When Will It All End?

That’s what my son asked me. What will it take for you to feel comfortable walking into a restaurant without a mask? Good question. I thought about it. A treatment, I said. An accessible, effective, oral treatment.

Treatments that are approved or authorized by the FDA for COVID-19 include the antiviral drug remdesivir (Veklury), the  IL-6 inhibitor tocilizumab (Actemra), the Janus kinase inhibitor baricitinib (Olumiant), and monoclonal antibodies, all administered intravenously, except for baritinib, which is taken orally, but must be used with remdesivir.^1,2  Both remdesivir and monoclonal antibodies are most likely to be effective if they are started early in the illness, as they were for treatment of former President Trump, former Governor Christie, and former Mayor Giuliani. For more typical patients, though, an IV infusion, especially if it needs to be repeated for 5 days (remdesivir), is not a practical treatment for mild early illness.

Many studies have been published on the use of oral hydroxychloroquine and other older drugs such as ivermectin and azithromycin to treat COVID-19, and these are annotated in the Treatments Considered for COVID-19 table available to all on our web site. Some practitioners and some investigators have been impressed by the results achieved in some studies, but the NIH and IDSA have recommended against the use of hydroxychloroquine or azithromycin with hydroxychloroquine to treat COVID-19, and neither organization has endorsed the use of ivermectin to treat the disease.

So, what’s new? The furthest along is an outlier: the oral selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Luvox, and generics), which was reviewed recently in The Medical Letter.³ The question mark in the title reflects its outlier status: an inexpensive psychiatric drug that is available generically, so no pharmaceutical powerhouse is pushing for its consideration. The clinical trial that sparked interest in its possibilities enrolled only 152 patients with mild disease. It was published in JAMA; the former Editor in Chief said the only reason he accepted it for publication was that among the thousands of submissions he had received on drugs for treatment of COVID, this was the only one with a randomized controlled trial that produced a statistically significant outcome. A much larger trial is in progress, with results anticipated in September.

Multiple investigational oral antiviral drugs are currently being tested in clinical trials. Pfizer announced in a press release in March that a Phase 1 study of an oral antiviral agent with good activity against SARS-CoV-2 in vitro is progressing from single ascending doses to multiple ascending doses. PF-07321332 is a 3-chymotrypsin-like protease (3CLpro) inhibitor that blocks replication of the coronavirus.⁴ Protease inhibitors have been effective and well tolerated in treating other viral pathogens such as HIV and hepatitis C virus. 3CLpro inhibitors typically have limited oral availability, but PF-07321332 has been chemically optimized for oral delivery. According to Pfizer’s CEO, the drug could be through Phase 3 trials by the end of the year.

Merck and Ridgeback Therapeutics also have been pursuing an oral treatment for COVID-19. Molnupravir, an investigational ribonucleoside analog, has well documented antiviral activity in plasma after oral administration.⁵ The manufacturers recently announced the preliminary results of a Phase 2a randomized, double-blind, placebo-controlled trial in 202 nonhospitalized adults with confirmed active SARS-CoV-2 infection who had signs or symptoms within 7 days. The primary endpoint was the time to viral negativity of nasopharyngeal swabs. On day 5, 0% of cultures were positive in patients treated with molnupravir, compared to 24% positivity among those who received placebo.A Phase 3 trial evaluating molnupiravir in nonhospitalized adults with laboratory-confirmed COVID-19 and at least one risk factor associated with poor disease outcomes is ongoing.

Roche and Atea announced on June 30 the interim results of a Phase 2 trial of an oral antiviral that, like remdesivir, targets RNA polymerase and prevents viral replication. On the second day of treatment, AT-527 produced an 80% greater reduction in viral load than placebo did. After 2 weeks, 47% of patients treated with the drug had no virus detectable, compared to 22% of those who received placebo, and there were no safety concerns. 

On July 8, 2020, Gilead Sciences, the manufacturer of remdesivir, announced the initiation of a clinical trial to evaluate the safety, tolerability, and pharmacokinetics of an inhaled, nebulized formulation of the drug in outpatients with early SARS-CoV-2 infection. According to clinicaltrials.gov, a randomized, double-blind, placebo-controlled, Phase 1b/2a clinical trial with 156 participants from 28 sites began on September 14, 2020 and was completed on March 22, 2021. The last update was posted on April 9. That is all we know, and inhalation is not as simple as oral administration, but the demonstrated clinical activity of remdesivir against SARS-CoV-2 makes this product an intriguing possibility.

Will any of these make it all end? Hard to say. For now, we had better keep up with the avalanche of news about vaccines.

1. Remdesivir (Veklury) for COVID-19. Med Lett Drugs Ther 2020; 62:186.
2. An EUA for sotrovimab for treatment of COVID-19. Med Lett Drugs Ther 2021; 63:97.
3. Fluvoxamine for COVID-19? Med Lett Drugs Ther 2021; 63:69.
4. K Vandyck and J Deval. Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection. Curr Opin Virol 2021; 49:36.
5. WP Painter et al. Human safety, tolerability, and pharmacokinetics of molnupiravir, a novel, broad-spectrum oral antiviral agent with activity against SARS-CoV-2. Antimicrob Agents Chemother 2021 March 1 (epub).

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