Prevention of COVID-19 Following a Single Intramuscular Administration of Adintrevimab: Results From a Phase 2/3 Randomized, Double-Blind, Placebo-Controlled Trial (EVADE)

Abstract

Background The prevention of COVID-19 in vulnerable populations is a global health priority. EVADE was a phase 2/3 multicenter, double-blind, randomized, placebo-controlled trial of adintrevimab, an extended–half-life monoclonal antibody, for post-exposure (PEP) and pre-exposure prophylaxis (PrEP) of symptomatic COVID-19. Methods Eligible participants (vaccine-naïve, aged ≥12 years) were randomized 1:1 to receive a single 300-mg intramuscular injection of adintrevimab or placebo. Primary efficacy endpoints were reverse-transcription polymerase chain reaction (RT-PCR)-confirmed symptomatic COVID-19 through day 28 in the PEP cohort (RT-PCR-negative at baseline) and through month 3 in the PrEP cohort (RT-PCR-negative and seronegative at baseline) among participants randomized before emergence of the SARS-CoV-2 Omicron variant (30 November 2021). Safety was assessed through 6 months. Results Between 27 April 2021, and 11 January 2022, 2582 participants were randomized. In the primary efficacy analysis, RT-PCR-confirmed symptomatic COVID-19 occurred in 3/175 (1.7%) vs 12/176 (6.8%) adintrevimab- and placebo-treated PEP participants, respectively (74.9% relative risk reduction [RRR]; standardized risk difference –5.0%; 95% CI, –8.87 to –1.08; P=.0123), and in 12/752 (1.6%) vs 40/728 (5.5%) adintrevimab- and placebo-treated PrEP participants, respectively (71.0% RRR; standardized risk difference –3.9%; 95% CI, –5.75 to –‍2.01; P<.0001). In a prespecified exploratory analysis of 428 PrEP participants randomized after emergence of Omicron, adintrevimab reduced RT-PCR-confirmed symptomatic COVID-19 by 40.6% (standardized risk difference −8.4%; 95% CI, −15.35 to −1.46; nominal P=.0177) vs placebo. Adintrevimab was well tolerated with no serious drug-related adverse events reported. Conclusions A single intramuscular injection of adintrevimab provided prophylactic efficacy against COVID-19 due to susceptible variants without safety concerns.

A generalized framework to identify SARS-CoV-2 broadly neutralizing antibodies

“…Recombinant monoclonal antibodies or antibody cocktails have been demonstrated to be clinically active in the prevention of symptomatic COVID 12,14,50–55 . Alternative means for delivery of therapeutic antibodies to patients – to the current standard of recombinant mAb products - could prove advantageous towards more rapid and widespread deployment in a pandemic or epidemic context.…”

Synthetic coevolution reveals adaptive mutational trajectories of neutralizing antibodies and SARS-CoV-2

“…Such an approach would be analogous to updating seasonal vaccines (i.e., COVID-19 and influenza), as the re-engineered antibody may retain similar drug developability and safety profiles and offer a possible strategy for accelerated regulatory approval. An example of this was the monoclonal antibody AGD2 (precursor of ADG20/adintrevimab), which exhibited broad reactivity to pre-Omicron variants (37), but resulted in a substantial loss of neutralization potency to Omicron variants and was subsequently withdrawn from clinical development (38). A process very similar to sSHM was used to re-engineer ADG20 to have broader reactivity to Omicron variants, this resulted in the antibody VYD222 (pemivibart) (39) which recently received FDA approval (emergency use authorization) (40) To perform coevolution, we used yeast display screening of RBD combinatorial mutagenesis libraries to map the mutational landscape of antibody escape.…”