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Safety, Efficacy, and Pharmacokinetics of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies BMS-986414 (C135-LS) and BMS-986413 (C144-LS) Administered Subcutaneously in Non-Hospitalized Persons with COVID-19 in a Phase 2 Trial

Corada et al., Pathogens & Immunity, doi:10.20411/pai.v9i1.660
May 2024  
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Hospitalization -36% Improvement Relative Risk Worsening of ≥1 symptom 17% Recovery time 20% Viral clearance, day 7 4% Viral clearance, day 14 0% Viral clearance, day 3 3% BMS mAbs  Corada et al.  EARLY TREATMENT  DB RCT Is early treatment with BMS mAbs beneficial for COVID-19? Double-blind RCT 211 patients in the USA Lower progression with BMS mAbs (p=0.03) Corada et al., Pathogens & Immunity, May 2024 FavorsBMS mAbs Favorscontrol 0 0.5 1 1.5 2+
RCT 211 outpatients with COVID-19 showing no significant difference in time to symptom improvement with subcutaneous BMS-986414 (C135-LS, ogalvibart) and BMS-986413 (C144-LS, crexavibart) monoclonal antibodies compared to placebo. There was a trend favoring the treatment arm and participants on the monoclonal antibodies were less likely to have worsening symptoms. No significant differences were found for the proportion of patients with undetectable viral load or hospitalization. The study included a low-risk population, which may have limited the treatment effect. Higher early plasma monoclonal antibody concentrations were associated with more favorable outcomes, suggesting the subcutaneous route may not have achieved adequate concentrations quickly enough at the site of infection.
risk of hospitalization, 35.9% higher, RR 1.36, p = 0.72, treatment 4 of 104 (3.8%), control 3 of 106 (2.8%).
worsening of ≥1 symptom, 17.0% lower, RR 0.83, p = 0.03, treatment 104, control 106.
recovery time, 20.0% lower, relative time 0.80, p = 0.19, treatment 105, control 106.
risk of no viral clearance, 3.8% lower, RR 0.96, p = 0.45, treatment 104, control 106, inverted to make RR<1 favor treatment, mid-recovery, day 7.
risk of no viral clearance, no change, RR 1.00, p = 1.00, treatment 104, control 106, inverted to make RR<1 favor treatment, day 14.
risk of no viral clearance, 2.9% lower, RR 0.97, p = 0.83, treatment 104, control 106, inverted to make RR<1 favor treatment, day 3.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Corada et al., 6 May 2024, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 17 authors.
This PaperBMS mAbsAll
Safety, Efficacy, and Pharmacokinetics of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies BMS-986414 (C135-LS) and BMS-986413 (C144-LS) Administered Subcutaneously in Non-Hospitalized Persons with COVID-19 in a Phase 2 Trial AUTHORS
Katya C Corado, Kara W Chew, Mark J Giganti, Ying Mu, Courtney V Fletcher, Judith S Currier, Eric S Daar, David A Wohl, Jonathan Z Li, Carlee B Moser, Justin Ritz, Arzhang Cyrus Javan, Gene Neytman, Marina Caskey, Michael D Hughes, Davey M Smith, Joseph J Eron
Background: Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration. Methods: ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days. Results: A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA <LLoQ at day 3 (risk ratio [RR] for BMS mAbs versus placebo: 1.03; 95%CI: 0.80, 1.32), at day 7 (RR: 1.04; 95%CI: 0.94, 1.15), or at day 14 (RR: 1.00; 95%CI: 0.90, 1.12). Fewer grade 3 TEAEs were reported for the BMS mAbs arm than placebo (RR: 0.58 [95%CI: 0.25, 1.32]). Through day 28, there were no deaths, and there were 4 hospitalizations in the BMS mAbs arm versus 3 in the placebo arm. Higher early plasma mAb concentrations were associated with more favorable outcomes. Conclusions: While safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.
Sciences, Merck, and GSK/ViiV and research support through the institution from Gilead Sciences and GSK/ViiV. DAW has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. JZL consulted for Abbvie. DMS has consulted for Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. JJE is an ad hoc consultant to GSK/VIR and data monitoring committee chair for Adagio Phase III studies. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. SUPPLEMENTARY DATA Supplementary materials are available at the Pathogens and Immunity website. Supplementary data may be provided by the authors to benefit the reader. Supplementary data are not copyedited and are the sole responsibility of the authors. Questions or comments related to supplementary materials should be addressed to the corresponding author. Supplementary Tables and Figures
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