estimated glomerular ltration rate (eGFR) <30 mL/min/
1.7 3 m
2
by the Modication of Diet in Renal Disease (MDRD)
equation, having any of the following conditions: human immu-
nodeciency virus (HIV), history of hepatitis B virus (HBV) or
hepatitis C virus (HCV) with cirrhosis, end-stage liver disease, he-
patocellular carcinoma, aspartate aminotransferase (AST) and/or
ALT) >3X upper limit of normal and low platelet count <100,000/
m
L. The primary outcome of this trial included ei) % of participants
who are hospitalized (all cause hospitalization 24 h of acute care)
and/or die (death due to any cause) in a time frame of 29 days, ii) %
of participants with an adverse event (AE) in a time frame up to ~7
months, iii) % of participants who discontinued study intervention
due to an AE in a time frame up to 6 days [18].
The interim analysis (n ¼775) of this phase 3 study
(NCT04575597) showed a signicant reduction in risk of hospital
admission or death by 50% (p ¼0.0012) at day 29. Study found 7.3%
of patients (28/385) on molnupiravir as compared to 14.1% of pa-
tients on placebo (53/377) had either been admitted to hospital or
died, and no death was reported in the molnupiravir group as
compared to 8 deaths in the placebo group on day 29. Moreover,
the efcacy of molnupiravir was unaffected by the SARS-CoV-2
variant (gamma, delta or mu), the time of onset of symptoms and
with the underlying risk factors. The incidence of any adverse
events (35% vs. 40% in molnupiravir vs. placebo arm, respectively)
and drug-related adverse events (12% vs. 11% in molnupiravir vs.
placebo arm, respectively) were found to be similar in both the
molnupiravir and placebo arm. However, fewer people in the
molnupiravir arm discontinued treatment as compared to the
placebo arm (1.3% vs. 3.4%, respectively) [19,20]. Other phase 3
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
4
double-blind, randomized study (MOVe-IN, NCT04575584) that
was planned to assess efcacy and safety of molnupiravir in 304
hospitalized adult (18 years or older) participants with COVID-19
(MK-4482-001) was terminated following an interim analysis of
data that found it is unlikely to demonstrate a clinical benetin
hospitalized patients [21,22]. Nonetheless, a large (n ¼1,332) phase
3, multicentric, randomized, double-blind, placebo-controlled
study (NCT04939428) is currently evaluating the efcacy and safety
of molnupiravir for the prevention of COVID-19 in adults (MOVe-
AHEAD) residing with a person with COVID-19, with a hypothesis
that molnupiravir would be superior to placebo in preventing
laboratory-conrmed COVID-19 infection through day 14 [23].
Meanwhile, few interim result of phase 3 trials conducted with
molnupiravir in mild (upper respiratory tract symptoms and or
fever without shortness of breath or hypoxia) and moderate
(pneumonia with no signs of severe disease but with presence of
clinical feature of dyspnea and or hypoxia, fever, cough including
SpO2 93% [range 90e93%] on room air, respiratory rate 24 per
minute) COVID-19 in Indian patients (age between 18 and 60 years
of age), were announced by the different Indian pharmaceutical
companies recently. Hetero Labs Limited, Hyderabad, India
announced the interim results on July 9, 2021, from their open-
label, randomized, multicenter clinical trial (CTRI/2021/05/
033739) of 741 mild COVID-19 patients in which the efcacy and
safety of molnupiravir 800 mg (4 200 mg) every 12 h (twice daily)
for 5 days plus SOC vs. SOC (control arm) alone within 5 days of
onset of symptoms were evaluated. The interim results from this
study of mild COVID-19 patients (n ¼741) revealed ei) earlier
clinical improvement (2-point decrease in WHO Clinical Progres-
sion Scale) in molnupiravir vs. SOC at day 5 (63.4% vs. 22.3%,
respectively; p <0.0001), day 10 (79.0% vs. 49.5%, respectively;
p<0.0001) and day 14 (81.6% vs. 73.2%, respectively; p ¼0.02), ii)
faster time to clinical improvement in molnupiravir vs. SOC (me-
dian time: 8 days vs. 12 days, respectively; p ¼0.0001), iii) higher
RT-PCR negativity (all p <0.0001) in molnupiravir vs. SOC at day 5
(77.4% vs. 26.1%, respectively), day 10 (94.0% vs. 57.2%, respectively)
and day 14 (97.0% vs. 85.2%, respectively), iv) signicantly fewer
hospital admissions in molnupiravir vs. SOC alone (1.9% vs. 6.2%
respectively; p ¼0.003) over 14 days. No death reported in either
group. Nausea, diarrhea and headache were most common side
effect reported eall with mild severity. No one discontinued from
the trial [24]. Collectively, this interim report from the ongoing
phase 3, open-label, randomized clinical trial from India showed a
signicantly lower hospitalization in molnupiravir recipients
compared to SOC alone arm in people with mild COVID-19 and with
no obvious drug-induced adverse events, although no difference in
death rate was observed between the two arms.
Another interim report from the phase 3 trial of molnupiravir in
mild COVID-19 patients from India was announced by Optimus
pharma (CTRI/2021/06/033992) on July 21, 2021. The rst interim
result on 353 patients has shown a higher RT-PCR negativity in
molnupiravir arm vs. SOC alone (78.3% vs. 48.4%, respectively;
p¼not reported) on day 5 [25]. In a personal communication,
Optimus Pharma noted a signicant increase in RT-PCR negativity
with molnupiravir vs. SOC alone at day 5 (77.4% vs. 51.5%,
p<0.0001) and day 10 (99.5% vs. 69.5% respectively; p <0.0001),
although no difference noted at day 14 (99.5% vs. 98.5%; p ¼0.62) in
a second interim analysis of 403 patients. Faster clinical improve-
ment (at least one-point improvement from baseline on WHO
ordinal scale) was also observed in molnupiravir vs. SOC at both day
5 (79.0% vs. 51.3%, respectively; p <0.0001) and day 10 (97.8% vs.
82.3% respectively; p <0.0001). However, no difference was noted
at day 14. There has been 1 hospitalization in molnupiravir arm
compared to 3 in SOC, and 6.5% subjects in molnupiravir arm had
adverse events compared to 8.9% in SOC group. Serious adverse
events were reported in 1 subject in molnupiravir arm comparedto
3 in SOC. Collectively, this interim report from an ongoing open-
label, randomized clinical trial from India also found a faster clin-
ical and viral recovery (RT-PCR negativity) with molnupiravir
compared to SOC alone, without any obvious drug-related adverse
events in mild COVID-19. Several other ongoing studies of molnu-
piravir in mild COVID-19 by other Indian pharmaceutical com-
panies 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 (CTRI/2021/06/
034130); Dr. Reddys Lab, Hyderabad, India (CTRI/2021/06/033938)
and Stride Pharma, Bengaluru, India (CTRI/2021/06/034015) are yet
to report their results. Notably, all these trials of molnupiravir in
mild COVID-19 have been originally planned for a total of
1218e1220 patients, as per the discretion of Drug Controller Gen-
eral of India (DCGI) [26].
Trials of molnupiravir in people with moderateCOVID-19
(SpO2 93% [range 90e93%] on room air) that was conducted by
MSN Lab, India (CTRI/2021/05/033864) and Aurobindo Pharma,
India (CTRI/2021/08/035424) has been stopped, arguably due to no
benet[27]. Argument of futile results in these trials have been
hypothesized to inclusion of sicker patients in Indian studies which
would have been otherwise deemed severerather than moder-
ateCOVID-19, since an SpO2 of <93% is considered severe
COVID-19 in US based trials, as per the USFDA denition. However,
studies of Hetero Labs, India (CTRI/2021/05/033736) and BDR
Pharmaceuticals, India (CTRI/2021/06/034220) is still undergoing
with molnupiravir vs. SOC in people with moderate COVID-19.
Table 1 summarizes published, unpublished (interim results),
stopped and ongoing studies with molnupiravir in COVID-19.
4. Discussion
Summarily, molnupiravir is a broad spectrum, directly acting
oral antiviral agent that acts on the RdRp enzyme and by competing
with uridine and cytidine triphosphate substrates nally leads to
incorporation of A and G forming stable complexes in the active
RdRp center leading to mutagenesis, escaping proof reading. Mol-
nupiravir aims to stop viral replication by its 2-step mutagenesis
model and error catastrophemechanisms. In other words, it
mutates the virus to kill itself. Molnupiravir is required to be given
only for a short term (5 days) via oral route, easier to be adminis-
tered in outpatient department and hence has better compliance.
The advantage for a drug like molnupiravir is that it can be pro-
duced at a larger scale and doesn't require cold transportation, nor
it requires in-hospital settings for its administration, unlike other
EUA approved drugs for COVID-19. Available data so far suggests
that molnupiravir has been well tolerated and found to be safe
without any major adverse events in phase 1, 2 and 3 clinical trials,
at least in short-terms. Given in mild to moderate (SpO2 >93% on
room air as per US-based denition) COVID-19 within 5 days of
symptoms, it can drastically decrease the disease progression by
reducing hospitalization and/or death as observed in the interim
report of MOVe-OUT study. These emerging ndings 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.
However, it is still premature to predict whether it would really
work as Thor's hammer eas the name suggests egiven the min-
imal evidence available at the moment, and majorly the futility of
molnupiravir in moderate (SpO2 90e93% on room air) to severe
COVID-19. Importantly, since absolute risks were reduced to 7.3%
from 14.1% in placebo arm, number needed to treat (NNT) to pre-
vent one hospitalization or death is 14.7. This means on an average;
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
5
Table 1
A. Published and unpublished (interim results), B. Stopped, and C. Ongoing studies with molnupiravir in COVID-19.
Study, First author CTRL/CTRI identier,
Eponyms
N; Types of study Severity of COVID-19 Arms (n) Results Side effects Strength/Limitations
A. Published and unpublished interim results
Phase 1 studies
Painter et al.
14
NCT04392219 130; DBRPC NA i) SD 50e1600 mg
MOLNU or PBO (64)
ii) MD 50e800 mg BID
MOLNU or PBO (56)
iii) 200 mg MOLNU
(10) eFood effect
A range from 50 to
800 mg twice daily
dosing for 5.5 days and
a single dose up to
1600 mg was found to
be safe and well
tolerated
A greater proportion of
patients in placebo arm
had higher adverse
events compared to
molnupiravir in both
single (43.8% vs. 35.4%,
respectively) and
multiple ascending
doses (50.0% vs. 42.9%,
respectively) arm.
While headache was
the most frequently
reported adverse event
in single ascending
doses study (placebo
arm had
proportionately higher
headache compared to
molnupiravir [18.8% vs.
12.5%, respectively]),
diarrhea was the most
frequently reported
adverse event noted in
multiple ascending
dose study (7.1% each in
placebo and
molnupiravir).
Peer reviewed,
Published
Khoo et al.
15
NCT04746183, AGILE 18; R, OL Mild or moderate i) 300 mg MOLNU BID
(4)
ii) 600 mg MOLNU BID
(4)
iii) 800 mg MOLNU BID
(4)
iv) SOC (6)
Primary outcome e
dose-limiting toxicity
All (4/4, 100%) patients
receiving 300 and
600 mg, 1/4 (25%)
patients receiving
800 mg, and 5/6
patients (83%) receiving
SOC were found to have
mild adverse events.
This nds highest dose
of 800 mg twice daily
had a 0.9% probability
of having 30% excess
toxicity over the
controls, and therefore
molnupiravir was safe
and well tolerated with
a plasma concentration
within the target range.
Peer reviewed,
Published
Phase 2 studies
Fischer et al.
16
NCT04405570 202; DBRPC Mild or moderate i) 300 mg MOLNU BID
(23)
ii) 400 mg MOLNU BID
(62)
iii) 800 mg MOLNU BID
(55)
iv) PBO (62)
Time to clearance (RNA
negativity) - the
primary outcome - was
signicantly reduced in
the molnupiravir
800 mg arm twice daily
compared to the
Very few adverse
events were noted in
this study and was
found to be lowest in
molnupiravir 800 mg
twice daily group.
Headache, insomnia
Peer reviewed,
Published
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
6
placebo (log-rank p
value ¼0.013, median:
14 days). Moreover,
reduction in time to
clearance of viral RNA
was also greater and
signicant when
compared to placebo
(median: 14 days vs. 27
days; p value ¼0.01).
and increased levels of
alanine
aminotransferase (ALT)
were the only adverse
events reported by
more than 4
participants and 5% and
8.1% of molnupiravir
and placebo groups,
respectively showed
grade 3 level of adverse
events. Two (2/140,
1.4%) as compared to
one (1/62, 1.6%)
adverse event led to
discontinuation in
molnupiravir and
placebo groups
respectively
Phase 3 studies
eNCT04575597, MOVe-
OUT
18-20
775; DBRPC Mild to moderate with
1 risk factor
i) MOLNU (385
a
)
ii) PBO (377
a
)
Study found 7.3% of
patients (28/385) on
molnupiravir as
compared to 14.1% of
patients on placebo
(53/377) had either
been admitted to
hospital or died
suggesting a signicant
reduction in the risk of
hospital admission or
death by 50%
(p ¼0.0012) at day 29.
No death was reported
in the molnupiravir
group as compared to 8
deaths in the placebo
group on day 29.
The incidence of any
adverse events (35% vs.
40% in molnupiravir vs.
placebo arm,
respectively) and drug-
related adverse events
(12% vs. 11% in
molnupiravir vs.
placebo arm,
respectively) were
found to be similar in
both molnupiravir and
placebo arm. Fewer
people in the
molnupiravir arm
discontinued treatment
as compared to the
placebo arm (1.3% vs.
3.4%, respectively).
Limitations: Interim
report, not peer
reviewed and
unpublished.
eCTRI/2021/05/033739
24
741; OL, R, PC Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
i) Earlier clinical
improvement (2-point
decrease in WHO
Clinical Progression
Scale) in molnupiravir
vs. SOC at day 5 (63.4%
vs. 22.3%, respectively;
p<0.0001), day 10
(79.0% vs 49.5%,
respectively;
p<0.0001) and day 14
(81.6% vs. 73.2%,
respectively; p ¼0.02).
ii) Faster time to clinical
improvement in
molnupiravir vs. SOC
(median time 8 days vs.
12 days, respectively;
p¼0.0001).
iii) Higher RT-PCR
Nausea, diarrhea and
headache were most
common side effect
reported eall with
mild severity. No one
discontinued from the
trial.
Limitations: Interim
report, not peer
reviewed and
unpublished. Trial still
undergoing.
(continued on next page)
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
7
Table 1 (continued )
Study, First author CTRL/CTRI identier,
Eponyms
N; Types of study Severity of COVID-19 Arms (n) Results Side effects Strength/Limitations
negativity (all
p<0.0001) in
molnupiravir vs. SOC at
day 5 (77.4% vs. 26.1%,
respectively), day 10
(94.0% vs. 57.2%,
respectively) and day
14 (97.0% vs. 85.2%,
respectively).
iv) Signicantly fewer
hospital admissions in
molnupiravir vs. SOC
alone (1.9% vs. 6.2%
respectively; p ¼0.003)
over 14 days.
No death reported in
either group.
eCTRI/2021/06/033992
25
353- FIA, OL, R, OC
403- SIA; OL, R, PC
Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
i) The rst interim
results on 353 patients
have shown higher RT-
PCR negativity in
molnupiravir arm vs.
SOC alone (78.3% vs.
48.4%, respectively;
p¼not reported) on
day 5.
ii) Second interim
results from 403
patients showed e
a. signicant increase in
RT-PCR negativity with
molnupiravir vs. SOC
alone at day 5 (77.4% vs.
51.5%, p <0.0001) and
day 10 (99.5% vs. 69.5%
respectively;
p<0.0001), although
no difference noted at
day 14 (99.5% vs. 98.5%;
p¼0.62).
b. Faster clinical
improvement (at least
one-point
improvement from
baseline on WHO
ordinal scale) was also
observed in
molnupiravir vs. SOC at
both day 5 (79.0% vs.
51.3%, respectively;
p<0.0001) and day 10
(97.8% vs. 82.3%
respectively;
p<0.0001). However,
no difference was noted
at day 14.
6.5% subjects in
molnupiravir arm had
adverse events
compared to 8.9% in
SOC group. Serious
adverse events were
reported in 1 subject in
molnupiravir arm
compared to 3 in SOC.
Limitations: Interim
report, not peer
reviewed and
unpublished. Trial still
undergoing.
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
8
c. There have been 1
hospitalization in
molnupiravir arm
compared to 3 in SOC.
B. Stopped phase 3 studies due to futility
eNCT04575584, MOVe-
IN
21, 22
304; DBRPC Severe, Hospitalized NR Stopped due to futility eLimitations: Interim
report, not peer review
and unpublished.
eCTRI/2021/05/033864
27
NA; OL, R, PC Moderate NR Stopped due to futility eLimitations: Interim
report, not peer review
and unpublished.
eCTRI/2021/08/035424
27
100; OL, R, PC Moderate NR Stopped due to futility eLimitations: Interim
report, not peer review
and unpublished.
B. Ongoing phase 2 and 3 studies
eNCT04405739, END-
COVID
17
96; DBRPC Mild to moderate but
hospitalized
i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessing virological
clearance.
Being assessed e
eNCT04939428, MOVe-
AHEAD
23
1332; DBRPC Non-COVID i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessing prevention
with molnupiravir as a
post-exposure
prophylaxis.
Being assessed First prevention trial
eCTRI/2021/05/033736
26
1282, OL, R, PC Moderate i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessing proportion of
clinical improvement at
day 14 as a primary
outcome. Secondary
outcome assessment
includes proportion of
clinical improvement at
day 28, mortality rate at
day 28; viral negativity
at day 10, day 14 and
day 28.
Being assessed e
eCTRI/2021/06/034220
26
1282, OL, R, PC Moderate i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessing proportion of
clinical improvement at
day 14 as a primary
outcome. Secondary
outcome assessment
includes proportion
and time to clinical
improvement at day 28,
mortality rate at day
28; viral load at day 10,
day 15 and day 28.
Being assessed e
eCTRI/2021/07/034588
26
1220; OL, R, PC Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessment of rate of
hospitalization
#
from
randomization up to
day 14 as a primary
outcome. Secondary
outcome assessment
includes rate of
hospitalization up to
day 28; and proportion
of clinical improvement
at day 10, day 14 and
day 28.
Being assessed e
eCTRI/2021/05/033693
26
1218; OL, R, PC Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessment of rate of
hospitalization
#
from
randomization up to
Being assessed e
(continued on next page)
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
9
Table 1 (continued )
Study, First author CTRL/CTRI identier,
Eponyms
N; Types of study Severity of COVID-19 Arms (n) Results Side effects Strength/Limitations
day 14 as a primary
outcome. Secondary
outcome assessment
includes rate of
hospitalization up to
day 28; mortality rate
at day 14; RT-PCR
negativity at day 10 and
day 15; time to clinical
improvement at day
14; and proportion of
clinical improvement at
day 10, day 14 and day
28.
eCTRI/2021/05/033904
26
1218; OL, R, PC Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessment of rate of
hospitalization
#
from
randomization up to
day 14 as a primary
outcome. Secondary
outcome assessment
includes rate of
hospitalization up to
day 28; proportion of
clinical improvement at
day 10, day 14 and day
28; time to clinical
improvement up to day
14; and change in viral
load up to EOT.
Being assessed e
eCTRI/2021/06/034130
26
1218; OL, R, PC Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessment of rate of
hospitalization
b
from
randomization up to
day 14 as a primary
outcome. Secondary
outcome assessment
includes rate of
hospitalization up to
day 28; proportion of
clinical improvement at
day 10, day 14 and day
28; time to clinical
improvement up to day
14; and mortality rate
at day 14 and day 28.
Being assessed e
eCTRI/2021/06/033938
26
1218; OL, R, PC Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessment of rate of
hospitalization
#
from
randomization up to
day 14 as a primary
outcome. Secondary
outcome assessment
includes rate of
hospitalization up to
day 28; proportion of
clinical improvement at
day 10, day 14 and day
28; time to clinical
Being assessed e
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
10
15 patients would have to receive molnupiravir treatment instead
of placebo for one additional patient of not needing hospitalization
or to die. This also suggests that the drug needs to be very safe and
affordable for widespread use. Second, molnupiravir has to be used
too early (5 days from symptom onset) before someone is deemed
ill enough when it won't work. Issue remains with asymptomatic
individuals and how early to start their treatment. Third, we still
lack any study that is evaluating the role of molnupiravir in
breakthrough infections following vaccination especially since
many of the counties will soon have a reasonably good proportion
of vaccinated people. Fourth, further studies need to be done to
establish its interference with available vaccines. From the safety
perspective, theoretically, while its mutagenic potential on one
hand is a boon for reducing the viral RNA, it might turn into a bane
by inducing mutations in the virus further leading to an increased
resistance. At least one study [9] in animal cell cultures found
mutations in cells treated with molnupiravir and recommends to
assess mutagenic potential and potential genotoxic side effects
in vivo, focusing on rapidly dividing cells. Skepticism about safety
still remains given the fact that the participants in the trial had to
maintain abstinence or use contraception for the fear of birth defect
if they conceived. Although this appears to be highly unlikely with
the short-term use of 5 days. Moreover, since the mutations occur
randomly it's difcult for the virus to evolve resistance. Further-
more, Merck has conducted a comprehensive nonclinical program
Big Blue and PIG-a which were designed to provide a robust mea-
sure of a drug or chemical's ability to induce mutations in vivo and
found molnupiravir neither mutagenic nor genotoxic in in vivo
mammalian systems [22]. In any case, USFDA should not have given
permission to conduct human trials had they suspected any ounce
of doubt. Finally, cost effectiveness and accessibility for all is a
major issue that needs to be dealt with and effect of molnupiravir
with other therapies for COVID-19 needs to be examined. The major
limitation of this systematic review is absence of even a single peer-
reviewed published phase 3 study at the moment-precluding any
conclusion. However, jury is still out to call molnupiravir a magic
pill. We would be curiously waiting for the complete results from
the 10 ongoing studies in India (8 studies in mild COVID-19, 2
studies in moderate COVID-19) and much awaited international
prevention trial of molnupiravir - MOVe-AHEAD. The caveat for
Indian studies lies with the fact that all of them are open-label
though randomized.
Funding
No funding.
Authorship
All authors meet the International Committee of Medical Journal
Editors (ICMJE) criteria for authorship and take responsibility for
the integrity of the work. They conrm that this paper will not be
published elsewhere in the same form, in English or in any other
language, including electronically.
Author's contribution
AKS conceptualized, searched the literature; AS and RS wrote
the rst draft; AKS, AS, RS and AM edited the nal draft. All authors
agreed mutually to submit for publication.
Declaration of competing interest
Nothing to declare for all authors.
improvement up to day
14; rate of viral
negativity at day 10,
day 15 and day 28; and
mortality rate at day 14
and day 28.
eCTRI/2021/06/034015
26
1220; OL, R, PC Mild i) MOLNU 800 mg
BID þSOC (NA)
ii) SOC (NA)
Assessment of rate of
hospitalization
#
from
randomization up to
day 14 as a primary
outcome. Secondary
outcome assessment
includes rate of
hospitalization up to
day 28; proportion of
clinical improvement at
day 10, day 14 and day
28; time to clinical
improvement up to day
14; and mortality rate
at day 14 and day 28
Being assessed e
a
Completed the trial.
b
Hospitalization is dened as hospital admission for >24 h with RR 24/minute and SpO2 93% in room air requiring O2 supplementation; DBRPC: Double-blind, randomized, placebo-controlled; OL: Open-label; R:
Randomized; PC; Placebo-controlled; SOC: Standard of care; MOLNU: Molnupiravir; PBO; Placebo; RT-PCR: Reverse transcriptase polymerase chain reaction; NA: Not applicable/available; NR; Not retrievable; BID: Twice daily;
FIA: First interim analysis; SIA: Second interim analysis.
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
11
References
[1] Cannalire R, Cerchia C, Beccari AR, et al. Targeting SARS-CoV-2 proteases and
polymerase for COVID-19 treatment: state of the art and future opportunities.
J Med Chem. DOI: 10.1021/acs.jmedchem.0c01140.
[2] Subissi L, Posthuma CC, Collet A. One severe acute respiratory syndrome
coronavirus protein complex integrates processive RNA polymerase and
exonuclease activities. Proc Natl Acad Sci U S A 2014 Sep 16;111(37):
E3900e9.
[3] Crotty S, Cameron CE, Andino R. RNA virus error catastrophe: direct molecular
test by using ribavirin. Proc Natl Acad Sci USA 2001;98:6895e900.
[4] Agostini ML, et al. Small-molecule antiviral
b
-d-N4-hydroxycytidine inhibits a
proofreading-intact coronavirus with a high genetic barrier to resistance.
J Virol 2019;93:24.
[5] Toots M, Yoon J-J, Hart M, Natchus MG, Painter GR, Plemper RK. Quantitative
efcacy paradigms of the inuenza clinical drug candidate EIDD-2801 in the
ferret model. Transl Res 2020;218:16e28.
[6] Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum
antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and
multiple coronaviruses in mice. Sci Transl Med 2020 Apr 29;12(541):
eabb5883.
[7] Kabinger F, Stiller C, Schmitzov
a J, et al. Mechanism of molnupiravir-induced
SARS-CoV-2 mutagenesis. Nat Struct Mol Biol 2021 Sep;28(9):740e6.
[8] Gordon CJ, Tchesnokov EP, Schinazi RF, G
otte M. Molnupiravir promotes
SARS-CoV-2 mutagenesis via the RNA template. J Biol Chem 2021 Jul;297(1):
100770.
[9] Zhou S, Hill CS, Sarkar S, et al.
b
-d-N4-hydroxycytidine inhibits SARS-CoV-2
through lethal mutagenesis but is also mutagenic to mammalian cells.
J Infect Dis 2021 Aug 2;224(3):415e9.
[10] Yoon JJ, et al. Orally efcacious broad-spectrum ribonucleoside analog in-
hibitor of inuenza and respiratory syncytial viruses. Antimicrob Agents
Chemother 2018;62:e00766.
[11] Wahl A, Gralinski LE, Johnson CE, et al. SARS-CoV-2 infection is effectively
treated and prevented by EIDD-2801. Nature 2021 Mar;591(7850):451e7.
[12] Cox RM, Wolf JD, Plemper RK. Therapeutically administered ribonucleoside
analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat
Microbiol 2021 Jan;6(1):11e8.
[13] Rosenke K, Hansen F, Schwarz B, et al. Orally delivered MK-4482 inhibits
SARS-CoV-2 replication in the Syrian hamster model. Nat Commun 2021;12:
2295.
[14] Painter WP, Holman W, Bush JA, et al. Human safety, tolerability, and phar-
macokinetics of molnupiravir, a novel broad-spectrum oral antiviral agent
with activity against SARS-CoV-2. Antimicrob Agents Chemother 2021 Mar
1;65(5). e02428-20.
[15] Khoo SH, Fitzgerald R, Fletcher T, et al. Optimal dose and safety of molnu-
piravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-esca-
lating, randomized controlled study [Online ahead of print] J Antimicrob
Chemother 2021 Aug 27. https://doi.org/10.1093/jac/dkab318. dkab318.
[16] Fischer W, Eron JJ, Holman W, et al. Molnupiravir, an oral antiviral treatment
for COVID-19. Preprint medRxiv 2021 Jun 17. https://doi.org/10.1101/
2021.06.17.21258639. 2021.06.17.21258639.
[17] The safety of molnupiravir (EIDD-2801) and its effect on viral shedding of
SARS-CoV-2 (END-COVID) - full text view - ClinicalTrials.gov (Last accessed on
October 20, 2021).
[18] Efcacy and safety of molnupiravir (MK-4482) in non-hospitalized adult
participants with COVID-19 (MK-4482-002) - full text view - Clinical-
Trials.gov. (Last accessed on October 20, 2021).
[19] Mahase E. Covid-19: molnupiravir reduces risk of hospital admission or death
by 50% in patients at risk, MSD reports. BMJ 2021 Oct 4;375:n2422.
[20] Merck and Ridgeback's investigational oral antiviral molnupiravir reduced the
risk of hospitalization or death by approximately 50 percent compared to
placebo for patients with mild or moderate covid-19 in positive interim
analysis of phase 3 study. Oct 2021. https://www.merck.com/news/
merckand-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-
the-riskof-hospitalization-or-death-by-approximately-50-percent-compared-
toplacebo-for-patients-with-mild-or-moderat. [Accessed 20 October 2021].
[21] Efcacy and safety of molnupiravir (MK-4482) in hospitalized adult partici-
pants with COVID-19 (MK-4482-001) - full text view - ClinicalTrials.gov. (Last
accessed on October 20, 2021).
[22] Merck and Ridgeback biotherapeutics provide update on progress of clinical
development program for molnupiravir, an investigational oral therapeutic
for the treatment of mild-to-moderate COVID-19 - Merck.com. (Last accessed
on October 20, 2021).
[23] Study of MK-4482 for prevention of coronavirus disease 2019 (COVID-19) in
adults (MK-4482-013) - full text view - ClinicalTrials.gov (Last accessed on
October 20, 2021).
[24] Press_Release_Molnupiravir_Interim_Clinical_Results_Final_090721.pdf (het-
eroworld.com). (Last accessed on October 20, 2021).
[25] Optimus announces interim clinical results from phase III clinical trials of
molnupiravir conducted in India eThePrint. (Last accessed on October 20,
2021).
[26] Search result, clinical trials registry - India (CTRI). CTRI (Last accessed on
October 20, 2021).
[27] Two Indian drugmakers to end trials of generic Merck pill for moderate
COVID-19 | Reuters. (Last accessed on October 20, 2021).
A.K. Singh, A. Singh, R. Singh et al. Diabetes &Metabolic Syndrome: Clinical Research &Reviews 15 (2021) 102329
12
... AIFA, the Italian Medicines Agency, approved the prescription of molnupiravir [1,2] on 30/12/2021. Molnupiravir is a prodrug metabolized to the ribonucleoside analog N-hydroxycytidine (NHC). ...
Article
Full-text available
Background The SARS-CoV-2 pandemic has prompted clinicians to develop an early and effective treatment of viral infections. To date, vaccines, monoclonal antibodies, and antivirals are the cornerstone of therapy for SARS-CoV-2. AIFA approved the prescription of molnupiravir on 30/12/2021. Molnupiravir is a prodrug that causes the accumulation of errors in the viral genome.Methods We prescribed molnupiravir to a total of 74 patients in a range between 26 and 96 years old and followed-up them for 30 days. 10 patients affected by idiopathic pulmonary fibrosis (IPF) were treated.ResultsThe follow-up showed that all of the treated patients presented a regression of symptoms. No patients were hospitalized and/or showed sequelae after the infection by SARS-CoV-2, even though the examined population was older and with more co-morbidities than other patients treated with different antivirals.Conclusion Molnupiravir is safe and well-tolerated by patients with high-risk of progression to severe COVID. No patients were hospitalized or showed sequelae, including all patients affected by IPF.
... Several control drugs, such as EIDD-2801 and PF-07321332, are used for the treatment of SARS-CoV-2, although they do not have definite scientific evidence. The drug EIDD-2801 or Molnupiravir is predicted to inhibit the replication process of SARS-CoV-2 during the budding phase, PF-07321332 or nirmatrelvir/ritonavir can interfere with the activity of viral protease enzymes (Ahmad et al., 2021;Singh et al., 2021). However, several studies revealed that the activity of EIDD-2801 and PF-07321332 decreased in efficacy due to several factors such as viral mutations that trigger unstrategic interaction positions and unstable bonds (Kabinger et al., 2021). ...
Article
Full-text available
COVID-19 was caused by the spread and transmission of SARS-CoV-2 at the end of 2019 until now. The problem comes when antiviral drugs have not yet been found and patients infected with SARS-CoV-2 can trigger a cytokine storm condition due to the effects of viral replication. Indonesia has various kinds of medicinal plants, such as Sonchus arvensis L., which are used as medicinal plants. Aims: To analyze the activity of the inhibitor as SARS-CoV-2 antiviral agents from n-hexane fractions of S. arvensis leaves. Methods: The sample was collected from GC-MS analysis, PubChem, and Protein Databank database, then drug-likeness identification using Lipinski Rule of Five server and bioactive prediction of bioactive compounds as inhibitor activity was conducted by Molinspiration server. Furthermore, the docking simulation was performed using PyRx 0.9.9 software to determine the binding activity, molecular interaction by Discovery Studio software to identify position and interaction type, 3D molecular visualization by PyMol 2.5. software, and dynamic by CABS-flex 2.0 server to predict interaction stability. Results: α-Amyrin and β-amyrin from n-hexane fractions of S. arvensis leaves had activity as SARS-CoV-2 inhibitors through interactions on helicase, RdRp, Mpro, and RBD-Spike, both compounds had more negative binding affinity than control drug and can produce stable chemical bond interactions in the ligand-protein complexes. However, the results were merely computational, so they must be validated through an in vivo and in vitro research approach. Conclusions: Sonchus arvensis L. leaves were predicted to have SARS-CoV-2 antiviral through inhibitor activity by α-amyrin and β-amyrin.
... A third dose is not able to improve the humoral response in patients previously NR to two doses. Although these results should be confirmed in larger series, other preventive strategies such as tixagevimab/cilgavimab [30] or early administration of antiviral regimes [31,32] should therefore be considered in patients with CVID, CID, or TI. In contrast, based on the variability of their humoral response, unPAD patients should be evaluated with caution and other variables such as lymphocyte subpopulations counts should be taken into account. ...
Article
Full-text available
Background: Prophylactic vaccination has proven to be the most effective strategy to fight the COVID-19 pandemic. Methods: This was a prospective observational cohort study involving 30 predominantly antibody deficiency disorders (ADD)-afflicted adult patients on immunoglobulin replacement therapy vaccinated with three doses of the mRNA-1273 COVID-19 vaccine, and 10 healthy controls. Anti-RBD IgG antibodies were determined in plasma samples collected just before the first dose of mRNA-based COVID-19 vaccine and on weeks 4, 8, 24, and 28 following the first vaccination. Patients were categorized based on the levels of anti-RBD antibodies determined on w8 as non-, low-, and responders. Chi-square and Kruskal-Wallis tests were used to see if any variables correlated with humoral response levels. Any adverse effects of the mRNA-based vaccine were also noted. Results: The COVID-19 vaccine was safe and well-tolerated. The humoral response elicited at w8 after vaccination depended on the type of ADD, the type of immunoglobulin deficiency, the presence of granulomatous lymphocytic interstitial lung disease, recent use of immunosuppressive drugs, and the switched memory B cells counts. The third vaccine dose boosted humoral response in previous responders to second dose but seldom in non-responders. Conclusions: The humoral response of patients with predominant ADD depends mostly on the type of immunodeficiency and on the frequency of B and T cell populations.
... The product requires no special terms for storage, and peroral administration mode enables to apply it on off-ward basis. Molnupiravir successfully passed all 3 phases of clinical trials revealing no significant side effects [17]. The drug dose sufficient and safe for the patients infected with coronavirus was established experimentally by S. H. Khoo et al. [18]. ...
Article
The ongoing COVID-19 pandemic accompanied by the emergence of new successive pathogenic variants makes problematic the prospects of the approach based on application of exclusively prophylactic vaccines to combat SARSCoV-2. This reason motivated the urgent need in search and development of chemical formulas showing direct antiviral action. The present mini-review provides data on chemical and enzymatic methods of producing molnupiravir regarded so far as one of the most effective pharmaceuticals for treatment of COVID-19. In conclusion of the literature survey it is suggested to administer lipid-containing analog instead of molnupiravir in COVID-19 therapeutic protocols. In this respect the authors reported the successful synthesis catalyzed by bacterial phospholipase D of 5′-dimyristoyl derivative of N4-hydroxycytidine – the compound allegedly more efficient than molnupiravir in inhibiting SARS-CoV-2 replication.
... Across all methods and data sources, we see that the early estimates for the CFR are much larger than the later estimates. This can partially be explained by the relative lack of available testing early in the pandemic, but it could also be the case that many of the frailest care home residents died during the first wave and that treatments have improved over time [28,29]. We also notice that during the summer months of 2020, when prevalence of the disease in England was particularly low, that the estimates of the CFR decreased, but the uncertainty increased significantly in both the forward and backward methods, because of the small numbers. ...
Article
Full-text available
The COVID-19 pandemic has had high mortality rates in the elderly and frail worldwide, particularly in care homes. This is driven by the difficulty of isolating care homes from the wider community, the large population sizes within care facilities (relative to typical households), and the age/frailty of the residents. To quantify the mortality risk posed by disease, the case fatality risk (CFR) is an important tool. This quantifies the proportion of cases that result in death. Throughout the pandemic, CFR amongst care home residents in England has been monitored closely. To estimate CFR, we apply both novel and existing methods to data on deaths in care homes, collected by Public Health England and the Care Quality Commission. We compare these different methods, evaluating their relative strengths and weaknesses. Using these methods, we estimate temporal trends in the instantaneous CFR (at both daily and weekly resolutions) and the overall CFR across the whole of England, and dis-aggregated at regional level. We also investigate how the CFR varies based on age and on the type of care required, dis-aggregating by whether care homes include nursing staff and by age of residents. This work has contributed to the summary of measures used for monitoring the UK epidemic.
... With current immunization methods focusing mainly on adults, the pediatric population remains vulnerable to COVID-19 infection [9]. Though the unrelenting efforts of scientists have provided the first oral antiviral (Molnupiravir), which has been approved and shows a significant reduction in hospitalization or mortality in mild COVID-19 cases with good safety and tolerability profile in adults, there is little to insufficient data on pediatric cases [10,11]. Hence, it is critical to be prepared for new waves in terms of pediatric protection and infection control. ...
Article
Full-text available
Background Several individual studies from specific countries have reported rising numbers of pediatric COVID-19 cases with inconsistent reports on the clinical symptoms including respiratory and gastrointestinal symptoms as well as diverse reports on the mean age and household exposure in children. The epidemiological characteristics of COVID-19 in children are not fully understood, hence, comprehensive meta-analyses are needed to provide a better understanding of these characteristics. Methods This review was conducted in Medline, Scopus, Cochrane library, Embase, Web of Science, and published reports on COVID-19 in children. Data were extracted by two independent researchers and a third researcher resolved disputes. STATA software and the random-effect model were used in the synthesis of our data. For each model, the heterogeneity between studies was estimated using the Q Cochrane test. Heterogeneity and publication bias were calculated using the I² statistic and Egger’s/Begg’s tests. Results The qualitative systematic review was performed on 32 articles. Furthermore, the meta-analysis estimated an overall rate of involvement at 12% (95% CI: 9–15%) among children, with an I² of 98.36%. The proportion of household exposure was calculated to be 50.99% (95% CI: 20.80%–80.80%) and the proportion of admitted cases was calculated to be 45% (95% CI: 24%–67%). Additionally, the prevalence of cough, fatigue, fever and dyspnea was calculated to be 25% (95% CI: 0.16–0.36), 9% (95% CI: 0.03–0.18), 33% (95% CI: 0.21–0.47) and 9% (95% CI: 0.04–0.15), respectively. It is estimated that 4% (95% CI: 1–8%) of cases required intensive care unit admission. Conclusions The pediatric clinical picture of COVID-19 is not simply a classic respiratory infection, but unusual presentations have been reported. Given the high incidence of household transmission and atypical clinical presentation in children, we strongly recommend their inclusion in research and population-based preventive measures like vaccination as well as clinical trials to ensure efficacy, safety, and tolerability in this age group.
Article
Full-text available
The COVID-19 pandemic caused by SARS-CoV-2 has placed severe constraints on healthcare systems around the globe. The SARS-CoV-2 virus has caused upheaval in the healthcare and economic sectors worldwide. On the 20th of May 2020, the World Health Organisation declared COVID-19 a global pandemic due to the unprecedented number of cases reported around the globe. As of the 4th of November 2022, there were 637,117,429 coronavirus cases reported globally by Worldometer stats, with 6,602,572 related deaths. In South Africa, there were approximately 4,029,496 coronavirus cases and 102,311 associated deaths. As such, there is a need for efficacious therapeutic regimes. There has been a paucity of knowledge encompassing the use of effective and specific antiviral drug therapies for treating COVID-19 since the outbreak. In this review, we provide valuable insights into the repurposing of current drugs for COVID-19. Drug repurposing provides a suitable option for the discovery of efficacious drugs for COVID-19, thereby decreasing the costs and turnaround times of drug development strategies. This review provides an overview of ten drugs, including antimalarial, antiparasitic, anti-inflammatory, nucleoside analogue, monoclonal-antibody drugs, that were repurposed for the potential treatment of COVID-19.
Article
Background: COVID-19 incidence is high in patients with cancer. The fatality rate was high for the Delta variant, necessitating infection prevention by vaccination. This study evaluated the safety of a SARS-CoV-2 vaccine in patients with advanced lung cancer receiving anticancer therapy. Methods: We prospectively enrolled patients receiving anticancer drugs for advanced lung cancer and planning SARS-CoV-2 vaccination. Early side effects within 7 days of vaccination were evaluated using patient-reported outcome (PRO) surveys. Chi-square test and multivariate logistic regression analyses were used. Results: Post-vaccination PROs were collected from 406 patients (252 were males). The mean age was 72 years. Treatment at the time of initial vaccination included chemotherapy, immune checkpoint inhibitors (ICI), a combination of chemotherapy and ICI, targeted therapy including tyrosine kinase inhibitors, and others in 115, 93, 45, 147, and six cases, respectively. The vaccines administered were BNT162b2 and mRNA273 in 361 and three cases, respectively and unknown in 42 cases. A total of 16.1% of patients developed fever (38°C) after the second mRNA vaccination (95% confidence interval: 12.6%-20.1%). This rate is comparable to data previously reported in 120 patients and slightly higher than that of healthy participants of the BNT162b2 study. Patients receiving treatment with cytotoxic anticancer agents were more likely to have high fever. Multivariate analysis showed no correlation between fever frequency and patient background. No serious initial adverse events due to vaccination were observed. Conclusions: Anti-SARS-CoV-2 mRNA vaccination is safe; however, post-vaccination fever is more common in patients undergoing lung cancer treatment than in healthy individuals.
Article
Molnupiravir is an antiviral drug with a broad spectrum of activity against RNA viruses. The safety of molnupiravir in clinical trials with COVID-19 was analyzed. In a Phase I study (NCT04392219), molnupiravir was well tolerated at doses of 50 to 800 mg twice daily for 5.5 days and at single doses up to 1600 mg. Common adverse events were headache (18.8 % placebo versus 12.5 % molnupiravir) with a single dose and diarrhea (7.1 % in both groups) with multiple doses. In a phase II study in the molnupiravir 800 mg group, adverse events were noted in the form of headache, insomnia, and an increase in the level of alanine aminotransferase. Serious adverse events leading to hospitalization occurred in the placebo group (1.6 %) due to hypoxia, in the molnupiravir 400 mg group in two (3.2 %) participants due to cerebrovascular accident and in one (1.8 %) of a participant at a dose of 800 mg due to acute respiratory failure. In the phase III MOVe-OUT study (NCT04575597), adverse events were reported in 30.4 % in the molnupiravir group and 33.0 % in the placebo group. In the phase III study CTRI/2021/06/033992, adverse events occurred in 6.5 % in the molnupiravir group versus 8.9 % in the placebo group. The results of the conducted studies demonstrate the safety, tolerability of molnupiravir in phase I, II and III clinical trials and the antiviral efficacy of the drug against COVID-19. Use of molnupiravir for mild to moderate (SpO 2 > 93 %) COVID-19 within 5 days of symptom onset significantly reduces disease progression by reducing hospitalizations and/or deaths.
Article
Full-text available
Purpose The most recent challenge being faced by the healthcare system during the worldwide COVID-19 pandemic is increase in the incidence rate of coinfection or superinfection; one of the most fatal being mucormycosis. This study aimed to estimate the risk factors, symptoms and signs, treatment outcome and prognosis of COVID-19-associated mucormycosis (CAM) patients. Methods This is an interventional study of 35 patients diagnosed and managed as CAM at a tertiary care centre in New Delhi, India. Results The mean age of patients was 40.45 ± 6 years with a male preponderance. CAM did not affect healthy individuals; the major risk factors included diabetes in 65.7% and injudicious steroid use in 51.4% patients. Orbital/facial edema was the most common presenting symptom (25.7%) as well as sign (28.57%). 68.5% patients were stage 3 (involvement of orbit) at presentation; 33.3% showed medial wall involvement. Treatment included intravenous Amphotericin and oral Posaconazole in all patients, paranasal sinus (PNS) debridement in 94.2%, orbital exenteration was done in 8 patients. Adjuvant retrobulbar Amphotericin B injection was administered in 12 patients with radiological resolution seen in 50% after 1 cycle. In patients with Stage 4 disease who underwent exenteration along with PNS debridement, survival rate was 100% at 30 days, and disease reduction occurred in 87.5% patients (P < 0.01). Overall, 68.5% responded to therapy, 8.5% showed progression and mortality rate was 22.85%, at a mean follow up period of 59.5 days. Conclusion A multidisciplinary and aggressive approach is essential in the management of CAM patients.
Article
Full-text available
Objectives AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.
Article
Full-text available
Molnupiravir is an orally available antiviral drug candidate currently in phase III trials for the treatment of patients with COVID-19. Molnupiravir increases the frequency of viral RNA mutations and impairs SARS-CoV-2 replication in animal models and in humans. Here, we establish the molecular mechanisms underlying molnupiravir-induced RNA mutagenesis by the viral RNA-dependent RNA polymerase (RdRp). Biochemical assays show that the RdRp uses the active form of molnupiravir, β- d - N ⁴ -hydroxycytidine (NHC) triphosphate, as a substrate instead of cytidine triphosphate or uridine triphosphate. When the RdRp uses the resulting RNA as a template, NHC directs incorporation of either G or A, leading to mutated RNA products. Structural analysis of RdRp–RNA complexes that contain mutagenesis products shows that NHC can form stable base pairs with either G or A in the RdRp active center, explaining how the polymerase escapes proofreading and synthesizes mutated RNA. This two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir.
Article
Full-text available
The RNA-dependent RNA polymerase (RdRp) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target in current drug development efforts for the treatment of coronavirus disease 2019 (COVID-19). Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue β-D-N⁴-hydroxycytidine (NHC). Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses. These increases in mutation frequencies can be linked to increases in antiviral effects; however, biochemical data of molnupiravir-induced mutagenesis have not been reported. Here we studied the effects of the active compound NHC 5’-triphosphate (NHC-TP) against the purified SARS-CoV-2 RdRp complex. The efficiency of incorporation of natural nucleotides over the efficiency of incorporation of NHC-TP into model RNA substrates followed the order GTP (12,841) > ATP (424) > UTP (171) > CTP (30), indicating that NHC-TP competes predominantly with CTP for incorporation. No significant inhibition of RNA synthesis was noted as a result of the incorporated monophosphate (NHC-MP) in the RNA primer strand. When embedded in the template strand, NHC-MP supported formation of both NHC:G and NHC:A base pairs with similar efficiencies. The extension of the NHC:G product was modestly inhibited, but higher nucleotide concentrations could overcome this blockage. In contrast, the NHC:A base pair led to the observed G to A (G:NHC:A) or C to U (C:G:NHC:A:U) mutations. Together, these biochemical data support a mechanism of action of molnupiravir that is primarily based on RNA mutagenesis mediated via the template strand.
Article
Full-text available
The COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients. While vaccines protecting against SARS-CoV-2 infection are approved, currently, there are no drugs suitable for high-risk exposure use against SARS-CoV-2. Here, Rosenke et al. provide evidence that orally delivered MK-4482, a nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model.
Article
Full-text available
Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses. Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics. EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). 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. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure. Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.
Article
Full-text available
All known recently emerged human coronaviruses probably originated in bats1. Here we used a single experimental platform based on human lung-only mice (LoM) to demonstrate efficient in vivo replication of all recently emerged human coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) and two highly relevant endogenous pre-pandemic SARS-like bat coronaviruses. Virus replication in this model occurs in bona fide human lung tissue and does not require any type of adaptation of the virus or the host. Our results indicate that bats harbour endogenous coronaviruses capable of direct transmission into humans. Further detailed analysis of pandemic SARS-CoV-2 in vivo infection of LoM human lung tissue showed predominant infection of human lung epithelial cells, including type II pneumocytes present in alveoli and ciliated airway cells. Acute SARS-CoV-2 infection was highly cytopathic and induced a robust and sustained type I interferon and inflammatory cytokine/chemokine response. Finally, we evaluated a therapeutic and pre-exposure prophylaxis strategy for coronavirus infection. Our results show that therapeutic and prophylactic administration of EIDD-2801, an oral broad spectrum antiviral currently in phase II-III clinical trials, dramatically inhibited SARS-CoV-2 replication in vivo and thus has significant potential for the prevention and treatment of COVID-19.
Article
Full-text available
The newly emerged coronavirus, called SARS-CoV-2, is the causing pathogen of pandemic COVID-19. The identification of drugs to treat COVID-19 and other coronavirus diseases is an urgent global need, thus different strategies targeting either virus or host cell are still under investigation. Direct-acting agents, targeting protease and polymerase functionalities, represent a milestone in antiviral therapy. The 3C-like (or Main) protease (3CLpro) and the nsp12 RNA-dependent RNA-polymerase (RdRp) are the best characterized SARS-CoV-2 targets and show the highest degree of conservation across coronaviruses fostering the identification of broad-spectrum inhibitors. Coronaviruses also possess a papain-like protease, another essential enzyme, still poorly characterized and not equally conserved, limiting the identification of broad-spectrum agents. Herein, we provide an exhaustive comparative analysis of SARS-CoV-2 proteases and RdRp with respect to other coronavirus homologues. Moreover, we highlight the most promising inhibitors of these proteins reported so far, including the possible strategies for their further development.
Preprint
Background: Easily distributed oral antivirals are urgently needed to treat coronavirus disease-2019 (COVID-19), prevent progression to severe illness, and block transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the results of a Phase 2a trial evaluating the safety, tolerability, and antiviral efficacy of molnupiravir in the treatment of COVID-19 (ClinicalTrials.gov NCT04405570). Methods: Eligible participants included outpatients with confirmed SARS-CoV-2 infection and symptom onset within 7 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 5 days. Antiviral activity was assessed as time to undetectable levels of viral RNA by reverse transcriptase polymerase chain reaction and time to elimination of infectious virus isolation from nasopharyngeal swabs. Results: Among 202 treated participants, virus isolation was significantly lower in participants receiving 800 mg molnupiravir (1.9%) versus placebo (16.7%) at Day 3 (p = 0.02). At Day 5, virus was not isolated from any participants receiving 400 or 800 mg molnupiravir, versus 11.1% of those receiving placebo (p = 0.03). Time to viral RNA clearance was decreased and a greater 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. Conclusions: 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.
Article
Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in the genomes of RNA viruses during viral replication. β-D-N 4-hydroxycytidine (NHC, the initial metabolite of molnupiravir) is more than 100-fold more active than ribavirin or favipiravir against SARS-CoV-2, with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate that highly active mutagenic ribonucleosides may hold risk for the host.