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Table 4d. Granulocyte-Macrophage Colony-Stimulating Factor Inhibitors: Selected Clinical Data

Last Updated: July 8, 2021

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for GM-CSF inhibitors. The studies summarized below are those that have had the greatest impact on the Panel’s recommendations.

Table 4d. Granulocyte Macrophage-Colony Stimulating Factor Inhibitors: Selected Clinical Data
Study Design Methods Results Limitations and Interpretation
Otilimab in Severe COVID-19 Pneumonia (OSCAR Trial)1

Phase 2, double-blind RCT in patients with severe COVID-19 pulmonary disease in 17 countries, including the United States (n = 806)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

  • Hospitalized adults with confirmed SARS-CoV-2 pneumonia
  • New onset of oxygenation impairment requiring high-flow oxygen (≥15 L/min), noninvasive ventilation, or IMV ≤48 hours before dosing
  • CRP or ferritin >ULN

Key Exclusion Criteria:

  • Death considered likely within 48 hours
  • Multiple organ failure
  • SOFA score >10 if in the ICU
  • ECMO
  • Dialysis
  • High-dose noradrenaline (>0.15 ug/kg/min) or equivalent
  • More than 1 vasopressor

Interventions:

1:1 Randomization:
  • Otilimab 90 mg IV as a single infusion
  • Placebo

Primary Endpoint:

  • Proportion of participants alive and free of respiratory failure at Day 28

Key Secondary Endpoints:

  • All-cause mortality at Day 60 and time to all-cause mortality
  • Time to recovery
  • Admission to ICU
  • Time to ICU discharge

Number of Participants:

  • mITT analysis (n = 793): otilimab (n = 395) and placebo (n = 398)
  • Participants were enrolled from May 28–November 15, 2020, across 108 study sites.

Participant Characteristics:

  • Mean age was 59 years.
  • 77% received high-flow oxygen or noninvasive ventilation.
  • 22% were on IMV.
  • 52% were in the ICU but not on IMV.
  • 83% received corticosteroids; 34% received RDV
  • Participants were stratified by clinical status (ordinal scale 5 or 6) and age (<60 years, 60–69 years, and ≥70 years).

Primary Outcome:

  • 277 of 389 participants (71%) in the otilimab arm vs. 262 of 393 participants (67%) in the placebo arm were alive and free of respiratory failure at Day 28 (model-adjusted absolute difference of 5.3%; 95% CI, -0.8 to 11.4; P = 0.09)

Key Secondary Outcomes:

  • No difference in all-cause mortality at Day 60 between the otilimab arm and the placebo arm (23% vs. 24%; model-adjusted difference -2.4%; 95% CI, -8.0 to 3.3; P = 0.41)
  • No difference between the arms for other secondary endpoints
  • In a preplanned analysis, a benefit of otilimab was observed among those aged ≥70 years (n = 180):
    • 65.1% of otilimab recipients vs. 45.9% of placebo recipients met the primary endpoint (model-adjusted difference 19.1%; 95% CI, 5.2–33.1; P = 0.009)
    • Mortality at Day 60 was lower in otilimab arm than in placebo arm (27% vs. 41%; model-adjusted difference of 14.4%; 95% CI, 0.9–27.9; P = 0.04).

Key Limitations:

  • Changes in SOC occurred during the study period and may have affected outcomes.
  • A preplanned subgroup analysis suggested a benefit of otilimab in participants aged ≥70 years, but subgroup analyses were not adjusted for multiple comparisons.

Interpretation:

  • In this large study, no differences in outcomes were observed between the otilimab or placebo recipients with severe COVID-19 pneumonia, except for those in a subgroup of participants aged ≥70 years.
Lenzilumab in Hospitalized Patients With COVID-19 Pneumonia (LIVE-AIR Trial)2

Phase 3, double-blind RCT in hospitalized patients with severe COVID-19 pneumonia in the United States and Brazil (n = 520 across 29 study sites)

This is a preliminary report that has not yet been peer reviewed.

Key Inclusion Criteria:

  • Hospitalized adults with confirmed SARS-CoV-2 pneumonia
  • SpO2 ≤94% on room air or requiring low-flow supplemental oxygen, high-flow oxygen support, or NIPPV

Key Exclusion Criteria:

  • Requiring IMV
  • Pregnancy
  • Confirmed bacterial pneumonia or active/uncontrolled fungal or viral infection
  • Not expected to survive the 48 hours following randomization
  • Use of IL-1 inhibitors, IL-6 inhibitors, kinase inhibitors, or SARS-CoV-2 neutralizing monoclonal antibodies within prior 8 weeks

Interventions:

1:1 Randomization:
  • Lenzilumab 600 mg IV every 8 hours for 3 doses
  • Placebo

Primary Endpoint:

  • Ventilator-free survival through Day 28 (composite endpoint of time to death and time to IMV)

Key Secondary Endpoints:

  • Survival
  • Proportion of IMV, ECMO, or death
  • Time to recovery

Number of Participants:

  • mITT (n = 479): lenzilumab (n = 236) and placebo (n = 243)

Participant Characteristics:

  • Mean age was 60.5 years.
  • 64.7% were men.
  • 43.2% were White.
  • 55.1% had a BMI ≥30.
  • 40.5% received high-flow oxygen support or NIPPV at baseline.
  • 93.7% received corticosteroids; 72.4% received RDV; 69.1% received both corticosteroids and RDV.

Primary Outcome:

  • Lenzilumab improved ventilator-free survival through Day 28:
    • mITT participants: HR 1.54; 95% CI, 1.02–2.31; P = 0.041
    • ITT participants: HR 1.90; 95% CI, 1.02–3.52; P = 0.043
  • Kaplan-Meier estimate for proportion of participants who had required IMV or died through Day 28:
    • mITT lenzilumab arm: 15.6% (95% CI, 11.5–21.0); placebo arm: 22.1% (95% CI, 17.4–27.9)
    • ITT lenzilumab arm: 18.9% (95% CI, 14.5–24.3); placebo arm: 23.6% (95% CI, 18.8–29.3)
  • Primary outcome sensitivity mITT analyses showed lenzilumab improved the likelihood of ventilator-free survival in participants:
    • Aged <85 years with CRP <150 mg/L (n = 336): HR 2.96; 95% CI, 1.63–5.37; P = 0.0003
    • Receiving corticosteroids plus RDV (n = 331): HR 1.92; 95% CI, 1.20–3.07; P = 0.0067
    • Hospitalized ≤2 days prior to randomization (n = 297): HR 1.88; 95% CI, 1.13–3.12; P = 0.015

Key Secondary Outcomes:

  • No difference in proportion of participants who died: 9.6% in lenzilumab arm vs. 13.9% in placebo arm (HR 1.38; 95% CI, 0.81–2.37; P = 0.239)
  • No difference between the arms in the incidence of IMV, ECMO, or death: HR 0.67; 95% CI, 0.41–1.10; P = 0.111
  • No difference between the arms in time to recovery: HR 1.09; 95% CI, 0.88–1.35; P = 0.43)

Key Limitations:

  • The study was not powered to detect a survival benefit.
  • There were differences in access to supportive care across the study sites.

Interpretation:

  • In this large, unpublished, placebo-controlled study, lenzilumab improved ventilator-free survival in participants who were hypoxic but not mechanically ventilated.
Mavrilimumab in Patients With Severe COVID-19 Pneumonia and Systemic Hyperinflammation (MASH-COVID Trial)3

Multicenter, double-blind RCT in hospitalized patients with COVID-19 pneumonia in the United States (n = 40)

Key Inclusion Criteria:

  • Hospitalization with SARS-CoV-2 pneumonia
  • Hypoxemia (SpO2 <92% or requirement for supplemental oxygen)
  • CRP >5 mg/dL

Key Exclusion Criteria:

  • Mechanical ventilation
  • ANC <1,500/mm3
  • Uncontrolled bacterial infection

Interventions:

1:1 Randomization:
  • Mavrilimumab 6 mg/kg as a single IV infusion
  • Placebo

Primary Endpoint:

  • Proportion of participants alive and off supplemental oxygen at Day 14

Key Secondary Endpoints:

  • Survival at Day 28
  • Respiratory failure-free survival at Day 28

Number of Participants:

  • Mavrilimumab (n = 21) and placebo (n = 19)
  • Study enrollment was from May 28–September 15, 2020.

Participant Characteristics:

  • 65% were men.
  • 40% were African American.
  • 50% required nasal high-flow oxygen or noninvasive ventilation.
  • Corticosteroids use: 67% in the mavrilimumab arm, 63% in the placebo arm
  • RDV use: 76% in the mavrilimumab arm, 74% in the placebo arm

Primary Outcome:

  • No significant difference in primary outcome: 12 of 21 participants (57%) in the mavrilimumab arm vs. 9 of 19 participants (47%) in the placebo arm (OR 1.48; 95% CI, 0.43–5.16; P = 0.76)

Key Secondary Outcomes:

  • No difference in survival: 1 participant in the mavrilimumab arm vs. 3 in the placebo arm had died by Day 28 (HR 3.72; 95% CI, 0.39–35.79; P = 0.22)
  • No difference in respiratory failure free survival at Day 28: 20 participants (95%) in the mavrilimumab arm vs. 15 (79%) in the placebo arm (OR 5.33; 95% CI, 0.54–52.7; P = 0.43)

Key Limitations:

  • The small sample size resulted in low power to identify a clinically meaningful treatment effect.
  • The study was stopped early due to slow enrollment.

Interpretation:

  • In this small study, no differences in outcomes were observed between the mavrilimumab and placebo arms among participants who were not mechanically ventilated.

References

  1. Patel J, Beishuizen A, Ruiz XB, et al. A randomized trial of otilimab in severe COVID-19 pneumonia (OSCAR). medRxiv. 2021;Preprint. Available at: https://www.medrxiv.org/content/10.1101/2021.04.14.21255475v1.
  2. Temesgen Z, Burger CD, Baker J, et al. Lenzilumab efficacy and safety in newly hospitalized COVID-19 subjects: results from the live-air Phase 3 randomized double-blind placebo-controlled trial. medRxiv;Preprint. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33972949.
  3. Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatol. 2021;3(6):e410-e418. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33754144.