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

Last Updated: July 08, 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 4b. 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This is a preliminary report that has not yet been peer reviewed.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.