Table 3a. Anti-SARS-CoV-2 Monoclonal Antibodies: Selected Clinical Data

Double-blind, Phase 3 RCT in outpatients with mild to moderate COVID-19 who are at high risk for progressing to severe COVID-19 and/or hospitalization as defined in the BAM plus ETE EUA (n = 1,035)

Note: These data are from the FDA EUA for BAM plus ETE and from a conference abstract presentation.

• Aged ≥12 years
• Not currently hospitalized
• ≥1 mild or moderate COVID-19 symptom
• At high risk for progressing to severe COVID-19 and/or hospitalization

Key Exclusion Criteria:

• SpO₂ ≤93% on room air, or
• Respiratory rate ≥30 breaths/min, or
• Heart rate ≥125 bpm

Interventions:

• Single IV infusion of:
  • BAM 2,800 mg plus ETE 2,800 mg, or
  • Placebo
• Administered within 3 days after receiving a positive result on a SARS-CoV-2 virologic test

Primary Endpoint:

• Proportion of participants with COVID-19 related hospitalization (defined as ≥24 hours of acute care) or death by any cause by Day 29

Secondary Endpoints:

• Proportion of participants with persistently high VL (defined as SARS-CoV-2 level >5.27 log₁₀ copies/mL) at Day 7
• Mean change in VL from baseline to Days 3, 5, and 7

• BAM plus ETE (n = 518) and placebo (n = 517)

Participant Characteristics:

• Median age was 56 years; 31% of the participants were aged ≥65 years.
• 48% of the participants were men.
• 87% of the participants were White; 8% were Black or African American; and 29% were Hispanic/Latinx.
• Mean duration of symptoms was 4 days.
• 77% of the participants had mild COVID-19.

Primary Outcomes:

• Proportion of participants with COVID-19 related hospitalization or death by any cause by Day 29:
  • 11 of 518 participants (2.1%) in the BAM plus ETE arm vs. 36 of 517 (7.0%) in the placebo arm (P = 0.0004)
  • Relative reduction: 70%
• Proportion of participants who had died from any cause by Day 29:
  • 0 of 518 participants (0%) in the BAM plus ETE arm vs. 10 of 517 (1.9%) in the placebo arm (P < 0.001).

Secondary Outcomes:

The proportion of participants with persistently high VLs at Day 7 was 10% in the BAM plus ETE arm vs. 29% in the placebo arm (P < 0.000001).

• Trial data have not yet been peer reviewed and published.

Interpretation:

• There was a 5% absolute reduction and a 70% relative reduction in COVID-19-related hospitalizations or deaths from any cause among the participants who received BAM plus ETE compared to those who received placebo.
• Data are for a BAM plus ETE dose which is not the dose authorized in the EUA.

Double-blind, Phase 3 RCT in outpatients with mild to moderate COVID-19 (n = 4,180 for modified full analysis subset of the Phase 3 trial)

These data are publicly available but have not been peer reviewed or published.

• Onset of COVID-19 symptoms ≤7 days before randomization
• SARS-CoV-2 PCR positive at baseline
• Criteria only for the modified full analysis:
  • Aged ≥18 years
  • ≥1 risk factor for severe COVID-19

Interventions:

• Single IV infusion of:
• CAS 600 mg plus IMD 600 mg,
• CAS 1,200 mg plus IMD 1,200 mg, or
• Placebo

Endpoint:

• Proportion of participants with COVID-19-related hospitalization or all-cause death through Day 29

• CAS 600 mg plus IMD 600 mg (n = 736) vs. placebo (n = 748)
• CAS 1,200 mg plus IMD 1,200 mg (n = 1,355) vs. placebo (n = 1,341)

Participant Characteristics:

• Median age was 50 years.
• 35% of the participants were Hispanic/Latinx and 5% were Black or African American.
• Median duration of symptoms prior to enrollment was 3 days (IQR 2–5 days).⁴

Outcomes:

• Percentage of participants with COVID-19-related hospitalization or all-cause death through Day 29 (based on participants in the modified cohort):
  • 7 of 736 (1.0%) in the CAS 600 mg plus IMD 600 mg arm vs. 24 of 748 (3.2%) in the placebo arm (P = 0.0024)
  • 18 of 1,355 (1.3%) in the CAS 1,200 mg plus IMD 1,200 mg arm vs. 62 of 1,341 (4.6%) in the placebo arm (P < 0.0001)
• Percentage of participants who died (based on all study participants):
  • 1 of 827 (0.1%) in the CAS 600 mg plus IMD 600 mg arm
  • 1 of 1,849 (0.05%) in the CAS 1,200 mg plus IMD 1,200 mg arm
  • 5 of 1,843 (0.3%) in the placebo arm

• The modified full analysis data have not been peer reviewed or published.
• Details of the study design, follow-up, and full methods are limited.

Interpretation:

• There was a 2.2% absolute reduction and a 70% relative risk reduction in COVID-19-related hospitalizations or all-cause deaths in participants who received CAS 600 mg plus IMD 600 mg compared to those who received placebo.
• There was a 3.3% absolute reduction and a 71% relative risk reduction in COVID-19 related hospitalizations and all-cause deaths in participants who received CAS 1,200 mg plus IMD 1,200 mg compared to those who received placebo.

Double-blind, Phase 1 and 2 RCT in outpatients with mild to moderate COVID-19 (n = 799)

Note: These data are from the FDA EUA for CAS plus IMD.

• Onset of COVID-19 symptoms ≤7 days before randomization
• SpO₂ ≥93% on room air

Key Exclusion Criteria:

• Hospitalization before or at randomization due to COVID-19
• Prior, current, or planned future use of any of the treatments specified in the protocol (e.g., COVID-19 CP, IVIG for any indication)

Interventions:

• Single IV infusion of:
  • CAS plus IMD 2,400 mg (CAS 1,200 mg and IMD 1,200 mg),
  • CAS plus IMD 8,000 mg (CAS 4,000 mg and IMD 4,000 mg), or
  • Placebo
• Administered ≤3 days after receiving a positive result on a SARS-CoV-2 virologic test

Primary Endpoint:

• TWA change in NP VL from baseline to Day 7

Secondary Endpoints:

• COVID-19-related medical visits including hospitalization or ED, urgent care, or physician office/telemedicine visit within 28 days of treatment
• Safety
• Symptom improvement

• CAS plus IMD (n = 533):
  • CAS plus IMD 2,400 mg (n = 266)
  • CAS plus IMD 8,000 mg (n = 267)
• Placebo (n = 266)

Participant Characteristics:

• Median age was 42 years; 7% of the participants were aged ≥65 years.
• 34% of the participants had risk factors for severe COVID-19.
• Median duration of symptoms was 3 days.

Primary Outcomes:

• The primary endpoint was evaluated in the modified full analysis set of participants with detectable virus at baseline (n = 665).
• TWA change in NP VL at Day 7 was greater among the CAS plus IMD-treated participants overall than among the placebo-treated participants (-0.36 log₁₀ copies/mL; P < 0.0001).

Secondary Outcomes:

• The proportion of participants who had COVID-19-related medical visits within 28 days of treatment was lower in the combined CAS plus IMD arms than in the placebo arm:
  • Combined CAS plus IMD arms: 2.8% of patients
  • Placebo arm: 6.5% of patients
• In a post hoc analysis, percentage of participants who were hospitalized or had a medical visit within 28 days of treatment:
  • All CAS plus IMD doses: 8 of 434 (2%)
  • CAS plus IMD 2,400 mg: 4 of 215 (2%)
  • CAS plus IMD 8,000 mg: 4 of 219 (2%)
  • Placebo: 10 of 231 (4%)
• In a post hoc analysis, percentage of participants at high-risk for progression to severe COVID-19 and/or hospitalization who required hospitalization or ED visit:
  • All CAS plus IMD doses: 4 of 151 (3%)
  • Placebo: 7 of 78 (9%)
• Median time to symptom improvement:
  • Combined CAS plus IMD arms: 5 days
  • Placebo arm: 6 days
• The safety profile of CAS plus IMD was similar to the profile for the placebo.
• 4 infusion related reactions of grade 2 severity or higher were reported in the CAS plus IMD 8,000 mg arm resulting in permanent discontinuation of the infusion in 2 participants; 1 participant had an anaphylactic reaction that resolved with treatment.

• Relatively small number of participants in each arm
• Low number of hospitalizations or ED visits

Interpretation:

• Compared to placebo, a single infusion of CAS plus IMD showed a reduction in NP VL at Day 7 among outpatients with mild or moderate COVID-19.
• The combined hospitalization or ED visit rate was lower in the CAS plus IMD arms than in the placebo arm, but the number of events in each arm was small.
• Because of the small number of clinical events, it is difficult to draw definitive conclusions about the clinical benefit of CAS plus IMD from this study. Additional data from a follow-up trial have been reported but remain unpublished.

REGN10933 (Casirivimab) Plus REGN10987 (Imdevimab) Versus Placebo in Outpatients With COVID-19 (R10933-10987-COV-2067 Interim Analysis)⁶

Note: The data presented in this published interim analysis represent a subset of participants described in the CAS plus IMD EUA (see study above).

• Onset of COVID-19 symptoms ≤7 days before randomization
• SpO₂ ≥93% on room air

Key Exclusion Criteria:

• Hospitalization before or at randomization due to COVID-19
• Prior, current, or planned future use of any of the treatments specified in the protocol (e.g., COVID-19 CP, IVIG for any indication)

Interventions:

• Single IV infusion of:
  • CAS plus IMD 2,400 mg (CAS 1,200 mg and IMD 1,200 mg),
  • CAS plus IMD 8,000 mg (CAS 4,000 mg and IMD 4,000 mg), or
  • Placebo
• Administered ≤3 days after receiving a positive result on a SARS-CoV-2 virologic test

Primary Endpoint:

• TWA change in NP VL from baseline to Day 7 in participants with negative serum antibody status at baseline

Secondary Endpoints:

• COVID-19-related medical visits, including hospitalization or ED, urgent care, or physician office/telemedicine visit within 28 days of treatment
• Safety
• Symptom improvement

• All CAS plus IMD doses (n = 182):
  • CAS plus IMD 2,400 mg (n = 92)
  • CAS plus IMD 8,000 mg (n = 90)
• Placebo (n = 93)

Participant Characteristics:

• Median age was 44 years (range 35–52 years).
• Median time from symptom onset to randomization was 3 days.
• Baseline serum antibody status:
  • Positive: 45% of participants
  • Negative: 41% of participants
  • Unknown: 14% of participants

Primary Outcomes:

• Primary endpoint evaluated in modified full analysis set of participants with detectable virus at baseline (n = 221).
• TWA change in NP VL at Day 7 was greater among the participants who received CAS plus IMD (-1.74 ± 0.11 log₁₀ copies/mL; 95% CI, -1.95 to -1.53) than among those who received placebo (-1.34 ± 0.13 log₁₀ copies/mL; 95% CI, -1.60 to -1.08).
• Among the participants with a negative serum antibody status at baseline, TWA change in VL was greater among those who received CAS plus IMD (-1.94 ± 0.13 log₁₀ copies/mL; 95% CI, -2.20 to -1.67) than among those who received placebo (-1.37 ± 0.20 log₁₀ copies/mL; 95% CI, -1.76 to -0.98).

Secondary Outcomes:

• The percentage of participants who had COVID-19-related medical visits within 28 days of treatment was lower in the CAS plus IMD arms than in the placebo arm:
  • All CAS plus IMD doses: 6 of 182 (3%)
  • Placebo: 6 of 93 (6%)
• Among participants with negative serum antibody status at baseline, the percentage of those who had COVID-19-related medical visits within 28 days of treatment was lower in the CAS plus IMD arms:
  • All CAS plus IMD doses: 5 of 80 (6%)
  • Placebo: 5 of 33 (15%)
• The safety profile of CAS plus IMD was similar to the profile of the placebo; 2 hypersensitivity or infusion related reactions of grade 2 severity or higher were reported in both the CAS plus IMD 8,000 mg arm and the placebo arm.
• The mean half-life for both CAS and IMD antibodies ranged from 25–37 days.

• No formal hypothesis testing
• Interim analysis
• Relatively small number of participants in each arm
• These data represent only a subset of participants described in the CAS plus IMD EUA (see the study above).
• Low number of medical visits

Interpretation:

• Compared to placebo, a single infusion of CAS plus IMD showed a reduction in VL at Day 7 among outpatients with mild or moderate COVID-19.
• The percentage of participants with medical visits was lower in the CAS plus IMD arms than in the placebo arm, but the number of events in each arm was small.
• CAS plus IMD may have a greater effect in patients who are serum antibody negative but further investigation is needed.
• Because of the small number of clinical events, it is difficult to draw definitive conclusions about the clinical benefit of CAS plus IMD from this study.