Federal Response to COVID-19: Monoclonal Antibody Clinical Implementation Guide Outpatient administration guide for healthcare providers 2 SEPTEMBER 2021 1 Introduction to COVID-19 Monoclonal Antibody Therapy 2 Overview of Emergency Use Authorizations 3 Site and Patient Logistics Site preparation Patient pathways to monoclonal administration 4 Team Roles and Responsibilities Leadership Administrative Clinical Table of 5 Monoclonal Antibody Indications and Administration Indications Contents Preparation Administration Response to adverse events 6 Supplies and Resources Infrastructure Administrative Patient Intake Administration 7 Examples: Sites of Administration and Staffing Patterns 8 Additional Resources 1 1. Introduction to Monoclonal Therapy 2 As of 08/13/21 Summary of COVID-19 Therapeutics 1 • No Illness . Health, no infections • Exposed Asymptomatic Infected . Scope of this Implementation Guide . Not hospitalized, no limitations . Monoclonal Antibodies for post-exposure prophylaxis (Casirivimab + Imdevimab (RGN)) – EUA Issued. • Early Symptomatic . Scope of this Implementation Guide . Not hospitalized, with limitations . Monoclonal Antibodies for treatment (EUA issued): Bamlanivimab + Etesevimab1 (Lilly) Casirivimab + Imdevimab (RGN) Sotrovimab (GSK/Vir) • Hospital Adminission. Treated with Remdesivir (FDA Approved) or Tocilizumab (EUA Issued) . Hospitalized, no acute medical problems . Hospitalized, not on oxygen . Hospitlaized, on oxygen • ICU Admission . Hospitalized, high flow oxygen, non-invasive ventilation . Hospitalized, mechanical ventilation/ECMO 1. Not authorized for use in states, territories, and US jurisdictions in which the combined frequency of variants resistant to bamlanivimab and etesevimab exceeds 5%. A list of states, territories, and US jurisdictions in which bamlanivimab and etesevimab are and are not currently authorized is available on the following FDA website: https://www.fda.gov/media/151719/download 3 1 Potential Mechanisms for the Clinical Effects of Monoclonal Antibodies Mechanism 1: neutralizing antibodies could block viral infection by binding to the viral spike protein and preventing it from interacting with the cellular receptor angiotensin-converting enzyme 2 (ACE2). Mechanism 2: neutralizing antibodies could bind to the viral spike protein and block the conformational changes that the spike protein must undergo to facilitate fusion of the viral and host cell membranes. b | Antibodies could enhance viral entry into immune cells by binding to the viral spike protein with their Fab portion and to Fc receptors (FcRs) with their Fc domain. Source: Nature • Monoclonal antibodies (mAbs) directly neutralize the COVID-19 virus and are intended to prevent progression of disease • mAbs are most effective when given early in infection 4 Monoclonal Antibodies and Variants of Concern 1 • Estimated biweekly proportions of the most common SARS-CoV-2 lineages circulating in the U.S available from the CDC variant proportions data tracker1. (See sample below). Providers should assess variant prevalence in their geographic area when choosing mAb • Information on variants of concern updated in Section 15 of FDA fact sheets2,3 1. CDC Variant tracker 5 2. FDA factsheets: REGEN-COVTM (www.fda.gov/media/145611/download); bamlanivimab and etesevimab (https://www.fda.gov/media/145802/download) 3. WHO Tracking SARS-CoV-2 Variants (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ ) As of 08/13/21 1 Review of Clinical Data (I/II) Date Source Trial design / Reported outcomes Notes patients Jan 2021 JAMA RCT, n = 577 • 70% reduction in hospitalization for high-risk patients Lillly trial (Ph 2) • 50% decrease in hospitalizations, 40% decrease in emergency Feb 2021 Website Observational St. Luke's department visits Mar 2021 Lily RCT, n = 769 • 87% relative reduction vs. placebo in hospitalizations / death Lilly trial (Ph 3) Regenero Mar 2021 RCT, n = 4,567 • 70% relative reduction vs. placebo in hospitalizations / death Regen. trial (Ph 3) n • 4.2% hospitalization rate for those treated with mAbs vs. 9-14.6% Observational, Mar 2021 NEJM reported for untreated high-risk Houston Methodist n not listed • Only 13% felt symptoms progressed after therapy • Patients receiving mAb had 69% lower odds of hospitalization or Observational, mortality, and 50% lower odds of hospitalization or ED visit without Mar 2021 Medrxiv n = 234 UPMC hospitalization matched, • 6% hospitalization in treated vs. 16.2% untreated, Observational, • 1.9% of treated patients presented to E.D. / required hospitalization Apr 2021 Medrxiv n = 270 treated, ASPR vs. 12% of untreated 328 untreated 6 As of 08/13/21 1 Review of Clinical Data (II/II) Date Source Trial design / Reported outcomes Notes patients • Hospitalization rate was 4.4% for patients who received MAB therapy Observational, n Apr 2021 Medrxiv w/in 0-4 days, 5% w/in 5-7 days, and 6.1% w/in ≥8 days of symptom Northwell Health = 2,818 onset (p = 0.15) • 2400mg & 1200mg drugs sig. reduced hospitalization or all-cause death Medrxiv May 2021 RCT, n = 4,057 compared to placebo (71.3% reduction [1.3% vs 4.6%; p<0.0001] and Regen. trial (preprint) 70.4% reduction [1.0% vs 3.2%; p=0.0024], respectively • Bam significantly reduced the incidence of COVID-19 in the prevention Jun 2021 JAMA RCT, n = 1175 population compared with placebo (p<.001) at skilled nursing/assisted Lilly trial (Ph 3) living facilities • Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household Aug 2021 NEJM RCT, n = 2475 contacts of infected persons (p<0.001) Regen. trial • Among participants who became infected, REGEN-COV reduced duration of symptomatic disease and high viral load (p<0.001) 7 1 Monoclonal Antibody Safety Data Monoclonal Reported Safety Data Antibody • Blaze 1 Trial Phase 3 Data (bamlanivimab 700mg and etesevimab 1400mg): Treatment n=511, Placebo n=258 . bamlanivimab and etesevimab Deaths: 0 in treatment group, 4 in placebo group . Adverse reactions observed in those who received bamlanivimab and etesevimab were anaphylaxis (n=1, 0.7%) https://www.covid19.lilly.com/bam- and infusion-related reactions (n=16, 1.1%. The most common treatment-emergent adverse events included ete/hcp/clinical-data nausea, dizziness, and pruritis. No treatment-emergent events occurred in more than 1% of participants and were comparable with placebo • ~16,000 subjects studies in clinical trials (~13,500 received intravenous infusion and 2,500 subcutaneous injection) REGEN-COV • COV-2067 (Phase 3 trial of non-hospitalized subjects receiving intravenous administration): 0/827 patients in the casirivimab and imdevimab treatment arm had a reaction requiring termination of the infusion (urticaria, pruritis, flushing, pyrexia, shortness of breath, chest tightness, nausea, vomiting, rash) https://www.regencov.com/hcp/clinical- information/safety • COV-2069 (PEP in COVID-19 negative individuals exposed to a household member; n= 1311): Injection site reactions (erythema, pruritis) 4% in treatment group/ 2% in placebo group. No cases of anaphylaxis sotrovimab • COMET-ICE: ongoing clinical trial in non-hospitalized patients . Infusion related reactions, including immediate hypersensitivity, observed in 1% of treatment group and 1% of https://www.sotrovimab.com/hcp/clinical- placebo group safety-variant-info/ . Most common treatment-emergent adverse events (all were grade 1- mild, or grade 2-moderate): rash (2%) diarrhea (1%), no other events were reported at a higher rate with treatment compared to placebo For non-severe infusion-related reactions, consider slowing or stopping the infusion and administer appropriate medications 8 2. Overview of Emergency Use Authorization 9 2 The Role of Emergency Use Authorization (EUA) in COVID-19 Therapeutics Q: What is an emergency use authorization and how is it being used to respond to COVID-19 A: In certain types of emergencies, the FDA can issue an emergency use authorization, or EUA, to provide more timely access to critical medical products (including medicines and tests) that may help during the emergency when there are no adequate, approved, and available alternative options. The EUA process is different than FDA approval, clearance, or licensing because the EUA standard may permit authorization based on significantly less data than would be required for approval, clearance, or licensing by the FDA. This enables the FDA to authorize the emergency use of medical products that meet the criterial within weeks rather than months to years. EUAs are in effect until the emergency declaration ends but can be revised or revoked as we evaluate the needs during the emergency and new data on the product’s safety and effectiveness, or as products meet the criteria to become approved, cleared, or licensed by the FDA. About Emergency Use Autorizations (EUAs) https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization#abouteuas 10 Indications for Outpatient COVID-19 mAbs Monoclonal Antibody Indications and Routes of Administration TREATMENT of Mild to Moderate COVID-19 Infection POST-EXPOSURE PROPHYLAXIS for individuals Monoclonal Antibody within 10 days of symptom onset in patient with high risk of who are not fully vaccinated or immunocompromised, progression to severe disease with high risk of progression to severe disease bamlanivimab and Dose: 700 mg bamlanivimab and 1400 mg etesevimab*** etesevimab1 Route: Intravenous administration N/A (Eli