Covid-19 started engulfing the world in December 2019 and by March 2020, WHO declared it a pandemic. Most physicians used repurposed drugs, which have potential in vitro antiviral activity against the old SARS-CoV-1 or MERS or other viruses like Ebola.

We have a host of medications ranging from antiparasitic agents like ivermectin, antimalarials like hydroxychloroquine to Ebola agents like Remdesivir. The anti-HIV cocktail of lopinavir and ritonavir was also tried, which failed the Solidarity trial. The quest to develop a specific antiviral anti-Covid-19 agent was then elusive but now looks real.

Two global majors namely Pfizer and Merck pursued two anti-Covid-19 strategies.

Pfizer used a combination of a ritonavir-boosted compound, which in a pivotal randomized exploratory trial for EUA for the US FDA appears very promising. This combination is called “Paxlovid®”, a new antiviral combination pill, which  has shown to cut the chances of hospitalization or death for adults at risk of developing severe disease by 89% in a trial that was prematurely stopped by the data safety board due to overwhelming results. The new antiviral is a protease inhibitor and is given in combination with an older antiviral called ritonavir. The dose schedule is three pills given twice-daily. We know that protease inhibitors, like in HIV, block an enzyme the coronavirus needs in order to multiply and thus stop multiplication of the virus. 

The trial done in 1219 patients looked at hospitalizations or deaths among people diagnosed with mild to moderate Covid-19 with at least one risk factor for developing severe disease, such as obesity or older age (other details not available). It found that 0.8% of those given this drug within 3 days of onset of symptoms were hospitalized and none had died by 28 days after treatment when compared with a hospitalization rate of 7% for patients who were given a placebo. No deaths occurred in the study group while there were seven deaths in the placebo group. The response rates were similar for patients treated within 5 days of symptoms - 1% of the treatment group was hospitalized, compared with 6.7% for the placebo group, which included 10 deaths. This led them to conclude in a press note that  the drug is effective only if given early. Thus, this medicine may have high efficacy, even if the patient was treated five days after being infected, as people might wait a couple of days before getting a test or consulting a doctor. This means that we have time to treat people and really provide a benefit from a public health perspective.

So early rapid self-testing may have a role in using this drug if it gets approved. The adverse events are still unknown in the public domain but the company said adverse events happened in about 20% of both treatment and placebo patients. Pfizer is also studying whether its pill could be used by people without risk factors for serious Covid-19 as well as to prevent coronavirus infection in people exposed to the virus in other trials.

Antivirals need to be given as early as possible, before an infection takes hold, in order to be most effective. Merck tested its drug within five days of symptom onset.

Once the virus takes hold, the inflammatory effects  drive the course of disease and then only anti-inflammatory drugs like corticosteroids work. In SARS-1 or even in flu, oseltamivir works only if given early in the course of infection. The Japanese flu drug Favipiravir also works best in the first 3 days, which was extensively used in India but did not have mortality data; only early symptom and viral clearance data were available.

The other early pill is the Emory university researched terminator antiviral “Molnupiravir”.

Molnupiravir has a different mechanism of action. It is designed to introduce errors into the genetic code of the virus, which is effective on similar lines like remdesivir. It has shown 50% efficacy in reducing death or hospitalization when given early in high-risk individuals. The drug was able to reduce the risk for severe disease by 50%. No deaths occurred in the group that took the drug versus 8 in the placebo group. The result was consistent across the various newer variants including delta, gamma and mu variants. Most importantly, no greater risk for adverse events was recorded.

We do not know how many participants in the trial were vaccinated, and whether there was any disparity in the number of vaccinated individuals between the drug and the placebo arms. We await the full trial report and again this was a company press release.

Phase 1 data (NCT04392219) of 130 healthy volunteers (published): No food interaction, good tolerability up to 1600 mg/day, headache and diarrhea common side effects. Interestingly, the overall side effects profile was higher in placebo vs Molnupiravir.

Phase 2 (NCT04405570) preprint in medRxiv by Fischer et al: Significantly faster RT-PCR viral clearance with Molnupiravir (both 400/800 mg per day) vs placebo. Good tolerability for 5-day doses.  800 mg dose showed better outcomes compared with 400 mg/day.

Phase 3 (NCT04575597) MOVe-OUT study prematurely stopped by the DSMB and FDA due to excessive benefit in molnupiravir vs PBO. Interim results in 775 subjects found 50% reduction in hospitalization or death (p=0.0012) at day 29. Topline result out. No detailed data available.

Another phase III study in India by Aurobindo Pharma found no benefit in primary outcome with Molnupiravir vs placebo. No details are available.

Merck claims that the difference in the definition of moderate Covid that was included in the trial was the likely reason for no benefit in Indian studies. Criteria for moderate Covid were different between US and Indian studies. Moderate Covid included in the Indian study was actually severe Covid as per CDC definition.

Molnupiravir may not work in the late stage or severe Covid. However, in-hospital study (MOVe-IN) of molnupiravir is currently ongoing (NCT04575584) in severe Covid-19.

First, it is an oral drug that prevents viral replication. Second, it is possible that it may be effective as postexposure prophylaxis. Third, it appears to be safe. Fourth, along with vaccines, this could be the key to our return to a pre-pandemic world. The best news is that the company has already licensed the drug to five Indian companies for conducting trials in India. We can expect the drug to be affordable and available in India if the data from the trials are consistent with what has been shown.

Thus, now we have some exciting new age antivirals, which may emerge as treatment options in mild to moderate Covid-19. We still need to look at the full data and how global regulators including US FDA and Indian DCGI look at it but all of them offer a promise as they are oral. Even if they will be affordable and accessible, early diagnosis of Covid-19 would still be a challenge as the virus replicates in the first 10 days and these drugs best work in the first 3 to 5 days, which will be the key.

Only time will tell if they will prove to be a true hope or just a hype.