Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Merck Sharp & Dohme (UK) Limited, 120 Moorgate, London, EC2M 6UR, United Kingdom
Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals
ATC code: not yet assigned.
Molnupiravir is a prodrug that is metabolised to the ribonucleoside analogue N-hydroxycytidine (NHC) which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP acts by a mechanism known as viral error catastrophe. NHC-TP incorporation into viral RNA by the viral RNA polymerase, results in an accumulation of errors in the viral genome leading to inhibition of replication.
NHC was active in cell culture assays against SARS-CoV-2 with 50% effective concentrations (EC50) ranging between 0.67 to 2.66 µM in A-549 cells and 0.32 to 2.03 µM in Vero E6 cells. NHC had similar activity against SARS-CoV-2 variants B.1.1.7 (Alpha), B.1351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) with EC50 values of 1.59, 1.77 and 1.32 and 1.68 µM, respectively. No impact was observed on the in vitro antiviral activity of NHC against SARS-CoV-2 when NHC was tested in combination with abacavir, emtricitabine, hydroxychloroquine, lamivudine, nelfinavir, remdesivir, ribavirin, sofosbuvir, or tenofovir.
The relationship between NHC and intracellular NHC-TP with antiviral efficacy has not been evaluated clinically.
No amino acid substitutions in SARS-CoV-2 associated with resistance to NHC have been identified in Phase 2 clinical trials evaluating molnupiravir for the treatment of COVID-19. Studies to evaluate selection of resistance to NHC with SARS-CoV-2 in cell culture have not been completed.
Clinical data are based on an interim analysis of data from 775 randomised subjects in the Phase 3 MOVe-OUT trial. MOVe-OUT was a randomised, placebo-controlled, double-blind clinical trial studying molnupiravir for the treatment of non-hospitalised patients with mild to moderate COVID-19 who were at risk for progressing to severe COVID-19 and/or hospitalisation. Eligible subjects were 18 years of age and older and had one or more pre-defined risk factors for disease progression: 60 years of age or older, diabetes, obesity (BMI >30), chronic kidney disease, serious heart conditions, chronic obstructive pulmonary disease, or active cancer. The study included symptomatic subjects not vaccinated against SARS-CoV-2 and who had laboratory confirmed SARS-CoV-2 infection and symptom onset within 5 days of enrolment. Subjects were randomised 1:1 to receive 800 mg of Lagevrio or placebo orally twice daily for 5 days.
At baseline, in all randomised subjects, the median age was 44 years (range: 18 to 88 years); 14% of subjects were 60 years of age or older and 3% were over 75 years of age; 52% of subjects were male; 52% were White, 6% Black or African American, 2% Asian; 58% were Hispanic or Latino. Forty-nine percent of subjects received Lagevrio or placebo within 3 days of COVID-19 symptom onset. The most common risk factors were obesity (77%), 60 years of age or older (14%), and diabetes (14%). Overall, baseline demographic and disease characteristics were well balanced between the treatment arms.
Table 2 provides the results of the primary endpoint (the percentage of subjects who were hospitalised or died through Day 29 due to any cause). Treatment with Lagevrio resulted in a 6.8 percentage point reduction in the risk of hospitalisation or death (approximately 50% relative risk reduction). All 8 subjects who died through Day 29 were in the placebo group and were hospitalised prior to their death.
Table 2. Interim Efficacy Results in Non-Hospitalised Adults with COVID-19:
| Lagevrio (N=385) n (%) | Placebo (N=377) n (%) | Risk difference* (95% CI) | p-value | |
|---|---|---|---|---|
| All-cause hospitalisation or death through Day 29† | 28 (7.3%) | 53 (14.1%) | -6.8 (-11.3, -2.4) | 0.0012 |
| Hospitalisation | 28 (7.3%) | 52 (13.8%) | ||
| Death | 0 (0%) | 8 (2.1%) | ||
| Unknown‡ | 0 (0%) | 1 (0.3%) |
* Risk difference of molnupiravir-placebo based on Miettinen and Nurminen method stratified by time of COVID-19 symptom onset (≤3 days vs. >3 [4-5] days).
† Defined as ≥24 hours of acute care in a hospital or an acute care facility (e.g., emergency room).
‡ Subjects with unknown status at Day 29 are counted as having an outcome of all-cause hospitalisation or death in the efficacy analysis.
Note: All subjects who died through Day 29 were hospitalised prior to death.
Efficacy results were consistent across sub-groups including age (>60 years), at risk medical conditions (e.g., obesity, diabetes) and SARS-CoV-2 variants.
The Agency has deferred the obligation to submit the results of studies with Lagevrio in one or more subsets of the paediatric population (see section 4.2 for information on paediatric use).
Molnupiravir is a 5'-isobutyrate prodrug that is hydrolysed to NHC prior to reaching systemic circulation. The pharmacokinetics of NHC are similar in healthy subjects and patients with COVID-19.
The pharmacokinetics of NHC at steady-state following administration of 800 mg molnupiravir every 12 hours are provided below in Table 3.
Table 3. Pharmacokinetics of NHC after administration of 800mg Lagevrio every 12 hours:
| NHC Geometric Mean (%CV) | ||
|---|---|---|
| AUC0-12hr (ng×hr/mL)* | Cmax (ng/mL)† | C12hr (ng/mL)* |
| 8260 (41.0) | 2970 (16.8) | 31.1 (124) |
%CV: Geometric coefficient of variation.
* Values were obtained from population PK analysis.
† Values were obtained from a Phase 1 study of healthy subjects.
Following twice daily oral administration of 800 mg molnupiravir, the median time to peak plasma NHC concentrations (Tmax) was 1.5 hours.
In healthy subjects, the administration of a single 200 mg dose of molnupiravir with a high-fat meal resulted in a 35% reduction in NHC peak concentrations (Cmax), AUC was not significantly affected.
NHC does not bind to plasma proteins.
The effective half-life of NHC is approximately 3.3 hours. The fraction of dose excreted as NHC in the urine was ≤3% in healthy participants.
Population pharmacokinetic analysis showed that age, gender, race and ethnicity do not meaningfully influence the pharmacokinetics of NHC.
Lagevrio has not been studied in paediatric patients.
Renal clearance is not a meaningful route of elimination for NHC. No dose adjustment in patients with any degree of renal impairment is needed. In a population PK analysis, mild or moderate renal impairment did not have a meaningful impact on the pharmacokinetics of NHC. The pharmacokinetics of molnupiravir and NHC has not been evaluated in patients with eGFR less than 30 mL/min or on dialysis (see section 4.2).
The pharmacokinetics of molnupiravir and NHC has not been evaluated in patients with hepatic impairment. Preclinical data indicate that hepatic elimination is not expected to be a major route of NHC elimination therefore hepatic impairment is unlikely to affect NHC exposure. No dose adjustment in patients with hepatic impairment is needed (see section 4.2).
Reversible, dose-related bone marrow toxicity affecting all haematopoietic cell lines was observed in dogs at ≥17 mg/kg/day (0.4 times the human NHC exposure at the recommended human dose (RHD)). Mild decreases in peripheral blood cell and platelet counts were seen after 7 days of molnupiravir treatment progressing to more severe haematological changes after 14 days of treatment. Neither bone marrow nor haematological toxicity was observed in a 1-month toxicity study in mice up to 2,000 mg/kg/day (19 times the human NHC exposure at the RHD) and a 3-month toxicity study in rats up to 1,000 mg/kg/day (9.3 and 15 times the human NHC exposure at the RHD in females and males, respectively).
Bone and cartilage toxicity, consisting of an increase in the thickness of physeal and epiphyseal growth cartilage with decreases in trabecular bone was observed in the femur and tibia of rapidly growing rats in a 3-month toxicity study at ≥500 mg/kg/day (5.4 times the human NHC exposure at the RHD). There was no bone or cartilage toxicity in a 1-month toxicity study in rapidly growing rats up to 500 mg/kg/day (4.2 and 7.8 times the human NHC exposure at the RHD in females and males, respectively), in dogs dosed for 14 days up to 50 mg/kg/day (1.6 times the human NHC exposure at the RHD), or in a 1-month toxicity study in mice up to 2,000 mg/kg/day (19 times the human NHC exposure at the RHD). Growth cartilage is not present in mature skeletons; therefore the bone and cartilage findings are not relevant for adult humans. The clinical significance of these findings for paediatric patients is unknown.
Carcinogenicity studies with molnupiravir have not been conducted.
Molnupiravir and NHC were positive in the in vitro bacterial reverse mutation assay (Ames assay) with and without metabolic activation. In 2 distinct in vivo rodent mutagenicity models (Pig-a mutagenicity assay and Big Blue (cII Locus) transgenic rodent assay) molnupiravir did not induce increased mutation rates relative to untreated historical control animals, and therefore is not mutagenic in vivo. Molnupiravir was negative for induction of chromosomal damage in in vitro micronucleus (with and without metabolic activation) and in vivo rat micronucleus assays. Based on the totality of the genotoxicity data, molnupiravir is of low risk for genotoxicity or mutagenicity in clinical use.
There were no effects on fertility, mating performance or early embryonic development when molnupiravir was administered to female or male rats at NHC exposures approximately 2 and 6 times, respectively, the human NHC exposure at the recommended human dose (RHD).
In an embryofoetal development (EFD) study in rats, molnupiravir was administered orally to pregnant rats at 0, 100, 250, or 500 mg/kg/day from gestation days (GDs) 6 to 17. Molnupiravir was also administered orally to pregnant rats at up to 1,000 mg/kg/day from GDs 6 to 17 in a preliminary EFD study. Developmental toxicities included post-implantation losses, malformations of the eye, kidney, and axial skeleton, and rib variations at 1,000 mg/kg/day (8 times the human NHC exposure at the RHD) and decreased foetal body weights and delayed ossification at ≥500 mg/kg/day (2.9 times the human NHC exposure at the RHD). There were no developmental toxicities at ≤250 mg/kg/day (0.8 times the human NHC exposure at the RHD). Maternal toxicities included decreased food consumption and body weight losses, resulting in the early sacrifice of individual animals at 1,000 mg/kg/day, and decreased body weight gain at 500 mg/kg/day.
In an EFD study in rabbits, molnupiravir was administered orally to pregnant rabbits at 0, 125, 400, or 750 mg/kg/day from GDs 7 to 19. Developmental toxicity was limited to reduced foetal body weights at 750 mg/kg/day (18 times the human NHC exposures at the RHD). There was no developmental toxicity at ≤400 mg/kg/day (7 times the human NHC exposures at the RHD). Maternal toxicities included reduced food consumption and body weight gains, and abnormal faecal output at 750 mg/kg/day.
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