ANTIVIRAL IN NON-HOSPITALIZED ADULT PATIENTS WITH COVID-19*

NEW AGE ANTIVIRAL IN NON-HOSPITALIZED ADULT PATIENTS WITH COVID-19*
*For the treatment of adult patients with COVID-19, with Spo2 >93% and who have high risk of progression of the disease including hospitalization or death. SARS-CoV-2 virus has been evolving since its discovery and reasoning for the National emergency since March 2020.

The current strains are highly infectious with the circulation of variants that are causing resurgence of the infection and related complications.
The clinical implications related to hyperregulated systemic inammatory response needs quick pre-emptive action against current or Variant under interest (VUI)
Patient compliance and adherence are important determinants for virologic clearance and clinical response rates that remain sub-optimally controlled.
MOLNUPIRAVIR:
New Age Antiviral in Non-hospitalized Adult Patients with COVID-19*
Molnupiravir (also known as EIDD-2801/MK-4482) is a prodrug of active antiviral ribonucleoside analogue b-D-N4- hydroxycytidine (NHC, EIDD-1931) that undergoes intracellular activation to get incorporated in the viral RNA causing high rate mutation (mutagenesis).

It’s multi-step or multimodal action translates to:
· Inhibition of viral replication
· Mutagenic action for self-destruction
After administration, Molnupiravir gets quickly cleaved in plasma to EIDD-1931 (NHC), which after distribution into various tissues, is converted to its corresponding triphosphate by host kinases. The active metabolite is a competitive alternative substrate for the virally encoded RNA-dependent RNA polymerase, and upon incorporation into nascent chain viral RNA, it induces an antiviral effect via viral error catastrophe. NHC escapes coronavirus associated proofreading exonuclease activity. Drug

Mechanism
In-vitro activity EC 50[μM]
Remdesivir
Delayed RNA chain termination
0.01-1.5
Favipiravir
Delayed RNA chain termination
60 – 250
Molnupiravir
Viral mutagenesis leading to viral error catastrophe
0.05-0.3
The anti-viral activity reected by EC50 concentration for Molnupiravir was comparable to Remdesivir.
Molnupiravir: Indication
Molnupiravir is indicated in non-hospitalized adult patients with COVID-19, with Spo2 >93% and who have high risk of progression of the disease including hospitalization or death.
Molnupiravir: Dosage
The recommended dose of Molnupiravir is 800 mg (4capsulesof200mg) twicedailyfor5days.
Molnupiravir is not authorised –
• Foruseinpatientslessthan18yearsofage
• Forinitiationoftreatmentinpatientsrequiringimmediate hospitalization due to COVID-19 at that stage (however, if it was initiated before hospitalization due to COVID -19, it may be continued). • Foruseforlongerthan5consecutivedays

• For pre-exposure or post-exposure prophylaxis for
prevention of COVID-19
• Forpregnantwomen
• Females of childbearing potential should use a reliable method of contraception correctly and consistently, as applicable, for duration of treatment and for 4 days after the last dose of molnupiravir
• Males of reproductive potential who are sexually active with females of child bearing potential should use a reliable method of contraception correctly and consistently during treatment and fo at least 3 months after the last dose
Special Population
Pregnant Women
Molnupiravir should not be administered to a pregnant woman or a woman who may be pregnant.
Lactating Women
Breast-feeding is not recommended during treatment and for 4 days after the last dose of Molnupiravir.
Paediatric Patients
No data are available and it should be avoided in children below 18 years Geriatric Patients

Nodoseadjustment isrequiredbasedonage.
Contraindications
Patients with a history of hypersensitivity to the components of this drug.
Side effects:
In human studies, severity of side effects with Molnupiravir reported are mild to moderate. Patient may experience dizziness, insomnia or headache. Molnupiravir: Clinical evidence

Phase II Trial
MOVe-Out Trial: This trial was phase IIa, double-blind, placebo-controlled, randomized trial, designed to compare the safety, tolerability, and antiviral activity of Molnupiravir versus placebo as measured by infectious virus detection in symptomatic adult outpatients with COVID-19.
Approximately 204 participants were randomized to receive Molnupiravir or Placebo orally twice a day (BID) for 5 days.
Antiviral activity, safety, and tolerability were assessed for 28 days following study treatment initiation.
Results:
SARS-CoV-2 Presence
Placebo
Molnupiravir
200mg
400mg
800mg
On Day 1
47.2%
50%
41.9%
38.5%
On Day 3
16.7%
18.2%
11.6%
1.9%
(p = 0.02)
On Day 5
11.1%
4.5%
0%
(p = 0.03)
0%
(p = 0.03) The proportion of participants who achieved SARS-CoV-2 negativity by end of study was also greater for those administered 800 mg Molnupiravir 49/53 (92.5%) compared with 21/23 (91.3%), 48/61(78.7%), and 49/61(80.3%) or 200 and 400 mg Molnupiravir and placebo, respectively.

Molnupiravir was well tolerated by participant, with similar numbers of adverse events across all groups. There were no safety signals or evidence of hematologic, renal, or hepatic toxicity were observed.
Result of this trial provided a strong biological evidence that in COVID-19 infected patients early administration of Molnupiravir reduce virus replication and interrupt progression of disease.
The proportion of participants who achieved SARS-CoV-2 negativity
100% 80% 60% 40% 20% 0%
80.30%
Placebo
92.50%
Molnupiravir 800mg
Reference: Fischer W et al. Molnupiravir, an Oral Antiviral Treatment for COVID-19. medRxiv [Preprint]. 2021 Jun 17:2021.06.17.21258639. doi: 10.1101/2021.06.17.21258639 Phase III Trial :

Molnupiravir for Oral Treatment of Covid-19 in Non hospitalized Patients
Aim
To evaluate the efcacy and safety of treatment with Molnupiravir started within 5 days after the onset of signs or symptoms in non hospitalized, unvaccinated adults with mild-to-moderate, laboratory-conrmed covid-19 and at least one risk factor for severe covid-19 illness.
Method
Phase 3, double-blind, randomized, placebo-controlled trial Participants in the trial were randomly assigned to receive 800 mg of Molnupiravir or placebo twice daily for 5 days.
Primary efcacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point.
A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. Results

A total of 1433 participants underwent randomization; 716 were assigned to receive Molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups.
Efcacy
The superiority of Molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with Molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% condence interval, −11.3 to −2.4; P = 0.001).
In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the Molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% condence interval, −5.9 to −0.1).
Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the Molnupiravir group and 9 were reported in the placebo group through day 29.

Safety
Adverse events were reported in 216 of 710 participants (30.4%) in the Molnupiravir group and 231 of 701 (33.0%) in the placebo group.
Conclusions
Early treatment with Molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19.
Reference: BernalA. Et al, N Engl J Med 2021 Dec 16 Phase III Trial - Interim Data analysis (Indian Data):

This was phase III multicenter double-blind placebo controlledtrial. Theobjectiveofstudywastoevaluatethe efcacy and safety of Molnupiravir plus standard of care (test arm) versus standard of care alone (control arm), in mild Covid-19 patients with a positive SARS CoV-2 RT PCR test for COVID-19. In interim analysis data of 741 patient was evaluated.
Treatment: Standard of Care Vs Standard of Care + Molnupiravir 800mg (4 x 200 mg) every 12 hours. The standard of care was given as per the Indian Council of Medical Research (ICMR) guidelines.
Treatment Duration: 5 Days
Interim results from mild COVID-19 patients (N=741)
Earlier clinical improvement (2-point decrease in WHO Clinical Progression Scale) in disease progression was observed in Molnupiravir group compared to standard of care.
Day of Assessment
SOC Alone
Molnupiravir + SOC
Clinical Improvement
2-point decrease in WHO Clinical Progression Scale
Day 5
22.33%
63.43%
p=<0.0001
Day 10
49.49%
78.96%
p=<0.0001
Day 14
73.22%
81.55%
p=0.0150
SARS CoV-2 RT-PCR negativity
Day 5
26.07%
77.35%
p=<0.0001
Day 10
57.20%
94.03%
p=<0.0001
Day 14
85.21%
97.01%
p=<0.0001 Median time to clinical improvement (2-point decrease in WHO Clinical Progression Scale) was as early as 8 days in Molnupiravir group compared to 12 days in SOC alone group (p=0.0001)

· Furthermore, fewer hospital admissions were observed in Molnupiravir group compared to standard of care alone (7 (1.89%) Vs 23 (6.22%) p= 0.0027) over 14 days of observation
14 12 10
8 6 4 2 0
12
SOC
8
Mol + Soc
Median time to clinical improvement (Days)
Most common adverse events reported were nausea, diarrhoea and headache that were resolved completely.
This interim data of phase III trial conducted showed that Indian patients treated with oral Molnupiravir 800mg b.i.d with standard of care was effective in reducing recovery time, clinical improvement with statistically signicant lower rate of hospitalization.
Days Favipiravir Vs Molnupiravir:

Favipiravir
Molnupiravir
Mechanism of action
Nucleoside precursor that requires successive activation for inhibition of RdRp
Nucleoside ‘analogue’ that has direct antiviral action Inhibits polymerase enzyme while inducing viral apoptosis or death
Effectivity index (CC50 :EC50)

6.46
18
(More potent inhibitor of SARS CoV2)
In vitro activity EC50 [μM]
60 -250
0.05 – 0.3
Loading dose requirement
YES
NO
Treatment duration
7-14 days
5 days
Side effect prole
Diarrhoea, Raised liver enzymes, Hyperuricemia
Diarrhea, nausea, dizziness, headache
Benets:
Broad spectrum oral antiviral drug that is suitable for outpatient clinical setting
Short-duration of treatment (5 days)
Early treatment with Molnupiravir provides effective clearance of virus; early recovery and reduction in disease progression
Molnupiravir can be easily prescribed with standard of care treatment
The efcacy of Molnupiravir was unaffected by the SARS-CoV-2 variant (gamma, delta or mu) and with the underlying risk factors.

References:

Fischer W et al. Molnupiravir, an Oral Antiviral Treatment for COVID-19. medRxiv [Preprint]. 2021 Jun 17:2021.06.17.21258639. doi: 10.1101/2021.06.17.21258639
Gordon CJ et al. J Biol Chem. 2021 Jul;297(1):100770..
Charles N et al. All Life.2020;13:1, 608-614, DOI: 10.1080/26895293.2
Hetero Press release. https://www.heteroworld.com/media.php (as accessed on 17th July 2021
Molnupiravir Capsule. Prescribing information. Torrent Pharmaceuticals Ltd.,
Fan S, Xiao D, Wang Y, Liu L, Zhou X, Zhong W. Research progress on repositioning drugs and specic therapeutic drugs for SARS-CoV-2. Future Med Chem. 2020;12(17):1565-1578. doi:10.4155/fmc-2020-0158
SARS-COV-2 Antiviral Therapeutics Summit Report.NIH. Nov 6 2020
Bakowski MA et al., Drug repurposing screens identify chemical entities for the development of COVID-19 interventions. Nat Commun. 2021 Jun 3;12(1):3309. doi: 10.1038/s41467-021-23328-0
Łagocka, R et al. A. Favipiravir in Therapy of Viral Infections. J. Clin. Med. 2021, 10, 273. https://doi.org/ 10.3390/jcm10020273 For the use of Registered Medical Practitioners only
Molnupiravir Capsules 200 mg
To be sold by retail only under prescription of Medical Specialists. Abbreviated Prescribing information for Molnupiravir (200mg Capsule)
[Please refer the complete prescribing information available at http://www.torrentpharma.com]
COMPOSITION: Each hard cellulose capsule contains: Molnupiravir 200 mg, Excipients q.s.
The excipients used are microcrystalline cellulose, hydroxy propyl cellulose, croscarmellose Sodium, magnesium stearate, HPMC shell size 0 and puried water. PHARMACOLOGICAL PROPERTIES: Mechanism of action: 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. Antiviral Activity: 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, nelnavir, remdesivir, ribavirin, sofosbuvir, or tenofovir. INDICATIONS: For treatment of adult patients with COVID-19, with SpO2 >93% and who have high risk of progression of the disease including hospitalization or death. DOSAGE AND ADMINISTRATION: The recommended dose of Molnupiravir is 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days. As directed by the Physician. Capsule should be taken orally. CONTRAINDICATION: Hypersensitivity to the active substance or to any of the excipients. WARNINGS & PRECAUTIONS: Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per dose of 4 capsules, that is to say essentially ‘sodium-free’. DRUG INTERACTIONS: No drug interactions have been identied based on the limited available data. No clinical interaction studies have been performed with molnupiravir. Molnupiravir is hydrolysed to n-hydroxycytidine (NHC) prior to reaching systemic circulation. Uptake of NHC and metabolism to NHC-TP are mediated by the same pathways involved in endogenous pyrimidine metabolism. NHC is not a substrate of major drug metabolising enzymes or transporters. Based on in vitro studies, neither molnupiravir nor NHC are inhibitors or inducers of major drug metabolising enzymes or inhibitors of major drug transporters. Therefore, the potential for molnupiravir or NHC to interact with concomitant medications is considered unlikely. ADVERSE REACTIONS: Nervous system disorders: dizziness, headache. Gastrointestinal disorders: diarrhoea, nausea, vomiting, Skin and subcutaneous tissue disorders: rash, urticaria.
Molnupiravir has been licensed by MSD to Torrent Pharmaceuticals and is to be used only for treatment of Covid-19 caused by SARS-CoV-2.