Monoclonal Antibodies for Treatment of COVID-19

Rajesh T. Gandhi, MD Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Management Across the COVID-19 Spectrum

Gandhi RT, CID, 2020; Gandhi RT, Lynch J, del Rio C. NEJM 2020 Boost immune responses Monoclonal Antibodies • Monoclonal antibodies against SARS-CoV-2 being studied for treatment and prevention • Target of SARS-CoV-2 • Emergency Use Authorizations for treatment of ambulatory patients with mild to moderate COVID-19 at high risk of progression and within 10 days of symptom onset: • Bamlanivimab (700 mg) • Casirivimab + Imdevimab (2400 mg) Antiviral Effect of Monoclonal Antibodies • In outpatients with mild to moderate COVID-19, bamlanivimab and casirivimab + imdevimab appear to accelerate decline in SARS CoV-2 level compared to placebo Bamlanivimab vs placebo Casirivimab/imdevimab vs placebo

Difference statistically significant for Largest reduction in viral load in intermediate dose participants seronegative at baseline

Chen P et al, NEJM, 2020; http://pi.lilly.com/eua/bamlanivimab-eua-factsheet-hcp.pdf; https://www.regeneron.com/sites/default/files/treatment-covid19-eua-fda-letter.pdf; Weinreich DM et al. N Engl J Med 2020 Dec 17 Bamlanivimab • In outpatients with mild to moderate Hospitalization/ED Visit: All Participants Treatment N Events Proportion disease (n=452) enrolled within 3 days Placebo 156 9 6% of positive SARS-CoV-2 test, lower rate 700 mg 101 1 1% of ED visits/hospitalization in those who 2800 mg 107 2 2% received bamlanivimab vs. placebo, 7000 mg 101 2 2% particularly among high-risk patients Pooled antibody 309 5 2% Hospitalization/ED Visit: Participants at Higher • Time to symptom improvement: median Risk of Hospitalization 6 days with antibody, 8 days with Treatment N Events Proportion placebo Placebo 69 7 10% 700 mg 46 1 2% • Safety of antibody and placebo 2800 mg 46 1 2% appeared to be similar 7000 mg 44 2 5% Pooled antibody 136 4 3%

Chen P et al, NEJM, 2020; http://pi.lilly.com/eua/bamlanivimab-eua-factsheet-hcp.pdf Casirivimab/Imdevimab (C/I)

• In outpatients with mild to moderate Hospitalization/ED Visit: All Participants disease (n=799) enrolled within 3 days of Treatment N Events Proportion positive SARS-CoV-2 test, lower rate of Placebo 231 10 4% hospitalization/ED visit in those who C/I 2400 mg 215 4 2% C/I 8000 mg 219 4 2% received casirivimab/imdevimab vs. Pooled antibody 434 8 2% placebo, particularly among high-risk patients Hospitalization/ED Visit: Participants at Higher Risk of Hospitalization • Median time to symptom improvement: 5 Treatment N Events Proportion days with C/I and 6 days with placebo Placebo 78 7 9% • Safety of antibodies and placebo similar C/I 2400 mg 70 2 3% C/I 8000 mg 81 2 2% • 1 anaphylactic reaction, 4 infusion reactions Pooled antibody 151 4 3% (8000 mg group)

https://www.regeneron.com/sites/default/files/treatment-covid19-eua-fda-letter.pdf; Weinreich DM et al. N Engl J Med 2020 Dec 17 Who Should be Considered for Therapy? Expanded Use Authorization Criteria: Ambulatory Patients with Mild to Moderate COVID-19 at High Risk for Progression - 1

• Body mass index (BMI) ≥35 • Chronic kidney disease • Diabetes • Immunosuppressive disease or receiving immunosuppressive treatment • ≥65 years of age • ≥55 years of age AND have • cardiovascular disease, OR • hypertension, OR • chronic obstructive pulmonary disease/other chronic respiratory disease

http://pi.lilly.com/eua/bamlanivimab-eua-factsheet-hcp.pdf https://www.regeneron.com/sites/default/files/treatment-covid19-eua-fda-letter.pdf Expanded Use Authorization Criteria: Ambulatory Patients with Mild to Moderate COVID-19 at High Risk for Progression - 2 • 12 – 17 years of age •BMI 85th percentile for their age and gender •Sickle cell disease •Congenital or acquired heart disease •Neurodevelopmental disorders, eg cerebral palsy •Medical related technological dependence, for example tracheostomy, gastrostomy or positive pressure ventilation •Asthma, reactive airway or other chronic respiratory disease that requires daily medicine

http://pi.lilly.com/eua/bamlanivimab-eua-factsheet-hcp.pdf https://www.regeneron.com/sites/default/files/treatment-covid19-eua-fda-letter.pdf Patients with Multiple Risk Factors Appear to be at Greatest Risk

COVID-NET: Adjusted rate ratios for COVID-19 Hospitalization

Kim L et al, CID 2020 What about patients hospitalized due to COVID-19? Bamlanivimab in Hospitalized Patients • Hospitalized patients with COVID-19 and without end organ failure randomized 1:1 to receive LY-CoV555 or placebo (ACTIV-3) • Stopped for futility after 314 participants enrolled: no evidence for efficacy of the antibody

NIAID Office of Communications, NIH-Sponsored ACTIV-3 Trial Closes LY-CoV555 Sub-Study, 2020; ACTIV-3/TICO LY-CoV555 Study Group, NEJM 2020 REGN-COV2 in Hospitalized Patients

• EUA recommends against Casirivimab/Imdevimab in patients who are hospitalized for COVID-19 or who require oxygen therapy due to COVID-19

• REGN-COV2 still being evaluated in hospitalized patients in the RECOVERY trial and in ongoing trial in people on low flow oxygen Management Across the COVID-19 Spectrum

Remdesivir Dexamethasone

Gandhi RT, CID, 2020; Gandhi RT, Lynch J, del Rio C. NEJM 2020 Monoclonal Antibodies: My Take • Monoclonal antibodies show promise but difficult to be certain as to magnitude of clinical benefit and which patients most likely to benefit • More data from ongoing clinical trials needed; we continue to refer patients to those trials (e.g. ACTIV-2, other trials) • For high-risk patients who are not eligible or interested in clinical trials (or if trial not available), discuss potential benefits/risks of receiving monoclonal antibodies through EUAs (shared decision making) • No comparative data to determine whether there are differences in efficacy or safety between bamlanivimab vs. casirivimab plus imdevimab • Monoclonal antibodies should not be used in patients hospitalized due to COVID-19 outside of a (e.g. ACTIV-3)