Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma

Nestor A Molfino, Piotr Kuna, Jonathan A Leff, Chad K Oh, Dave Singh, Marlene Chernow, Brian Sutton, Geoffrey Yarranton, Nestor A Molfino, Piotr Kuna, Jonathan A Leff, Chad K Oh, Dave Singh, Marlene Chernow, Brian Sutton, Geoffrey Yarranton

Abstract

Objectives: We wished to evaluate the effects of an antigranulocyte-macrophage colony-stimulating factor monoclonal antibody (KB003) on forced expiratory volume in 1 s (FEV1), asthma control and asthma exacerbations in adult asthmatics inadequately controlled by long-acting bronchodilators and inhaled/oral corticosteroids.

Settings: 47 ambulatory asthma care centres globally.

Primary outcome measures: Change in FEV1 at week 24.

Participants: 311 were screened, 160 were randomised and 129 completed the study.

Interventions: 7 intravenous infusions of either 400 mg KB003 or placebo at baseline and weeks 2, 4, 8, 12, 16 and 20.

Primary and secondary outcome measures: FEV1 at week 24, asthma control, exacerbation rates and safety in all participants as well as prespecified subgroups.

Main results: In the KB003 treated group, FEV1 at week 24 improved to 118 mL compared with 54 mL in the placebo group (p=0.224). However, FEV1 improved to 253 vs 26 mL at week 24 (p=0.02) in eosinophilic asthmatics (defined as >300 peripheral blood eosinophils/mL at baseline) and comparable improvements were seen at weeks 20 (p=0.034) and 24 (p=0.077) in patients with FEV1 reversibility ≥ 20% at baseline and at weeks 4 (p=0.029), 16 (p=0.018) and 20 (p=0.006) in patients with prebronchodilator FEV1 ≤ 50% predicted at baseline. There were no effects on asthma control or exacerbation rates. The most frequent adverse events in the KB003 group were rhinosinusitis and headache. There was no significant difference in antidrug antibody response between placebo and treated groups. There were no excess infections or changes in biomarkers known to be associated with the development of pulmonary alveolar proteinosis.

Conclusions: Higher doses and/or further asthma phenotyping may be required in future studies with KB003.

Trial registration number: NCT01603277; Results.

Keywords: THORACIC MEDICINE.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
Study schema: thick arrows denote dosing with KB003 or placebo; thin arrow denotes the primary end point assessment (forced expiratory volume in 1 s); a=week 32 visit was a phone call.
Figure 2
Figure 2
Participant disposition during the trial (see text for details).
Figure 3
Figure 3
(A) Mean change±SD in forced expiratory volume in 1 s (FEV1). At baseline: KB003 n=74; placebo n=76. Full Analysis Set (all participants who received at least 1 dose); (B) only participants who receive 4 doses of KB003 or placebo. At baseline: KB003 n=64; placebo n=65. Close circles=KB003 recipients.
Figure 4
Figure 4
Cumulative number of exacerbations in participants who received at least one dose of KB003 or placebo. Close circles=KB003 recipients (see text for details) (FEV1, forced expiratory volume in 1 s; LS, least square).
Figure 5
Figure 5
Changes from baseline in primary end point in three of the predetermined subgroups (see text for details). (A) Eosinophilic asthmatics at baseline; (B) severe airflow obstruction at randomisation and (C) augmented postbronchodilator reversibility (>20% improvement in FEV1) at baseline. Close circles=KB003 recipients (FEV1, forced expiratory volume in 1 s; LS, least square).

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