Table 1.

Main characteristics of molnupiravir and nirmatrelvir–ritonavir as of Dec 31, 2021

		Molnupiravir	Nirmatrelvir–ritonavir
Mechanism of action8, 9, 10, 11		Molnupiravir is a prodrug that is metabolised to the ribonucleoside analogue NHC; NHC distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP); NHC-TP incorporation into viral RNA by the viral RNA polymerase results in an accumulation of errors (error catastrophe) in the viral genome leading to inhibition of replication	Nirmatrelvir (PF-07321332) is a 3C-like protease inhibitor, preventing viral replication; ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir
Indication
	EU9 and UK8	Adult patients (aged ≥18 years) with mild-to-moderate COVID-19 diagnosis (not requiring supplemental oxygen) with a duration of symptoms of ≤5 days and positive SARS-CoV-2 diagnostic test; patients at increased risk of progressing to severe COVID-19; patients having at least one risk factor for developing severe COVID-19; not recommended during pregnancy or breastfeeding with a 4-day post-treatment window for use of effective contraception and interruption of breastfeeding	..
	UK11	..	Adults who do not require supplemental oxygen and who are at increased risk of progression to severe COVID-19
	USA10, 12	Adult patients (aged ≥18 years), with mild-to-moderate COVID-19 diagnosis with a duration of symptoms of ≤5 days, positive SARS-CoV-2 diagnostic test, and for whom alternative COVID-19 treatment options are not accessible or clinically appropriate; patients should be at high risk for progressing to severe COVID-19, including hospitalisation or death; according to animal studies, molnupiravir might cause fetal harm during pregnancy; is not recommended for use in pregnancy	Adult and adolescent patients (aged ≥12 years, weighing ≥40 kgs), with mild-to-moderate COVID-19 diagnosis with a duration of symptoms of ≤5 days, with positive SARS-CoV-2 diagnostic test; patients should be at high risk for progressing to severe COVID-19, including hospitalisation or death
Contraindications10, 11, 12		None identified so far	Co-administration with medicines highly dependent on CYP3A for clearance or with potent CYP3A inducers; patients with severe hepatic or severe renal impairment; patients with a history of clinically significant hypersensitivity to the active substances
Adverse events8, 9, 10, 11, 12		Common: dizziness, headache, diarrhoea, nausea; uncommon: vomiting, rash, urticaria	With incidence of ≥1% and a difference in number of participants affected of five or more versus the comparator group were dysgeusia, diarrhoea, hypertension, myalgia; common adverse reactions: dysgeusia, diarrhoea, vomiting
Phase 2 and 3 clinical trial data—primary outcome measure		MOVe-OUT (NCT04575597):12, 13 at enrolment, patients should be unvaccinated and should present at least one of the following risk factors for disease progression: aged ≥60 years, diabetes, obesity (body-mass index>30 kg/m2), chronic kidney disease, serious heart condition, chronic obstructive pulmonary disease, or active cancer; all-cause hospitalisation or death until day 29 (primary endpoint): molnupiravir, 6·8% (48/709); placebo, 9·7% (68/699); absolute risk reduction: 3·0 (95% CI 0·1–5·9) percentage points; relative risk reduction: 30%; number of deaths by day 29: molnupiravir, 0·14% (1/709); placebo, 1·3% (9/699); patients with baseline positive antibodies (recent infection): molnupiravir, 19·1% (137/678); placebo, 20·5% (147/666); total, 19·8% (284/1346); recruiting sites in Africa, Asia, Europe, North America, and South America	EPIC-HR (NCT04960202):10 all-cause hospitalisation or death through day 28 (primary endpoint): nirmatrelvir–ritonavir, 0·8% (8/1039); placebo, 6·3% (66/1046); absolute risk reduction: 5·6 (95% CI 4·0–7·2) percentage points; relative risk reduction: 88%; number of deaths by day 28: nirmatrelvir–ritonavir, 0% (0/1039); placebo, 1·1% (12/1046); having received or expecting to receive any dose of a SARS-CoV-2 vaccine before the day 34 visit was an exclusion criterion; recruiting sites in Africa, Asia, Europe, Latin America, and the USA
Number of patients needed to treat to prevent one hospitalisation or death		35 (95% CI 17–1000)	19 (95% CI 14–25)
Posology8, 9, 10, 11, 12		800 mg every 12 h for 5 days; oral route	300 mg (nirmatrelvir) + 100 mg (ritonavir) every 12 h for 5 days; oral route
Price and manufacturing		US$700 in the USA,14 $750 in Japan,15 per treatment course; estimated cost-based generic price: $17·74;16 Merck signed a license agreement with The Medicines Patent Pool to facilitate affordable access of the product in 105 low-income and middle-income countries;17 although in this agreement 100% of south Asian and sub-Saharan African populations are covered, only 5% of European and central Asian populations and 18% of Latin American and Caribbean populations are covered;18 Merck manufacturing capacity: 10 million courses by the end of 2021;19 the manufacturing capacity of licensee companies must also be taken into account; 13 Indian companies will roll out molnupiravir at a price of Rs2000–3000 ($26·9–40·4) per treatment course20	$530 (USA)21 per treatment course; Pfizer signed a license agreement with The Medicines Patent Pool to facilitate affordable access of the product in 105 low-income and middle-income countries,22 although some countries (eg, Brazil, Iraq, Kazakhstan, Lebanon, Peru) are excluded;23 Pfizer manufacturing capacity: 180 000 treatment courses by the end of 2021, and 120 million by the end of 2022;24 the manufacturing capacity of licensee companies must also be taken into account
Countries where it is authorised		Temporary authorisation granted in India,25 Israel,26 Japan,27 the UK,8 and the USA12	Temporary authorisation granted in Israel,28 South Korea,29 the UK,11 and the USA10

NHC=N-hydroxycytidine. NHC-TP=N-hydroxycytidine triphosphate.