As with vaccines, treatments are being reviewed at a rapid pace. This section will be updated frequently.
NIH Clinical Trials for Mild-to-Moderate and Severe COVID-19
- The ACTIV-6 trial will explore a pool of up to seven drugs that can be self administered that have already been FDA approved for other purposes.
- The ACTIV-3 trial will test Zyesami, a formulation of aviptadil acetate, a synthetic version of vasoactive intestinal peptide (VIP), with or without remdesivir in severely ill patients with acute respiratory failure.
- The ACTIV-2 trial, a Phase 2/3 trial to evaluate a new fully-human polyclonal antibody targeted to SARS-CoV-2, called SAB-185, has begun enrollment in non-hospitalized patients with mild or moderate cases of COVID-19. Other therapeutics being studies in ACTIV-2 include two other experimental antibodies, inhalable beta interferon (SNG001), a long-acting monoclonal antibody (AZD7442), and Camostat medilate, an orally administered serine protease inhibitor.
Treatment Trial Data and Emergency Use Authorizations (EUAs) for Monoclonal Antibody Therapy
LY-CoV555 (bamlanivimab) – Eli Lilly
- Was not effective in hospitalized patients with respect to sustained recovery during a 90-day period (A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19 | NEJM).
- In a Phase 2 trial with the same antibody in patients with mild or moderate COVID-19 who were outpatients, this treatment was associated with a greater reduction in viral load with the 2800mg dose, and reduction in symptoms and hospitalization or ER visits. In this trial, patients with persistently higher viral load were more likely to require hospitalization (SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19 | NEJM).
- Another paper published online on the same day (Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19: A Randomized Clinical Trial | JAMA) that reported later data from the same study, reversed the initial results, stating that bamlanivimab monotherapy did not result in a significant difference in viral load compared to placebo, but that a combination of bamlanivimab and etesevimab did.
- On February 9, the FDA granted an EUA for this combination for the treatment of mild-to-moderate COVID-19 in adults and children (over 12 years of age weighing at least 40 kg) who test positive for SARS-CoV-2 and who are at high risk for progressing to severe disease. The NIH Treatment Guidelines Panel recommends the use of this combination for the treatment of outpatients with mild-to-moderate COVID-19 who are at high risk for progression to severe disease and/or hospitalization. The recommended doses are 700mg bamlanivimab plus 1400mg of etesevimab and treatment should start as soon as possible after the patient has received a positive result on a SARS-CoV-2 antigen on nucleic acid amplification test and within 10 days of onset (note that this dose is less than that given in the Phase 3 trial). The panel recommends against the use in hospitalized patients with COVID-19, unless they are hospitalized for another reason and otherwise fulfill the criteria.
- In a March 10 press release, Eli Lilly announced the results of two Phase 3 cohorts comparing bamlanivimab and etesevimab at two different doses in high-risk adolescents and adults to placebo. In the cohort treated with bamlanivimab 2800mg and etesevimab 2800mg, the treated group had a 70% reduction in the risk of hospitalization or death, whereas in the second cohort using 700mg of bamlanivimab and 1400mg of etesevimab there was an 87% risk reduction.
- Trials are ongoing using monoclonal antibodies as prophylaxis in skilled nursing facilities and among household contacts of patients with infection. In a January 21 press release from Eli Lilly, the company noted that after 8 weeks of follow up in the 965 participants (299 residents and 66 staff) the OR for symptomatic COVID-19 was 0.43 in the treated group compared to placebo. In the nursing home residents, the OR was 0.20. There were no deaths in the treated group from COVID-19 versus four in the placebo group. While these monoclonal antibodies have received an EUA for treatment of mild to moderate COVID-19 in nonhospitalized patients, they do not have an EUA yet for prophylaxis. How these will be used in the settings of vaccinated patients remains to be seen, but current recommendations are to withhold vaccine for 90 days after receiving either of these treatments.
REGN-CoV2 (casirimvimab plus imdevimab) – Regeneron
- A preliminary analysis of data from an ongoing Phase 1-3 trial in nonhospitalized patients being treated with a neutralizing antibody cocktail of two fully human monoclonal antibodies showed a significant reduction in viral load compared to placebo and a trend toward reduction in patients who required a medically-attended visit (REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19 | NEJM). These trials suggest that a combination of antibodies may be more effective in combating viral resistance.
VIR-7831 - Vir Biotechnology and GSK
- In another press release, Vir Biotechnology and GSK announced that their Phase 3 trial on a monoclonal antibody treatment VIR-7831 was stopped early given an 85% reduction in hospitalization or death in adults at high risk for hospitalization. This was based on an interim analysis of data from 583 patients enrolled in the trial. These companies plan to submit an EUA application. The companies also announced the results of another study indicating that this monoclonal maintains activity against the virus variants of concern, which was submitted for publication in bioRxiv (pre-print, not peer-reviewed site).
Mavrilimumab – Kiniksa
- Investigators taking another approach to treatment performed a study using mavrilimumab, a monoclonal antibody to the GM-CSF receptor, in hospitalized patients with COVID-19 pneumonia and hypoxemia, but did not notice any benefit in the measure of being alive and off oxygen by day 14 (Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial | The Lancet Rheumatology). This is consistent with the findings with other monoclonal antibodies. They do not seem to help hospitalized patients.
- There is emerging evidence that the new SARS-CoV-2 variants, particularly the South African, are resistant to these therapies (Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization | bioRxiv).
- HHS has launched a web-based locator for COVID-19 outpatient treatment sites for monoclonal antibodies.
- The NIH, on its COVID-19 Treatment Guidelines webpage, also discusses therapy with these drugs, and feels that the current data is insufficient to recommend either for or against the use of bamlanivimab or the casirivimab plus imdevimab combination for the treatment of outpatients with mild to moderate COVID-19.
- CMS has announced that Medicare will cover these infusions without cost sharing and anticipate giving the antibody product to healthcare providers at no cost and paying for infusion. Later, Medicare anticipates setting the payment rate in the same way it set the payment rates for COVID-19 vaccines.
Treatment Trial Data and EUAs for High-Titer Convalescent Plasma Therapy
- A small study on the use of early high-titer plasma therapy in 160 adults age 65 or over with pre-existing conditions, or 75 and over without any pre-existing conditions, noted a 48% relative risk reduction for severe respiratory disease (Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults | NEJM).
- A meta-analysis of four peer reviewed and published randomized clinical trials including 1060 COVID-19 patients treated with convalescent plasms versus control noted that such treatment was not associated with improved survival or other positive outcomes (Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis | JAMA).
- A retrospective study that examined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat 3082 hospitalized adults with COVID-19 found that treatment with high-titer convalescent plasma was associated with a lower rate of death at 30 days than low-titer convalescent plasma therapy, in patients who were not being mechanically ventilated. (Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19 | NEJM).
- There are ongoing studies looking at the effect of high-titer plasma on SARS-CoV-2 variants, with mixed results. So far, these studies have not been published in peer-reviewed journals, but reports from some are encouraging.
- The FDA changed the EUA for convalescent plasma on February 4. Only high-titer convalescent plasma is authorized and only for hospitalized patients early in the course of the disease and those hospitalized with impaired humoral immunity. The authorization letter also lists those lab assays that are approved for qualifying convalescent plasma as high-titer. So far, an EUA has not been sought or granted for the use in non-hospitalized patients.
- On March 2, the NIH announced that it was halting its trial of COVID-19 convalescent plasma in ED patients with mild symptoms, noting that the treatment was unlikely to cause harm, but did not appear to benefit this group of patients.