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

• Aged ≥18 years
• Not currently hospitalized
• ≥1 mild or moderate COVID-19 symptom

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 700 mg, or
  • BAM 2,800 mg, or
  • BAM 7,000 mg
• Placebo
• Administered within 3 days after a positive SARS-CoV-2 virologic test result

Primary Endpoint:

• Mean decrease in NP SARS-CoV-2 VL from baseline to Day 11 (plus or minus 4 days)

Secondary Endpoints:

• COVID-19-related hospitalization, ED visit, or death within 28 days of treatment
• Safety
• Symptom burden

• BAM (n = 309):
  • BAM 700 mg (n = 101)
  • BAM 2,800 mg (n = 107)
  • BAM 7,000 mg (n = 101)
• Placebo (n = 143)

Participant Characteristics:

• Median age: 45 years in combined BAM arms (range: 18–86 years) vs. 46 years in placebo arm (range: 18–77 years)
• Percentage of participants with risk factors for severe COVID-19: 69.6% in combined BAM arms vs. 66.4% in placebo arm
• Percentage of participants aged ≥65 years: 10.7% in combined BAM arms vs. 14.0% in placebo arm
• Median time from symptom onset to infusion of BAM or placebo: 4 days

Primary Outcomes:

• The mean log change in NP SARS-CoV-2 VL from baseline to Day 11 was significantly greater among participants in the BAM 2,800 mg arm than among those in the placebo arm: -0.53 (95% CI, -0.98 to -0.08; P = 0.02)
• The decline in VL was not significantly different between the BAM 700 mg and BAM 7,000 mg arms and the placebo arm.

Secondary Outcomes:

• The number and percentage of participants with COVID-19-related hospitalizations or ED visits within 28 days of treatment was lower among the BAM recipients than the placebo recipients:
  • All BAM doses: 5 of 309 (1.6%)
  • BAM 700 mg: 1 of 101 (1.0%)
  • BAM 2,800 mg: 2 of 107 (1.9%)
  • BAM 7,000 mg: 2 of 101 (2.0%)
  • Placebo: 9 of 143 (6.3%)
• No deaths reported.
• In post hoc analysis of high-risk participants (defined as aged ≥65 years or BMI ≥35), number and percentage of participants who required hospitalization or ED visit:
  • 4 of 95 (4.2%) in combined BAM arms
  • 7 of 48 (14.6%) in placebo arm
• The change in symptom scores (i.e., improvement from baseline) was slightly better among the BAM recipients than among the placebo recipients.
• In the BAM arms, there were no SAEs, and the safety profile of BAM was similar to that of the placebo.

• Relatively small number of participants in each arm
• Low number of hospitalizations or ED visits
• NP RT-PCR not a validated surrogate marker of disease progression or recovery
• Interim analysis

Interpretation:

• Compared to placebo, a single infusion of BAM 2,800 mg hastened decline of VL at Day 11 among outpatients with mild or moderate COVID-19. This treatment effect was not statistically significant for the other BAM doses.
• The clinical meaningfulness of this reduction in VL is unclear.
• The combined hospitalization or emergency visit rate was lower in the BAM arms than in the placebo arm, but the number of events in each arm was small. Similar rates were seen for all 3 BAM doses.
• Because of the small number of clinical events, it is difficult to draw definitive conclusions about the clinical benefit of BAM; data from larger clinical trials are needed.

• Adult hospitalized patients
• Documented SARS-CoV-2 infection
• Duration of COVID-19 symptoms ≤12 days

Key Exclusion Criteria:

• End-organ failure

Interventions:

• Single infusion of BAM 7,000 mg
• Placebo
• Participants in both arms received RDV.
• All participants received supportive care, which could include supplemental oxygen, and/or glucocorticoids when indicated.

Primary Endpoints:

• Early futility assessments: 2 ordinal outcomes at Day 5 (pulmonary and pulmonary-plus)
• Efficacy: Time to a sustained recovery defined as hospital discharge to home and remaining at home for ≥14 days
• Safety: Composite of death, SAE, or incident grade 3 or 4 AE)

Secondary Endpoint:

• Time to hospital discharge

• mITT analysis (n = 314): BAM 7,000 mg (n = 163) and placebo (n = 151)

Participant Characteristics:

• Median age: 63 years (range: 50–72 years) in BAM arm vs. 59 years (range: 48–71 years) in placebo arm
• Percentage of participants with coexisting illness: 72% in BAM arm vs. 68% in placebo arm
• Median days since symptom onset: 7 days (range: 5–9 days) in BAM arm vs. 8 days (range: 5–9 days) in placebo arm
• Percentage of participants receiving RDV: 37% in BAM arm vs. 44% in placebo arm.
  • 95% of participants began RDV before or on the day of randomization.
• Percentage of participants receiving glucocorticoids: 49% in BAM and placebo arms
• Percentage of participants requiring supplemental oxygen:
  • None: 27% in BAM arm vs. 28% in placebo arm
  • <4 L/min: 37% in BAM arm vs. 38% in placebo arm
  • ≥4 L/min: 18% in BAM arm vs. 23% in placebo arm
  • Noninvasive ventilation or high-flow device: 18% in BAM arm vs. 12% in placebo arm
• Median duration of follow-up: 31 days

Primary Outcomes:

• The OR of being in a more favorable pulmonary category in the BAM arm than in the placebo arm was 0.85 (95% CI, 0.56–1.29; P = 0.45).
• The time to sustained recovery was similar between the arms (rate ratio 1.06; 95% CI, 0.77–1.47).
• The percentage of participants with composite safety outcome of death, SAE, or incident grade 3 or 4 AE was 19% in the BAM arm vs. 14% in the placebo arm (OR 1.56; 95% CI, 0.78–3.10).

Secondary Outcome:

• The occurrence of hospital discharge was similar between the 2 arms (rate ratio 0.97; 95% CI, 0.78–1.20).

• Enrollment was stopped after futility criteria were met, resulting in smaller sample size and limited follow-up period.
• Preliminary report

Interpretation:

• No clinical benefit of BAM in hospitalized patients with COVID-19

Note: The EUA for BAM or CAS plus IMD does not include use in patients hospitalized due to COVID-19.

Double-blind, placebo-controlled, Phase 1 and 2 randomized trial 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 convalescent plasma, IVIG for any indication)

Interventions:

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

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 visits 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: 42 years (7% aged ≥65 years)
• Percentage of participants with risk factors for severe COVID-19: 34%
• Median duration of symptoms: 3 days

Primary Outcomes:

• 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, the number and 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, the number and 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 that of 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
• NP RT-PCR is not a validated surrogate marker of disease progression or recovery.

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 clinical meaningfulness of this reduction in VL is unclear.
• Combined hospitalization or ED visit rate was lower in 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; more information is needed.

Published Preliminary Subset Analysis of REGN10933 (Casirivimab) Plus REGN10987 (Imdevimab) in Outpatients with COVID-19 (R10933-10987-COV-2067 Interim Analysis)⁴

Note: The data presented in this interim analysis represent a subset of participants described in the EUA above.

• Onset of COVID-19 symptoms <7 days
• 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 convalescent plasma, IVIG for any indication)

Interventions:

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

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

Primary Outcomes:

• 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; CI, -1.95 to -1.53) than among those who received placebo (-1.34 ± 0.13 log₁₀ copies/mL; 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; CI: -2.20 to -1.67) than among those who received placebo (-1.37 ± 0.20 log₁₀ copies/mL; CI, -1.76 to -0.98).

Secondary Outcomes:

• Compared to the placebo participants, the CAS plus IMD participants had fewer COVID-19-related medical visits within 28 days of treatment:
  • All CAS plus IMD doses: 6 of 182 (3%)
  • Placebo: 6 of 93 (6%)
• Among participants with negative serum antibody status at baseline, those who received CAS plus IMD had fewer COVID-19-related medical visits within 28 days of treatment:
  • All CAS plus IMD doses: 5 of 80 (6%)
  • Placebo: 5 of 33 (15%)
• The safety profile of CAS plus IMD was similar to that 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 EUA (above).
• Low number of medical visits
• NP RT-PCR is not a validated surrogate marker of disease progression or recovery.

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 clinical meaningfulness of this reduction in VL is unclear.
• 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 with a negative serum antibody status 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; more information is needed.