REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients With COVID-19 - REGN-COV2

Dec 23, 2020
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services
Date Published:
12/17/2020
Date Updated:
12/23/2020
Original Posted Date:
12/23/2020
References

Contribution To Literature:

The results of this interim analysis of a combined phase 1-2 trial comparing REGN-COV2 to placebo showed a faster reduction in viral load/clearance of virus (highest effect within 48 hours) among nonhospitalized patients with SARS-CoV-2 infection, particularly among those who did not have endogenous antibodies at baseline.

Description:

The goal of the trial was to assess the safety and efficacy of a REGN-COV2 cocktail in reducing viral load among outpatients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study Design

Patients were randomized in a 1:1:1 fashion (combined phase 1 and 2) to either REGN-COV2 8 g (n = 90), REGN-COV2 2.4 g (n = 92), or placebo (n = 93). At baseline (day 1), the study drug was administered intravenously in a 250 ml normal saline solution over a period of 1 hour.

  • Total screened: 306
  • Total number of enrollees: 275
  • Duration of follow-up: 7 days
  • Mean age: 44 years
  • Percentage female: 51%
  • Median duration of symptoms: 29 days
  • Hispanic or Latino: 56%, Black: 13%
  • Antibody positive at baseline: 45%

Inclusion criteria:

  • Age ≥18 years
  • Positive SARS-CoV-2 test within 72 hours
  • Not hospitalized for COVID-19
  • Symptom onset within 7 days

Principal Findings:

The primary outcome was time-weighted average change from baseline in viral load through day 7 (log10 scale) among antibody-negative patients.

  • Least means square change for combined REGN-COV2 vs. placebo: -1.94 vs. -1.37 log10 copies/ml; difference −0.56 log10 copies/ml (95% confidence interval [CI] −1.02 to −0.11)
  • High-dose vs. placebo: -1.96 vs. -1.37 log10 copies/ml (difference: -0.60 log10 copies/ml)
  • Low-dose vs. placebo: -1.89 vs. -1.37 log10 copies/ml (difference: -0.52 log10 copies/ml)

All patients (antibody positive + negative):

  • Least means square change for combined REGN-COV2 vs. placebo: -1.74 vs. -1.34 log10 copies/ml; difference −0.41 log10 copies/ml (95% CI −0.71 to −0.10)
  • High-dose vs. placebo: -1.9 vs. -1.34 log10 copies/ml (difference: -0.56 log10 copies/ml)
  • Low-dose vs. placebo: -1.6 vs. -1.34 log10 copies/ml (difference: -0.25 log10 copies/ml)

Secondary analyses for REGN-COV2 vs. placebo:

  • ≥1 medically attended visit within 29 days: 3% vs. 6%, with greater efficacy in those who were antibody negative at baseline: 6% vs. 15%
  • Any serious adverse event: 1% vs. 2%
  • Grade ≥2 hypersensitivity reaction within 29 days: 1% vs. 2%

Interpretation:

The results of this interim analysis of a combined phase 1-2 trial comparing REGN-COV2 to placebo showed a faster reduction in viral load/clearance of virus (highest effect within 48 hours) among nonhospitalized patients with SARS-CoV-2 infection, particularly among those who did not have endogenous antibodies at baseline. There also appeared to be a benefit in the need for a medically attended visit within 29 days, also primarily among antibody-negative patients. No safety concerns were identified.

REGN-COV2 is a cocktail made up of two noncompeting, neutralizing human IgG1 antibodies (casirivimab and imdevimab) that target the receptor-binding domain of the SARS-CoV-2 spike protein, thereby preventing viral entry into human cells through the angiotensin-converting enzyme2 (ACE2) receptor. A “cocktail” approach was pursued because of previous experience with the emergence of treatment-resistant mutant virus when a single antibody, suptavumab, was used to target respiratory syncytial virus. Of note, the neutralizing titers achieved with REGN-COV2 were >1,000 times the titers achievable with convalescent-phase plasma. The long-term effects of this antibody infusion are unknown and will need to be carefully assessed. The impact on vaccination candidacy will also need to be understood.

References:

Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients With Covid-19. N Engl J Med 2020;Dec 17:[Epub ahead of print].

Clinical Topics: COVID-19 Hub, Prevention

Keywords: Antibodies, Neutralizing, Coronavirus, COVID-19, Immunoglobulin G, Outpatients, Peptidyl-Dipeptidase A, Primary Prevention, Respiratory Syncytial Virus, Human, severe acute respiratory syndrome coronavirus 2, Spike Glycoprotein, Coronavirus, Viral Load


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