Review Of Present Therapies For Covid-19

As the world grapples with new and deadly mutant SARS-CoV2 strains, it would be worthwhile to keep in mind which drugs have been authorized so far, what drugs are in the pipeline, and those that have failed. 


Authorized drugs:

Remdesivir (Veklury)

Regeneron's Remdesivir is an antiviral that is given by intravenous (IV) infusion. On October 22, 2020, the FDA approved remdesivir for treatment of COVID-19 in patients over age 12, weighing at least 40 kg (88 lbs.), requiring hospitalization.  In contrast the World Health Organization (WHO) does not recommend using it for any COVID-19 patients due to a lack of consistent data.

Dexamethasone

Dexamethasone is a common steroid. In the RECOVERY trial, researchers found that there was a lower death rate at day 28 in the 2,104 hospitalized patients with COVID-19 who got 6 mg dexamethasone compared to the 4,321 patients who did not get it (23% versus 26%, respectively). The medication seemed to be most helpful for patients who were on a ventilator or needed extra oxygen. There was no benefit for those with less severe symptoms.

Additionally, based on a meta-analysis that looked at findings from seven different trials, death rates were lower in hospitalized patients who took one of three different corticosteroids — dexamethasone, hydrocortisone, or methylprednisolone — compared to those who took none (32% vs. 40%).   It should be used only in severe, hospitalized patients on a ventilator or needing oxygen.

Casirivimab and imdevimab (REGN-COV2)

Regeneron Pharmaceutical’s REGN-COV2 has been called an “antibody cocktail” because it is made from a combination of two monoclonal antibodies, casirivimab and imdevimab.  Both of these are monoclonal antibodies to the viral S protein, and the goal is to inhibit the SARS-CoV-2 virus from binding to its receptor, ACE2.  Patients who either got 2.4 grams of REGN-COV2, 8 grams of REGN-COV2, or placebo had clearing of symptoms after 6 days, 8 days, and 13 days, respectively after receiving the cocktail. Patients who had not yet developed their own antibodies and had more of the virus in their body saw the most benefit.

On November 21, 2020, the FDA issued an Emergency Use Authorization (EUA) for casirivimab and imdevimab to be used together to treat mild or moderate COVID-19 in patients 12 years and older who are at high risk of hospitalization. These medications should be given via IV infusion in an outpatient setting and not in hospitalized patients.  This combination was given to President Trump when he was infected.

Bamlanivimab and Etesevimab

Eli Lilly’s cocktail of bamlanivimab and etesevimab is similarly a combination of monoclonal antibodies to the S protein, so as to inhibit the SARS-CoV-2 virus from binding to its receptor, ACE2.

On February 9, 2021, the FDA granted an EUA for the combination of bamlanivimab and etesevimab to be used together for mild or moderate COVID-19 in high-risk patients who are 12 years and older. Patients who got the combination therapy had less amounts of the virus in their body (lower viral load) at day 11. This was not seen with bamlanivimab alone. Additionally, there were lower rates of hospitalization and death at day 29 for patients who got both bamlanivimab and etesevimab compared to those who did not.

Convalescent Plasma:

On March 24, 2020, the FDA issued an Emergency Investigational New Drug application for the use of convalescent plasma to treat people with COVID-19.  The plasma is rich in antibodies and is extracted from patients who have recovered from COVID-19. It is then infused into patients with the disease.

On August 23, 2020, the FDA issued an EUA for hospitalized patients with COVID-19.

This decision was based on a Mayo Clinic study of over 35,000 hospitalized patients. At day 7, the death rate was lower for the group who got convalescent plasma within 3 days of diagnosis compared to the group who got it after 4 or more days. A big drawback of the study was that there was no control group, so it’s unclear if the difference in death rates was actually because of the treatment or other factors. Death rates were also lower in patients who got convalescent plasma with higher antibody levels compared to plasma with lower antibody levels.

On February 5, 2021, the US Food and Drug Administration (FDA) on Thursday revised its EUA for COVID-19 convalescent plasma to limit its use to high titer units and only in hospitalized patients who are in the early stages of the disease or who have impaired humoral immunity.

Some Drugs in Development:

  1.  Merck’s molnupiravir.  An anti-viral, it failed early studies in severe patients and now is being studied only in those with mild – moderate disease as an outpatient therapy.
  2. Humanigen anti-GMCSF antibody lenzilumab interim results were published on May 5, 2021.  The LIVE-AIR Phase 3 randomized, double-blind, placebo controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator-free survival, beyond standard supportive care, in hospitalized subjects with severe COVID-19.  Lenzilumab improved the likelihood of survival without ventilation (SWOV) by 90% in the ITT population compared to placebo. SWOV also relatively improved by 54% in subjects who received both corticosteroids and remdesivir.  Full data will be available later.
  3. Relief Therapeutics ZYESAMI™ is Vasoactive Intestinal Polypeptide. It is an immune modulator being investigated for COVID19 in severe/critical hospitalized patients.  In hospitalized patients, the drug met the primary endpoint for successful recovery from respiratory failure at days 28 and 60 and also demonstrated a meaningful benefit in survival after controlling for ventilation status and treatment site. The prespecified analysis of recovery from respiratory failure was clinically and statistically significant in the 127 patients treated by High Flow Nasal Cannula (HFNC), compared to those treated with mechanical or non-invasive ventilation at tertiary care hospitals. In this group, ZYESAMI patients had a 71% chance of successful recovery by day 28 vs. 48% in the placebo group and a 75% rate of successful recovery by day 60 vs. 55% in the placebo group. 84% of HFNC patients treated at tertiary medical centers with ZYESAMI survived to day 60 compared with 60% of those treated with placebo.  The company has applied for Emergency Use Authorization with the FDA.

Some drugs that have been studied but failed in clinical trials:

Quite a few drugs have been tried and failed in clinical trials.  These include

1. Azithromycin, an antibiotic

2. Hydroxychloroquine and Chloroquine, an anti-malarial and immunomodulator drug

3.  Ivermectin, an anti-protozoal drug

4.  Antibodies against IL-6 such as Tocilizumab and Sarilumab

5.  Lopinavir and Ritonavir, both anti-virals used to treat HIV.

6.  Cytodyn’s Leronlimab.  The drug binds CCR5, one of many chemokines that is supposed to activate parts of the immune system believed by a small minority to play a role in COVID-19.  In studies in mild to moderate as well as another study in severe/critical patients, the drug missed its primary endpoint.  The FDA refused to consider an Emergency Use Authorization.  It appears the European Union and UK have similarly rejected the drug, though the management gives conflicting and unreliable updates.  It is now pinning its hopes that less stringent countries such as the Philippines and Brazil will approve the drug.

The following table from the NIH summarizes the present therapeutic algorithm.

 

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Comments

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Kurt Benson 1 year ago Member's comment

Excellent read. Highly recommended.

Ketan Desai 1 year ago Author's comment

Thanks

William K. 1 year ago Member's comment

This is a very educational and interesting article. It also brings out one thing, ignored by many. The cruel nature of the use of placebos so as to have a reference group. The cruel lie of telling folks that they are getting help while denying them that help is offensive indeed. Yes, I understand that it is needed to convince the skeptics and unbelievers, but that does not remove one speck of the cruelty of the lie..Certainly there should be another way.

Ketan Desai 1 year ago Author's comment

Thanks. Your point of placebo is well taken. Often though, it is not true placebo. The design is standard of care plus study drug versus standard of care plus placebo. The patients thus get the minimum of standard of care.