A Study of Immune System Proteins in Participants With Mild to Moderate COVID-19 Illness (BLAZE-4)

A Randomized, Double-blind, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy and Safety of Mono and Combination Therapy With Monoclonal Antibodies in Participants With Mild to Moderate COVID-19 Illness (BLAZE-4)

AbCellera Biologics Inc., Shanghai Junshi Bioscience Co., Ltd., GlaxoSmithKline, Vir Biotechnology, Inc.

The purpose of this study is to measure how well monoclonal antibodies work, either alone or in combination, against the virus that causes COVID-19. Study drug(s) will be given to participants with early symptoms of COVID-19. Samples will be taken from the back of the nose to determine how much virus is in the body at various times during the study. Participation could last about 12 or 24 weeks and includes at least 1 visit to the study site, with the remainder of assessments performed in the home, local clinic, or by phone.

Treatment 1: Pbo administered intravenously (IV). Treatment 8: Pbo For 700 mg Bamlanivimab (BAM) + 500 mg VIR-7831 (Amendment (C-e)) administered IV. Treatment 11: Pbo For 175 mg Bebtelovimab (BEB) & 700 mg BAM +1400 mg Etesevimab ( ETE) +175 mg BEB (Low Risk Participants) administered IV. Pooled Placebo (Addendum 4, IV) administered IV. Pooled Placebo (Addendum 4, SC) administered SC.

Treatment 2: 175 mg BAM +350 mg ETE administered IV. Treatment 3: 700 mg BAM +1400 mg ETE administered IV. Treatment 4: 2800 mg BAM +2800 mg ETE administered IV. Treatment 6: 350 mg BAM +700 mg ETE administered IV. Unintentional Dosing: 700 mg BAM +700 mg ETE administered IV. 700 mg BAM + 1400 mg ETE 30-min (Addendum (2)) administered IV. 700 mg BAM + 1400 mg ETE 15-min (Addendum (2)) administered IV.

Treatment 9: 175 mg BEB (Amendment (f), Low Risk Participants) administered IV. Treatment 12: 175 mg BEB (Amendment (f), High Risk Participants) administered IV. 70 mg BEB 140 mg/Min (Addendum 4, IV) administered IV. 175 mg BEB 140 mg/Min (Addendum 4, IV) administered IV. 175 mg BEB 350 mg/Min (Addendum 4, IV) administered IV. 1750 mg BEB 350 mg/Min (Addendum 4, IV) administered IV. 280 mg BEB (Addendum 4, SC) administered SC. 560 mg BEB (Addendum 4, SC) administered SC.

Treatment 10: 700 mg BAM +1400 mg ETE +175 mg BEB (Amendment (f), Low Risk Participants) administered IV. Treatment 13: 700 mg BAM +1400 mg ETE +175 mg BEB (Amendment (f), High Risk Participants) administered IV. Treatment 14: 700 mg BAM + 1400 mg ETE + 175 mg BEB(Amendment (g), High Risk, Updated Centers for Disease Control and Prevention (CDC) Criteria) administered IV. 175/700/1400 mg BAM + ETE + BEB 350 mg/Min (Addendum 4, IV) administered IV.

Treatment 1-6 and Unintentional Dosing Arms: Percentage of Participants With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Viral Load Greater Than 5.27

Percentage of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7. Missing data is estimated using Relevance Sequence Imputation (RSI). RSI is defined as follows: If Day 7 SARS-CoV-2 viral load is missing, then Day 7 will be imputed using data from the first available for Day 5, Day 3, Day 11, or Day 1.

Treatment 7-8, Amendments (C-e): Percentage of Participants With SARS-CoV-2 Viral Load Greater Than 5.27

Percentage of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7. Missing data is estimated using Last Observation Carried Forward (LOCF).

Treatment 9-11 Amendment (f), Low Risk Participants: Percentage of Participants With SARS-CoV-2 Viral Load Greater Than 5.27

Percentage of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7. Missing data is estimated using Last Observation Carried Forward (LOCF).

Treatment 12 -13, Amendment (f) High Risk Participants: Percentage of Participants With SARS-CoV-2 Viral Load Greater Than 5.27

Percentage of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7. Missing data is estimated using Last Observation Carried Forward (LOCF).

Treatment 14, Amendment (f) High Risk Participants Updated CDC Criteria: Percentage of Participants With SARS-CoV-2 Viral Load Greater Than 5.27

Percentage of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7. Missing data is estimated using Last Observation Carried Forward (LOCF).

Missing data is estimated using Relevance Sequence Imputation (RSI). RSI is defined as follows: If Day 7 SARS-CoV-2 viral load is missing, then Day 7 will be imputed using data from the first available for Day 5, Day 3, Day 11, or Day 1.

Addendum (4), Arm A - Intravenous: Percentage of Participants With SARS-CoV-2 Viral Load Greater Than 5.27

Percentage of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7. Missing data is estimated using Last Observation Carried Forward (LOCF).

Addendum (4) Arm B - Subcutaneous: Percentage of Participants With SARS-CoV-2 Viral Load Greater Than 5.27

Percentage of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7. Missing data is estimated using Last Observation Carried Forward (LOCF).

Treatment 1-6 and Unintentional Dosing Arms: Percentage of Participants Who Experience COVID-19 Related Hospitalization or Death From Any Cause

Treatment 7-8, Amendment (C-E): Percentage of Participants Who Experience COVID-19 Related Hospitalization or Death From Any Cause

Treatment 9-11 Amendment (f), Low Risk Participants: Percentage of Participants Who Experience COVID-19 Related Hospitalization or Death From Any Cause

Treatment 12 -13 Amendment (f), High Risk Participants: Percentage of Participants Who Experience COVID-19 Related Hospitalization or Death From Any Cause

Treatment 14 Amendment (f) High Risk Participants, Updated CDC Criteria: Percentage of Participants Who Experience COVID-19 Related Hospitalization or Death From Any Cause

Least squares mean (LSM) change from baseline was calculated using a mixed model repeating measures (MMRM) that included log base 10 transformed baseline as a covariate, treatment, day, treatment-by-day interaction as fixed effects. Viral load is reported as normalized viral and is unitless.

LSM change from baseline was calculated using a MMRM that included log base 10 transformed baseline as a covariate, treatment, day, treatment-by-day interaction as fixed effects. Viral load is reported as normalized viral and is unitless.

Treatment 9-11 Amendment (f), Low Risk Participants: Change From Baseline to Day 7 in SARS-CoV-2 Viral Load

LSM change from baseline was calculated using a MMRM that included log base 10 transformed baseline as a covariate, treatment, day, treatment-by-day interaction as fixed effects. Viral load is reported as normalized viral and is unitless.

Treatment 12 -13 Amendment (f), High Risk Participants: Change From Baseline to Day 7 in SARS-CoV-2 Viral Load

Baseline is defined as the last non-missing assessment recorded on or prior to the date of first study drug injection. Viral load is reported as normalized viral and is unitless.

Treatment 14, Amendment (f) High Risk Participants Updated CDC Criteria: Change From Baseline to Day 7 in SARS-CoV-2 Viral Load

Baseline is defined as the last non-missing assessment recorded on or prior to the date of first study drug injection. Viral load is reported as normalized viral and is unitless.

Baseline is defined as the last non-missing assessment recorded on or prior to the date of first study drug injection. Viral load is reported as normalized viral and is unitless.

Baseline is defined as the last non-missing assessment recorded on or prior to the date of first study drug injection. Viral load is reported as normalized viral and is unitless.

Baseline is defined as the last non-missing assessment recorded on or prior to the date of first study drug injection. Viral load is reported as normalized viral and is unitless.

Treatment 1-6 and Unintentional Dosing Arms: Percentage of Participants Demonstrating Symptom Resolution

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom resolution (yes/no) is defined as all symptoms (excluding loss of appetite, taste, and smell) on the symptom questionnaire scored as absent (score of 0). Missing data was imputed using a non-responder imputation.

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom resolution (yes/no) is defined as all symptoms (excluding loss of appetite, taste, and smell) on the symptom questionnaire scored as absent (score of 0). Missing data was imputed using a non-responder imputation.

Treatment 9-11 Amendment (f), Low Risk Participants: Percentage of Participants Demonstrating Symptom Resolution

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom resolution (yes/no) is defined as a score of 0 for shortness of breath, feeling feverish, body aches and pains, sore throat, chills, and headache, and a score of 0 or 1 for cough and fatigue on the symptom questionnaire. Missing data was imputed using a non-responder imputation.

Treatment 12 -13 Amendment (f), High Risk Participants: Percentage of Participants Demonstrating Symptom Resolution

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom resolution (yes/no) is defined as a score of 0 for shortness of breath, feeling feverish, body aches and pains, sore throat, chills, and headache, and a score of 0 or 1 for cough and fatigue on the symptom questionnaire. Missing data was imputed using a non-responder imputation.

Treatment 14, Amendment (g) High Risk Participants Updated CDC Criteria Amendment (g): Percentage of Participants Demonstrating Symptom Resolution

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom resolution (yes/no) is defined as a score of 0 for shortness of breath, feeling feverish, body aches and pains, sore throat, chills, and headache, and a score of 0 or 1 for cough and fatigue on the symptom questionnaire. Missing data was imputed using a non-responder imputation.

Treatment 1-6 and Unintentional Dosing Arms: Percentage of Participants Demonstrating Symptom Improvement

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom improvement (yes/no) is defined as a patient experiencing symptoms on the symptom questionnaire (excluding loss of appetite, taste, and smell) scored as moderate or severe (score of 2 or 3) at baseline are subsequently scored as mild or absent (score of 1 or 0), AND symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent.

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom improvement (yes/no) is defined as a patient experiencing symptoms on the symptom questionnaire (excluding loss of appetite, taste, and smell) scored as moderate or severe (score of 2 or 3) at baseline are subsequently scored as mild or absent (score of 1 or 0), AND symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent.

Treatment 9-11 Amendment (f), Low Risk Participants: Percentage of Participants Demonstrating Symptom Improvement

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom improvement (yes/no) is defined as a patient experiencing symptoms on the symptom questionnaire (excluding loss of appetite, taste, and smell) scored as moderate or severe (score of 2 or 3) at baseline are subsequently scored as mild or absent (score of 1 or 0), AND symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent.

Treatment 12 -13 Amendment (f), High Risk Participants: Percentage of Participants Demonstrating Symptom Improvement

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom improvement (yes/no) is defined as a patient experiencing symptoms on the symptom questionnaire (excluding loss of appetite, taste, and smell) scored as moderate or severe (score of 2 or 3) at baseline are subsequently scored as mild or absent (score of 1 or 0), AND symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent.

Symptoms associated with COVID-19 were evaluated using a questionnaire that contains the following symptoms: cough, shortness of breath, feeling feverish, fatigue, body aches and pain, sore throat, chills, headache, loss of appetite, and loss in taste and smell. Each symptom (excluding loss of taste and smell) was scored daily by the participant as experienced during the past 24 hours with following rating and score: None or absent (0), Mild (1), Moderate (2) and Severe (3). Loss of taste and smell was scored as Yes (Y) or No (N). Symptom improvement (yes/no) is defined as a patient experiencing symptoms on the symptom questionnaire (excluding loss of appetite, taste, and smell) scored as moderate or severe (score of 2 or 3) at baseline are subsequently scored as mild or absent (score of 1 or 0), AND symptoms on the symptom questionnaire scored as mild or absent at baseline are subsequently scored as absent.

Treatment 1-6 and Unintentional Dosing Arms: Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Treatment 7-8 Amendments (C-E): Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Treatment 9-11 Amendment (f), Low Risk Participants: Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Treatment 12 -13 Amendment (f), High Risk Participants: Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Treatment 14 Amendment (g): Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Percentage of Participants Who Experience COVID-19 Related Hospitalization, COVID-19 Related Emergency Room Visit, or Death From Any Cause

Inclusion Criteria: For low-risk participant arms 9-11 only: Are greater than or equal to (≥)18 and less than (<)65 years of age at the time of randomization and do not have the risk factors defined in the bullet point directly below For high-risk participant arms 12 and 13 only: -- Are ≥18 years of age and satisfy at least one of the following risk factors at the time of screening Are ≥65 years of age Have a body mass index (BMI) ≥ 35 Have chronic kidney disease Have type 1 or type 2 diabetes Have immunosuppressive disease Are currently receiving immunosuppressive treatment, or Are ≥55 years of age AND have cardiovascular disease, OR hypertension, OR chronic obstructive pulmonary disease or other chronic respiratory disease For high-risk participant arms 12 and 13 only: Are 12-17 years of age (inclusive) AND satisfy at least one of the following risk factors at the time of screening Have a BMI ≥85th percentile for their age and gender based on CDC growth charts, https://www.cdc.gov/growthcharts/clinical_charts.htm Have sickle cell disease Have congenital or acquired heart disease Have neurodevelopmental disorders, for example, cerebral palsy Have a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19) Have asthma or reactive airway or other chronic respiratory disease that requires daily medication for control Have type 1 or type 2 diabetes Have chronic kidney disease Have immunosuppressive disease, or Are currently receiving immunosuppressive treatment. For high-risk participants arm 14 only: Are ≥12 years of age and satisfy at least one of the following risk factors at the time of screening Are ≥65 years of age Are adults (≥18 years of age) with BMI >25 kg/m2 , or if age 12-17, have BMI ≥85th percentile for their age and gender based on CDC growth charts Have chronic kidney disease Have type 1 or type 2 diabetes Have immunosuppressive disease Are currently receiving immunosuppressive treatment Have cardiovascular disease (including congenital heart disease) or hypertension Have chronic lung diseases (for example, chronic obstructive pulmonary disease, asthma [moderate-to-severe], interstitial lung disease, cystic fibrosis and pulmonary hypertension) Have sickle cell disease Have neurodevelopmental disorder (for example, cerebral palsy) or other conditions that confer medical complexity (for example, genetic or metabolic syndromes and severe congenital anomalies) Have a medical-related technological dependence (for example, tracheostomy, gastrostomy, or positive pressure ventilation [not related to COVID-19] Are currently not hospitalized Have one or more mild or moderate COVID-19 symptoms: Fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms, or shortness of breath with exertion, nasal congestion or runny nose, new loss of smell, chills Must have sample taken for test confirming viral infection no more than 3 days prior to starting the drug infusion Are men or non-pregnant women who agree to contraceptive requirements Understand and agree to comply with planned study procedures Agree to the collection of nasopharyngeal swabs and venous blood The participant or legally authorized representative give signed informed consent and/or assent Exclusion Criteria: For low-risk participants only: BMI ≥35 Have oxygen saturation (SpO2) less than or equal to (≤)93 percent (%) on room air at sea level or ratio of arterial oxygen partial pressure (PaO2 in millimeters of mercury) to fractional inspired oxygen (FiO2) <300, respiratory rate ≥30 per minute, heart rate ≥125 per minute Require mechanical ventilation or anticipated impending need for mechanical ventilation Have known allergies to any of the components used in the formulation of the interventions Have hemodynamic instability requiring use of pressors within 24 hours of randomization Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking intervention Have any co-morbidity requiring surgery within <7 days, or that is considered life-threatening within 29 days Have any serious concomitant systemic disease, condition or disorder that, in the opinion of the investigator, should preclude participation in this study Have a history of a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test prior to the one serving as eligibility for this study Have received an investigational intervention for SARS-CoV-2 prophylaxis within 30 days before dosing Have received treatment with a SARS-CoV-2 specific monoclonal antibody Have a history of convalescent COVID-19 plasma treatment For low-risk arms only: have received a SARS-CoV-2 vaccine or have participated in a previous SARS-CoV-2 vaccine study and are currently blinded to treatment allotment Have participated, within the last 30 days, in a clinical study involving an investigational intervention. If the previous investigational intervention has a long half-life, 5 half-lives or 30 days, whichever is longer, should have passed Are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Are pregnant or breast feeding Are investigator site personnel directly affiliated with this study Have body weight <40 kilograms

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Data are available 6 months after the primary publication and approval of the indication studied in the US and European Union (EU), whichever is later. Data will be indefinitely available for requesting.

Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.

Hirsch C, Park YS, Piechotta V, Chai KL, Estcourt LJ, Monsef I, Salomon S, Wood EM, So-Osman C, McQuilten Z, Spinner CD, Malin JJ, Stegemann M, Skoetz N, Kreuzberger N. SARS-CoV-2-neutralising monoclonal antibodies to prevent COVID-19. Cochrane Database Syst Rev. 2022 Jun 17;6(6):CD014945. doi: 10.1002/14651858.CD014945.pub2.

Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

Nathan R, Shawa I, De La Torre I, Pustizzi JM, Haustrup N, Patel DR, Huhn G. A Narrative Review of the Clinical Practicalities of Bamlanivimab and Etesevimab Antibody Therapies for SARS-CoV-2. Infect Dis Ther. 2021 Dec;10(4):1933-1947. doi: 10.1007/s40121-021-00515-6. Epub 2021 Aug 10.