Mon, 10/18/2021 - 19:53
Dear colleagues,
I reported already several times on the first orally available anti-SARS-CoV-2 drug Molnupiravir, but rather superficially, based on “breaking news”. As is often the case, a critical remark by a colleague, triggered me to perform a more extensive literature search to put things into perspective and provide some food for thought….
Molnupiravir is a ribonucleoside analog referred to as either EIDD-1931 or -2801 or MK 4482
https://www.selleckchem.com/products/eidd-1931.html :
EIDD-1931 (Beta-d-N4-hydroxycytidine, β-d-N4-hydroxycytidine, NHC) is an active metabolite (triphosphate form) of EIDD-2801with
- broad spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c Bat-CoVs with average IC50 of 0.15 μM, (see Ep 183-6)
- as well as increased potency against a coronavirus bearing resistance mutations to the nucleoside analog inhibitor Remdesivir. (Ep 183-6)
Mechanism of action of Molnupiravir: induction of mutations in the viral RNA is
- similar as Ribavirin and Favipiravir, but it is more potent (see Ep 183-11).
- different from Remdesivir, which act as a premature RNA chain terminator.
Ep 183-1 for overview of structure and mechanism of Remdesivir and Molnupiravir
Ep 183-2: Brandon Malone (Nat Struct Mol Biology Sept 2021) explains in detail how the Cytidine to Uracil in viral RNA mutations come about during viral replication.
Importantly Molnupiravir is resistant to the “proofreading” capacity of the exonuclease function of the SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp).
→ Accumulation of these mutations is ultimately “catastrophic”, resulting in dead virus.
→ This mechanism might explain why the deleterious effect on infectious virus is more pronounced than the effect on viral RNA shedding (both in ferrets 183-6 and in hamsters Ep 183-8).
Clinical studies
Ep 183-3 As there is still no publication (not a preprint either) we rely on what the company released and was summarized by Elisabeth Mahasse in BMJ:
Eligibility for phase 3:
- confirmed mild or moderate covid-19,
- symptom onset within five days of study randomisation,
- and at least one risk factor associated with poor disease outcome.
At Day 29 of treatment
- Hospitalization or death: 7.3% Molnupiravir arm (28 of 385) and 14.1% placebo (53 of 377).
- No deaths in Molnupiravir arm versus 8 in placebo
Not clear which dose. See https://clinicaltrials.gov/ct2/show/NCT04405570
According to https://clinicaltrials.gov/ct2/history/NCT04575597?V_47=View the 3 doses of phase 2 (2 X 200, 2 X 400 and 2 X 800) were all trialled).
Ep 183-4: Khoo Phase ½ study published in JAC(Aug 2021: similar population as in phase 3, but no requirement for risk factor. Only 4 subjects in each treatment group (300, 600 and 800 mg twice daily). 1/4 withdrew in the highest dose, but all adverse effect were considered mild and 2 X 800 mg was selected as “safe and well tolerated”.
Ep 183-5: Phase 2 study, published by Fisher in medRxiv June 2021: similar population, also no requirement for risk factor. Over 200 participants. Main outcome: faster decline of infectious virus and of viral RNA in the groups, receiving either 2X 400 or 800 mg (as compared to placebo, but apparently also compared to 2 X 200 mg). See Table 1 and 2 p. 20 and 21).
No difference in side effects with placebo.
Preclinical (in vitro and animal) studies
Ep 183-6: Timothy Sheahan in Sc Transl Med (April 2020): Molnupiravir
- has potent in vitro activity against SARS, MERS, SARS-CoV-2 and bat viruses (in cell lines)
- is also active against remdesivir-resistant viruses
- acts prophylactically and therapeutically against SARS and MERS in mice
- is associated with increased transition mutation (Cytosine to Uracil = C-U and Guanine to Adenine = G-A) frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. (see also Ep 183 -
Ep 183-7: Walh in Nature (March 2021: SARS-CoV-2 replication in human lung only mice can be strongly inhibited (by 4 logs) if administered either 12 h before or 24 h after infection. Administering 48 h after infection inhibits only 2 logs. (Fig 4 p. 456)
Interestingly, in this model, not only SARS and MERS but also two bat Coronaviruses replicate well, which, according to these authors, indicates that coronaviruses circulating in bats have pandemic potential without the need for further adaptation to humans.
Ep 183-8: Cox in Nature Microbiology (Jan 2021): therapeutic treatment of infected ferrets with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact ferrets
Ep 183-9: Yining Wang Virology Sept 2021: Molnupiravir also active in vitro against the seasonal coronaviruses NL-63, OC43 and 229E. As compared to 183-4, it seems that the required conc for seasonal Cov is slightly higher than for SARS-CoV-2
Ep 183-10: Rana Abdelnabi EBioMedicine (Oct 2021): a combination of suboptimal Molnupiravir and Favipiravir, treated 6 h -2 days after infection of hamsters:
- Clearly synergistic inhibition of viral RNA and even more pronounced suppression of infectious titres
- Also synergistic effect on CT and GA mutations (both compounds are mutagenic)
- Prevents transmission to uninfected cage mates.
This is a nice result, but both compounds act on the same mechanism and have also potentially overlapping side effects
Concerns about Molnupiravir safety and efficacy
Ep 183-11: Shuntai Zhou (JID Aug 2021):
Molnupiravir (sNHC) clearly more potent in induction of mutations and correlated antiviral activity than either Ribavirin (RBV) or Favipiravir (FAV) (Fig 1 p. 416):
-
- an antiviral effect of rNHC could be observed at subtoxic concentrations (0.3–3 µM),
- the antiviral and mutagenic effects of RBV were observed only under conditions that were severely toxic to the host cell,
- while FAV demonstrated modest antiviral activity at high concentration but with undetectable mutagenic effect and with no cell toxicity at the highest concentrations
However, there is a possibility of mutagenesis of the cell, because the Molnupiravir-triphosphate could be de-oxygenated and be incorporated into DNA of dividing cells, with mutations and abrogation of function of the target gene. This is indeed shown in cell culture (Fig 2 p. 418).
The concern would be that mutations in host DNA could contribute to the development of cancer, or cause birth defects either in a developing fetus or through incorporation into sperm precursor cells.
One has to admit that the in vitro conditions of 30 days exposure to higher conc of the drug are different from the lower and shorter exposure in COVID patients.
Ep 183-12: Reuters press communication on 2 Indian drug makers suspending development of Molnupiravir, because of no effect in their trial. However:
- They included patients who were more advanced in the (inflammatory phase of?) the disease: with lower oxygen saturation
- Merck has also suspended the development in hospitalized patients
Clearly, the drug should be given early in the disease when patients are not yet desaturated and not yet hospitalized.
Ep 183-13: Cassandra Willyard in Nature provides an overview and some comments
Concluding remarks:
Just like the monoclonal antibodies (Regeneron) and Remdesivir (Gilead), Molnupiravir (Merck) can lower viral load and viral infectivity, with the potential to reduce the chances on severe COVID,
on condition that the treatment is started early (less than 1 week after infection), but for each of these compounds beneficial effects are limited to a proportion of the patients.
These 3 lead compounds act via different and potentially synergistic mechanism: monoclonals block entry, Remdesivir is RNA chain terminator and Molnupiravir is a mutation-inducer. From a practical point of view,
- Molnupiravir is the only of these that is orally bio-available;
- Antibodies are long lived and therefore 1 injection may suffice
- Remedesivir has to be administered intravenously on a daily basis
I could not find results of combination therapy, but it is certainly in the pipe-line.
Remdesivir and Molnupiravir have a broad antiviral activity in vitro and have been attempted in other viral infections (including influenza, ebola, dengue etc…) Their therapeutic concentrations are high nanomolar low micromolar range. Monoclonal antibodies are highly specific.
Although Molnupiravir was well tolerated in the short-term clinical trials, it should be checked for long-term mutagenic side effects in fast dividing cell systems of the host.
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