









































                                                                                                                         2021, Vol. 1 (S4) 20-21 
 https://doi.org/10.47488/dhrp.v1iS4.29 

  
 

http://dhrproceedings.org 20 © DHR Health Institute for Research and Development 
 

 

EDITORIAL 

Will Molnupiravir be the First Oral Treatment for High-Risk Non-
Hospitalized Patients with Mild-Moderate COVID-19? 

 
The first case of SARS-CoV-2 infection in United 
States was confirmed on January 19, 2020, in a man 
who had returned home to Snohomish County, 
Washington on January 15, 2020, after traveling to 
Wuhan, China. Since the outbreak of this pandemic, 
significant progress has been made in the 
development of vaccines that are used in preventing 
SARS-CoV-2 infection.  To date, over 392 million 
doses of the three vaccines approved under the 
Emergency Use Authorization (EUA) have been 
administered in the United States (1). Given the 
safety and efficacy of Pfizer/BioNTech mRNA-
based vaccine and after rigorous scientific review of 
available data, U.S. Food and Drug Administration 
(FDA) has fully approved this vaccine which is now 
marketed under the brand name Comirnaty for use 
in people 16 years of age or older (2). 

With well over 21 months into this pandemic, we 
still do not have any treatment that has received full 
FDA approval for COVID-19. Numerous agents 
have been approved under EUA for the treatment of 
SARS-CoV-2 infection in high-risk patients and 
several clinical trials are currently underway to 
discover the elusive drug for this purpose. The only 
agents currently approved for outpatient use under 
EUA for the treatment of mild-moderate SARS-
CoV-2 infection are the three monoclonal antibody 
cocktails that require intravenous infusion thus 
limiting their utility on a widespread basis (3).  

An ideal drug for the treatment of COVID-19 
would be an oral medication that could be 
administered out-of-hospitals to patients with 
mild-moderate disease. The full genome of SARS-
CoV-2 has been identified and researchers have also 
used advanced microscopy techniques to map the 
3D structure of the virus proteins in detail (4). 
Together, this information has propelled the search 
for new drugs to treat SARS-CoV-2 infection that 
specifically target its structure and functions. In a 
recent non-peer reviewed article, Fischer, et.al., 

have claimed that Molnupiravir – an experimental 
anti-viral agent when administered orally in patients 
with mild to moderated SARS-CoV-2 infection 
reduced the risk of hospitalization or death by about 
50% as compared to the placebo (5). These 
observations prompted a recent news release by 
Merck (who developed Molnupiravir in partnership 
with Ridgeback Biotherapeutics) indicating that 
they will be submitting an investigational new drug 
application to the FDA seeking EUA for oral 
treatment of patients with mild-moderate COVID-
19 (6).   

Molnupiravir was originally developed by Drug 
Innovations at Emory University to treat influenza 
(7). It is a pro-drug that is metabolized into a 
ribonucleoside (RNA) analog that resembles 
cytidine – a critical component of RNA.  
Molnupiravir’s anti-viral activity is exerted by a 
process known as lethal mutagenesis or viral 
error catastrophe. Essentially, during replication, 
the viral RNA incorporates Molnupiravir which 
leads to downstream mutations resulting in 
catastrophic errors that adversely impact the 
survival of the virus.  

The non-peer reviewed unpublished interim data 
that Merck is planning to use to obtain an EUA 
emanates from interim analysis of a Phase 3 trial 
(MOVe-OUT) which was a randomized, controlled, 
double-blinded assessment of Molnupiravir versus 
placebo in non-hospitalized adults with mild to 
moderate COVID-19 with symptom onset within 5 
days prior to their randomization. It is important to 
note that the eligible trial participants had ≥1 risk 
factor (such as obesity, diabetes, old age, etc.) that 
are associated with poor COVID-19 outcomes. The 
primary outcome of this trial was to determine the 
efficacy of Molnupiravir by evaluating the 
percentage of participants who are hospitalized 
and/or who have died through 29 days post-
randomization. 



DHRP, 2021, Vol. 1 (S4) 20-21  Editorial 

  
 

http://dhrproceedings.org 21 © DHR Health Institute for Research and Development 
    
 

The key observations of an interim analysis of this 
Phase 3 (MOVe-OUT) study were: 

• Molnupiravir reduced the patient’s risk of 
COVID-19 hospitalization or death by 
approximately 50%: 

o Only 28 (7.3%) patients who 
received Molnupiravir were 
hospitalized, versus 53 (14.1%) 
patients who were administered 
placebo 

o As compared to eight (8) patients in 
the placebo arm, no patients who 
received Molnupiravir died through 
29 days post-randomization 

• Molnupiravir was consistently effective 
against Delta, Gamma, and Mu SARS-CoV-
2 variants 

• Adverse events occurred in 35% and 40% of 
patients treated with Molnupiravir versus 
placebo, respectively, however, trial 
discontinuation due to adverse event was 
lower (1.3%) in the treatment group as 
compared to the placebo group (3.4%) 

With the human death toll in the US due to COVID-
19 now outstripping that during the 1918 Influenza 
pandemic, the quest to discover an oral drug that is 
approved by the FDA to treat patients with mild-
moderate SARS-CoV-2 infection has achieved the 
revered status of the Holy Grail in the field of 
medicine and public health. Interim data analysis 
suggests that Molnupiravir has the potential to be a 
“drug of interest” as an oral agent to treat patients 
with mild-moderate COVID-19. While this is 
indeed very encouraging, submission/review of 
data by the FDA and other regulatory agencies 
along with publication of long-term follow-up of 
ideally a larger cohort of patients in peer-reviewed 
journal is quintessential to unequivocally establish 
the efficacy of Molnupiravir in the oral treatment of 
non-hospitalized high-risk patients with mild-
moderate SARS-CoV-2 infection. 

References  

1. COVID-19 dashboard. John Hopkins University of Medicine. 
2021. https://coronavirus.jhu.edu/map.html  (Accessed October 
02, 2021; 21:48 p.m. CST)  

2. FDA approves first COVID-19 vaccine. 2021. 
https://www.fda.gov/news-events/press-announcements/fda-
approves-first-covid-19-vaccine  

3. Available COVID-19 treatment option. 2021. 
https://combatcovid.hhs.gov/i-have-covid-19-now/available-
covid-19-treatment-options   

4. Nazario-Toole AE, Xia H, Gibbons TF. Whole-genome 
Sequencing of SARS-CoV-2: Using Phylogeny and Structural 
Modeling to Contextualize Local Viral Evolution [published 
online ahead of print, 2021 Feb 20]. Mil Med. 2021; usab031. 
doi:10.1093/milmed/usab031 

5. Fischer W, Eron JJ, Holman W, Cohen MS, Fang L, Szewczyk 
LJ, Sheahan TP, Baric R, Mollan KR, Wolfe CR, Duke ER, 
Azizad MM, Borroto-Esoda K, Wohl DA, Loftis AJ, Alabanza 
P, Lipansky F, Painter WP. Molnupiravir, an Oral Antiviral 
Treatment for COVID-19. medRxiv [Preprint]. 2021 Jun 
17:2021.06.17.21258639. doi: 10.1101/2021.06.17.21258639. 
PMID: 34159342; PMCID: PMC8219109.  

6. 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 01, 2021. 
https://www.merck.com/news/merck-and-ridgebacks-
investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-
hospitalization-or-death-by-approximately-50-percent-
compared-to-placebo-for-patients-with-mild-or-moderat/   

7. Toots M, Yoon JJ, Cox RM, Hart M, Sticher ZM, Makhsous N, 
Plesker R, Barrena AH, Reddy PG, Mitchell DG, Shean RC, 
Bluemling GR, Kolykhalov AA, Greninger AL, Natchus MG, 
Painter GR, Plemper RK. Characterization of orally efficacious 
influenza drug with high resistance barrier in ferrets and human 
airway epithelia. Sci Transl Med. 2019 Oct 23;11(515): 
eaax5866. doi: 10.1126/scitranslmed. aax5866. PMID: 
31645453; PMCID: PMC6848974 

 

Sohail Rao, MD, MA, DPhil 

Executive Vice President, DHR Health, 5501 S. McColl 
Road, Edinburg, Texas 

President & Chief Executive Officer, DHR Health 
Institute for Research & Development, 5323 S. McColl 
Road, Edinburg, Texas 

Corresponding author email: s.rao@dhr-rgv.com  

Disclosures: None 

ORCID: Sohail Rao: https://orcid.org/0000-0001-5027-
9992 

Manish Singh, MD, FACS 

Chief Executive Officer, DHR Health, 5501 S. McColl 
Road, Edinburg, Texas 

Disclosures: None 

ORCID: Manish Singh: https://orcid.org/0000-0003-
4146-3282  

https://coronavirus.jhu.edu/map.html
https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine
https://www.fda.gov/news-events/press-announcements/fda-approves-first-covid-19-vaccine
https://combatcovid.hhs.gov/i-have-covid-19-now/available-covid-19-treatment-options
https://combatcovid.hhs.gov/i-have-covid-19-now/available-covid-19-treatment-options
https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
https://www.merck.com/news/merck-and-ridgebacks-investigational-oral-antiviral-molnupiravir-reduced-the-risk-of-hospitalization-or-death-by-approximately-50-percent-compared-to-placebo-for-patients-with-mild-or-moderat/
mailto:s.rao@dhr-rgv.com
https://orcid.org/0000-0001-5027-9992
https://orcid.org/0000-0001-5027-9992
https://orcid.org/0000-0003-4146-3282
https://orcid.org/0000-0003-4146-3282

