CME INDIA Presentation by Admin.
Quotes for The Drug That May ‘Completely’ Stop the Spread of Coronavirus In 24 Hours
- “Antiviral treatments that can be taken at home to keep people with COVID-19 out of the hospital are critically needed. We are very encouraged by the results from the interim analysis and hope molnupiravir, if authorized for use, can make a profound impact in controlling the pandemic. With the virus continuing to circulate widely, and because therapeutic options currently available are infused and/or require access to a healthcare facility, antiviral treatments that can be taken at home to keep people with COVID-19 out of the hospital are critically needed,” – Wendy Holman, chief executive officer of Ridgeback Biotherapeutics.
- “In the studies in very high-risk patients, it reduced the level of serious disease by only half. It’s not a magic pill.”- Prof. William Schaffner (professor of infectious diseases at the Vanderbilt University School of Medicine).
- “First and foremost, preventing Covid with a vaccine is always going to be preferable to treating it “Mistakes can be made in treating infectious disease, and people can die. – Timothy Sheahan, virologist at the University of North Carolina at Chapel Hill.
- “This is going to change the dialogue around how to manage COVID-19,” Robert Davis – Merck Chief Executive.
Beginning of the Hype
October 1 Press Statements by Merck and Ridgeback:
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.
At the Interim Analysis, 7.3 Percent of Patients Who Received Molnupiravir Were Hospitalized Through Day 29, Compared With 14.1 Percent of Placebo-Treated Patients Who were Hospitalized or Died. If Authorized, Molnupiravir Could be the First Oral Antiviral Medicine for COVID-19.
Not a peer reviewed data
- From Phase 3 MOVe-OUT trial in at risk, non-hospitalized adult patients with mild-to-moderate COVID-19.
- At the interim analysis, molnupiravir reduced the risk of hospitalization or death by approximately 50%; 7.3% of patients who received molnupiravir were either hospitalized or died through Day 29 following randomization (28/385), compared with 14.1% of placebo-treated patients (53/377); p=0.0012.
- Through Day 29, no deaths were reported in patients who received molnupiravir, as compared to 8 deaths in patients who received placebo.
About the Results of the Planned Interim Analysis
|The planned interim analysis|
|Evaluated data from 775 patients who were initially enrolled in the Phase 3 MOVe-OUT trial on or prior to Aug. 5, 2021.|
|Eligibility criteria required that all patients had laboratory-confirmed mild-to-moderate COVID-19, with symptom onset within 5 days of study randomization.|
|All patients were required to have at least one risk factor associated with poor disease outcome at study entry.|
|Molnupiravir reduced the risk of hospitalization and/or death across all key subgroups; efficacy was not affected by timing of symptom onset or underlying risk factor.|
|Additionally, based on the participants with available viral sequencing data (approximately 40% of participants), molnupiravir demonstrated consistent efficacy across viral variants Gamma, Delta, and Mu.|
|The incidence of any adverse event was comparable in the molnupiravir and placebo groups (35% and 40%, respectively).|
|Similarly, the incidence of drug-related adverse events was also comparable (12% and 11%, respectively).|
|Fewer subjects discontinued study therapy due to an adverse event in the molnupiravir group (1.3%) compared to the placebo group (3.4%).|
What anticipation of the results from MOVe-OUT led to
- Merck has been producing molnupiravir at risk.
- Merck expects to produce 10 million courses of treatment by the end of 2021.
- Merck will supply approximately 1.7 million courses of molnupiravir to the U.S. government, upon EUA or approval from the U.S. FDA.
- Merck is committed to providing timely access to molnupiravir globally, if it is authorized or approved, and plans to implement a tiered pricing approach
- 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.
- Two-step mutagenesis mechanism probably applies to various viral polymerases and can explain the broad-spectrum antiviral activity of molnupiravir.
- Molnupiravir, like remdesivir, is a nucleoside analogue, which means it mimics some of the building blocks of RNA. But the compounds work in entirely different ways.
- When SARS-CoV-2 enters a cell, the virus needs to duplicate its RNA genome to form new viruses. Remdesivir is a ‘chain terminator’. It stops the enzyme that builds these RNA ‘chains’ from adding further links.
- Molnupiravir, on the other hand, gets incorporated into burgeoning RNA strands and, once inside, wreaks havoc. The compound can shift its configuration, sometimes mimicking the nucleoside cytidine and sometimes mimicking uridine.
- https://youtu.be/5BzQhTa4cc4 (Watch to understand mechanism of action).
What we learnt from Phase 2a, randomized, double-blind, placebo-controlled, clinical trial
- Molnupiravir was well tolerated and associated with potent antiviral efficacy as evidenced by significantly reduced infectious virus isolation, time to elimination of SARS-CoV-2 RNA, increased proportion of participants that cleared SARS-CoV-2 RNA, and a greater reduction in SARS-CoV-2 viral RNA from baseline compared to placebo in outpatients with COVID-19.
- This trial provides strong biological evidence that supports development of molnupiravir as an oral agent to reduce infectious virus replication and interrupt progression of COVID-19 in early stages of disease.
- Current evidence suggests that uninterrupted viral replication is a major sign of progression to more severe disease.
Indian Studies are not suggesting a benefit
- The Indian drug regulator’s committee disclosed on its website that Aurobindo and MSN had presented interim clinical trial data for moderate COVID-19 patients and asked to end the trials.
- A source with the Drug Controller General of India said the pill has not shown “significant efficacy” against moderate COVID-19. But has shown success against mild cases.
- Aurobindo Pharma Ltd. and MSN Laboratories – did not exclude hospitalized patients in designing their moderate COVID-19 trials, according to study documents, although it was not known if the trials ultimately included people in the hospital.
- Dr. Reddy’s Laboratories, Cipla, Sun Pharma, Torrent Pharmaceutical and Emcure Pharmaceuticals are conducting a joint trial for the antiviral drug only in mild COVID-19 patients in an outpatient setting.
What do we know so far?
(Inputs by Dr. A K Singh, DM, Endo, Kolkata)
|1. Phase 1 data (NCT04392219) of 130 healthy volunteers (published) – no food interaction, good tolerability up to 1600 mg/d, headache and diarrhea common S/E. Interestingly, overall S/E profile higher in PBO vs. Molnupiravir.|
|2. Phase 2 (NCT04405570) preprint in medrxiv – Fischer et al – significantly faster RT-PCR viral clearance with Molnupiravir (both 400/800 mg per day) vs PBO. Good tolerability for 5-day doses. 800 mg dose shown better outcome compared with 400 mg/day.|
|3. Phase 3 (NCT04575597) MOVe-OUT study prematurely stopped by the DSMB and FDA due to excessive benefit in Molnupiravir vs. PBO. Interim result in 775 subjects found 50% reduction in hospitalization or death (p=0.0012) at day 29. Topline result out. No detail data available.|
|4. Another phase 3 study in India by Aurobindo pharma found no benefit in primary outcome with Molnupiravir vs. PBO. No details available. Merck claims – diff. in the definition of moderate Covid included was the likely reason for no benefit in Indian studies.|
|5. Criteria for Moderate Covid were different between US and Indian studies. Indian moderate Covid included in the study was actually severe Covid by CDC definition. Molnupiravir may not work in the late stage or severe Covid.|
|6. However, in-hospital study (MOVe-IN) of Molnupiravir is currently ongoing (NCT04575584) in severe Covid.|
CME INDIA Learning Points
- It is very important to note that two Indian drug makers independently tested generic molnupiravir in people with moderate illness due to COVID-19.
- They ended the trial because no “significant efficacy” for the experimental drug was found.
- Although they plan to continue trials for people with mild illness.
- Merck’s findings are applicable to people with mild-to-moderate cases of COVID-19 who were not hospitalized
- Molnupiravir have been linked to birth defects in animal studies. Merck has said that the drug does not affect mammalian DNA.
- Viral sequencing done so far shows molnupiravir is effective against all variants of the coronavirus including the highly transmissible Delta.
- So far, no specific safety issues have been found.
- Molnupiravir is also being studied in a Phase III trial for preventing infection in people exposed to the coronavirus.
- At present, it cannot be stated that Molnupiravir will be a game changer.
CME INDIA Tail Piece
- Molnupiravir began as a possible therapy for Venezuelan equine encephalitis virus at Emory University’s non-profit company DRIVE in Atlanta.
- In 2015, DRIVE’s chief executive George Painter offered it to a collaborator, virologist Mark Denison at Vanderbilt University in Nashville, Tennessee, to test against coronaviruses.
- “I was pretty blown away by it,” Denison remembers. He found that it worked against multiple coronaviruses: MERS and mouse hepatitis virus.
- Cox, R.M., Wolf, J.D. & Plemper, R.K. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol 6,11–18 (2021). https://doi.org/10.1038/s41564-020-00835-2
- Nature.19th October,2021.doi: https://doi.org/10.1038/d41586-021-02783-1
- Fischer, W., Eron, J., Holman, W. et al. (2021). Molnupiravir, an Oral Antiviral Treatment COVID19. medRxiv. doi:10.1101/2021.06.17.21258639. https://www.medrxiv.org/content/10.1101/2021.06.17.21258639v1
- Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2021;384(3):229–37. 3.
- Wölfel R, Corman VM, Guggemos W, et al. Author Correction: Virological assessment of hospitalized patients with COVID-2019. Nature 2020;588(7839):E35–E35.
- William Fischer, MD, Institute for Global Health and Infectious Disease, Division of Pulmonary Diseases and Critical Care Medicine, The University of North Carolina and Chapel Hill, Chapel Hill, NC, USA et al. Molnupiravir, an Oral Antiviral Treatment for COVID-19. medRxiv preprint doi: https://doi.org/10.1101/2021.06.17.21258639; this version posted June 17, 2021
- Kabinger, F., Stiller, C., Schmitzová, J. et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol 28,740–746 (2021). https://doi.org/10.1038/s41594-021-00651-0
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