key: cord-1003297-83ja6zr8
authors: Mylonakis, Eleftherios; Somersan-Karakaya, Selin; Sivapalasingam, Sumathi; Ali, Shazia; Sun, Yiping; Bhore, Rafia; Mei, Jingning; Miller, Jutta; Cupelli, Lisa; Hooper, Andrea T; Hamilton, Jennifer D; Pan, Cynthia; Pham, Viet; Zhao, Yuming; Hosain, Romana; Mahmood, Adnan; Davis, John D; Turner, Kenneth C; Kim, Yunji; Cook, Amanda; Menon, Vidya; Wells, Jason C; Kowal, Bari; Soo, Yuhwen; DiCioccio, A Thomas; Geba, Gregory P; Stahl, Neil; Lipsich, Leah; Braunstein, Ned; Herman, Gary; Yancopoulos, George D; Weinreich, David M
title: LB4. Casirivimab and Imdevimab for Treatment of Hospitalized Patients With COVID-19 Receiving Low Flow or No Supplemental Oxygen
date: 2021-12-04
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab466.1645
sha: 9f15d5f760d8baed3367c0167507c069a478ec82
doc_id: 1003297
cord_uid: 83ja6zr8

BACKGROUND: Casirivimab and imdevimab (CAS/IMDEV) is authorized for emergency use in the US for outpatients with COVID-19. We present results from patient cohorts receiving low flow or no supplemental oxygen at baseline from a phase 1/2/3, randomized, double-blinded, placebo (PBO)-controlled trial of CAS/IMDEV in hospitalized patients (pts) with COVID-19. METHODS: Hospitalized COVID-19 pts were randomized 1:1:1 to 2.4 g or 8.0 g of IV CAS/IMDEV (co-administered) or PBO. Primary endpoints were time-weighted average (TWA) change in viral load from baseline (Day 1) to Day 7; proportion of pts who died or went on mechanical ventilation (MV) through Day 29. Safety was evaluated through Day 57. The study was terminated early due to low enrollment (no safety concerns). RESULTS: Analysis was performed in pooled cohorts (low flow or no supplemental oxygen) as well as combined treatment doses (2.4 g and 8.0 g). The prespecified primary virologic analysis was in seronegative (seroneg) pts (combined dose group n=360; PBO n=160), where treatment with CAS/IMDEV led to a significant reduction in viral load from Day 1–7 (TWA change: LS mean (SE): -0.28 (0.12); 95% CI: -0.51, -0.05; P=0.0172; Fig. 1). The primary clinical analysis had a strong positive trend, though it did not reach statistical significance (P=0.2048), and 4/6 clinical endpoints prespecified for hypothesis testing were nominally significant (Table 1). In seroneg pts, there was a 47.0% relative risk reduction (RRR) in the proportion of pts who died or went on MV from Day 1–29 (10.3% treated vs 19.4% PBO; nominal P=0.0061; Fig. 2). There was a 55.6% (6.7% treated vs 15.0% PBO; nominal P=0.0032) and 35.9% (7.3% treated vs 11.5% PBO; nominal P=0.0178) RRR in the prespecified secondary endpoint of mortality by Day 29 in seroneg pts and the overall population, respectively (Fig. 2). No harm was seen in seropositive patients, and no safety events of concern were identified. Figure 1: TWA daily viral load decreased from baseline (Day 1) in seronegative patients receiving low flow or no supplemental oxygen [Image: see text] Table 1. Primary virologic and clinical endpoints [Image: see text] Figure 2: Clinical outcomes in hospitalized patients receiving low flow or no supplemental oxygen* [Image: see text] CONCLUSION: Co-administration of CAS/IMDEV led to a significant reduction in viral load in hospitalized, seroneg pts requiring low flow or no supplemental oxygen. In seroneg pts and the overall population, treatment also demonstrated clinically meaningful, nominally significant reductions in 28-day mortality and proportion of pts dying or requiring MV. DISCLOSURES: Eleftherios Mylonakis, MD, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Chemic labs/KODA therapeutics (Grant/Research Support)Cidara (Grant/Research Support)Leidos Biomedical Research Inc/NCI (Grant/Research Support)NIH/NIAID (Grant/Research Support)NIH/NIGMS (Grant/Research Support)Pfizer (Grant/Research Support)Regeneron (Grant/Research Support)SciClone Pharmaceuticals (Grant/Research Support) Selin Somersan-Karakaya, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Sumathi Sivapalasingam, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Excision BioTherapeutics (Employee)Regeneron Pharmaceuticals, Inc. (Shareholder, Other Financial or Material Support, Royalties, patents planned, issued or pending, former employee) Shazia Ali, PharmD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Yiping Sun, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Rafia Bhore, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Jingning Mei, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Jutta Miller, BS, RN, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Lisa Cupelli, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee) Andrea T. Hooper, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Pfizer, Inc. (Shareholder, Other Financial or Material Support, Former employee)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Jennifer D. Hamilton, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Cynthia Pan, BPharm, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Viet Pham, BS, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Yuming Zhao, MS, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Romana Hosain, MD, MPH, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Adnan Mahmood, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) John D. Davis, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Kenneth C. Turner, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Yunji Kim, PharmD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Amanda Cook, BS, Dip Reg Aff, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Jason C. Wells, MD, BARDA (Other Financial or Material Support, HHSO100201700020C) Bari Kowal, MS, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Yuhwen Soo, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) A. Thomas DiCioccio, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Gregory P. Geba, MD, DrPH, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Shareholder) Neil Stahl, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Leah Lipsich, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Ned Braunstein, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Gary Herman, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) George D. Yancopoulos, MD, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) David M. Weinreich, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder)

Background. Casirivimab and imdevimab (CAS/IMDEV) is authorized for emergency use in the US for outpatients with COVID-19. We present results from patient cohorts receiving low flow or no supplemental oxygen at baseline from a phase 1/2/3, randomized, double-blinded, placebo (PBO)-controlled trial of CAS/IMDEV in hospitalized patients (pts) with COVID-19.

Methods. Hospitalized COVID-19 pts were randomized 1:1:1 to 2.4 g or 8.0 g of IV CAS/IMDEV (co-administered) or PBO. Primary endpoints were time-weighted average (TWA) change in viral load from baseline (Day 1) to Day 7; proportion of pts who died or went on mechanical ventilation (MV) through Day 29. Safety was evaluated through Day 57. The study was terminated early due to low enrollment (no safety concerns).

Results. Analysis was performed in pooled cohorts (low flow or no supplemental oxygen) as well as combined treatment doses (2.4 g and 8.0 g). The prespecified primary virologic analysis was in seronegative (seroneg) pts (combined dose group n=360; PBO n=160), where treatment with CAS/IMDEV led to a significant reduction in viral load from Day 1-7 (TWA change: LS mean (SE): -0.28 (0.12); 95% CI: -0.51, -0.05; P=0.0172; Fig. 1 ). The primary clinical analysis had a strong positive trend, though it did not reach statistical significance (P=0.2048), and 4/6 clinical endpoints prespecified for hypothesis testing were nominally significant ( Table 1) . In seroneg pts, there was a 47.0% relative risk reduction (RRR) in the proportion of pts who died or went on MV from Day 1-29 (10.3% treated vs 19.4% PBO; nominal P=0.0061; Fig.  2 ). There was a 55.6% (6.7% treated vs 15.0% PBO; nominal P=0.0032) and 35.9% (7.3% treated vs 11.5% PBO; nominal P=0.0178) RRR in the prespecified secondary endpoint of mortality by Day 29 in seroneg pts and the overall population, respectively (Fig. 2) . No harm was seen in seropositive patients, and no safety events of concern were identified. 

Vaccines effectively prevent COVID-19, but some individuals have medical comorbidities or receive therapies that impair their immune response to vaccination, or are ineligible for vaccination. For such individuals who remain at risk of COVID-19, monoclonal antibodies may provide additional rapid protection. AZD7442 comprises 2 fully human extended half-life SARS-CoV-2-neutralizing antibodies that bind distinct epitopes of the viral spike protein receptor binding domain. AZD7442 is in development for the prevention and treatment of COVID-19. Here, we report primary Phase 3 study results of AZD7442 for pre-exposure prophylaxis of symptomatic COVID-19.

Methods. PROVENT (NCT04625725) is a Phase 3, 2:1 randomized, double-blind, placebo-controlled study of a single 300-mg AZD7442 dose (2 intramuscular injections; 150 mg each of tixagevimab and cilgavimab) for symptomatic COVID-19 prevention. Participants were unvaccinated adults (≥ 18 years old) without prior SARS-CoV-2 infection, who may benefit from immunoprophylaxis with antibodies due to an increased risk of either inadequate response to vaccination or SARS-CoV-2 exposure. The primary study endpoints were first case of SARS-CoV-2 RT-PCR-positive symptomatic illness post dose and prior to Day 183 (efficacy), and safety of AZD7442.

Results. In total, 5197 participants (mean age 53.5 years, 46% female) were randomized and dosed (safety analysis set): AZD7442 n=3460; placebo n=1737. In the primary efficacy analysis (full pre-exposure analysis set, n=5172), AZD7442 reduced the risk of developing symptomatic COVID-19 by 77% (95% confidence interval 46.0, 90.0) vs placebo (P< 0.001) (Table) . Adverse events occurred in 35% and 34% of participants administered AZD7442 and placebo, respectively, and injection site reactions occurred in 2.4% and 2.1% of participants, respectively (safety analysis set). There was 1 case of severe/critical COVID-19 and 2 COVID-19-related deaths in the placebo arm.

BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Adnan Mahmood, MD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) John D. Davis, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Kenneth C. Turner, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Yunji Kim, PharmD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Amanda Cook, BS, Dip Reg Aff, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Jason C. Wells, MD, BARDA (Other Financial or Material Support, HHSO100201700020C) Bari Kowal, MS, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Yuhwen Soo, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) A. Thomas DiCioccio, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Gregory P. Geba, MD, DrPH, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Shareholder) Neil Stahl, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder, Royalties, patents planned, issued or pending) Leah Lipsich, PhD, BARDA (Other Financial or Material Support, HHSO100201700020C)Regeneron Pharmaceuticals, Inc. (Employee, Shareholder) Ned Braunstein

Phase 3 Study of Efficacy and Safety of AZD7442 (Tixagevimab/ Cilgavimab) for Pre-exposure Prophylaxis of COVID-19 in Adults

MD 5 ; 1 University of Colorado Anschutz Medical Campus, Aurora, CO; 2 North Manchester General Hospital

The primary study endpoints were met: a one-time dose of AZD7442 demonstrated statistically significant protection against symptomatic COVID-19 and was well tolerated. AZD7442 is the first long-acting monoclonal antibody combination that represents a potential new option to augment COVID-19 prevention.PROVENT funding statement image