A randomised, placebo-controlled trial of anti-interleukin-1 receptor 1 monoclonal antibody MEDI8968 in chronic obstructive pulmonary disease

Abstract

Background: Interleukin-1 receptor 1 (IL-1R1) inhibition is a potential strategy for treating patients with chronic obstructive pulmonary disease (COPD). MEDI8968, a fully human monoclonal antibody, binds selectively to IL-1R1, inhibiting activation by IL-1α and IL-1β. We studied the efficacy and safety/tolerability of MEDI8968 in adults with symptomatic, moderate-to-very severe COPD.

Methods: This was a phase II, randomised, double-blind, placebo-controlled, multicentre, parallel-group study. Subjects aged 45-75 years and receiving standard maintenance therapy with ≥2 exacerbations in the past year were randomised 1:1 to receive placebo or MEDI8968 300 mg (600 mg intravenous loading dose) subcutaneously every 4 weeks, for 52 weeks. The primary endpoint was the moderate/severe acute exacerbations of COPD (AECOPD) rate (week 56 post-randomisation). Secondary endpoints were severe AECOPD rate and St George's Respiratory Questionnaire-COPD (SGRQ-C) score (week 56 post-randomisation).

Results: Of subjects randomised to placebo (n = 164) and MEDI8968 (n = 160), 79.3% and 75.0%, respectively, completed the study. There were neither statistically significant differences between treatment groups in moderate/severe AECOPD rate ([90% confidence interval]: 0.78 [0.63, 0.96], placebo; 0.71 [0.57, 0.90], MEDI8968), nor in severe AECOPD rate or SGRQ-C scores. Post-hoc analysis of subject subgroups (by baseline neutrophil count or tertiles of circulating neutrophil counts) did not alter the study outcome. The incidence of treatment-emergent adverse events (TEAEs) with placebo and MEDI8968 treatment was similar. The most common TEAE was worsening of COPD.

Conclusions: In this phase II study, MEDI8968 did not produce statistically significant improvements in AECOPD rate, lung function or quality of life.

Trial registration: ClinicalTrials.gov, NCT01448850 , date of registration: 06 October 2011.

Keywords: C-reactive protein; COPD; Fibrinogen; Interleukin-1 receptor 1; MEDI8968; Neutrophils; Pharmacology.

Conflict of interest statement

Ethics approval and consent to participate

Written informed consent was obtained from all subjects before study entry, which was conducted in compliance with the principles of the Declaration of Helsinki/International Conference on Harmonisation Guidance for Good Clinical Practice. The study protocol was approved by the institutional review board (IRB) at each study site and can be accessed at https://astrazenecagrouptrials.pharmacm.com/. The central IRB was Copernicus Group IRB (Durham, NC, USA). A full list of the IRBs that approved the protocol is available upon request.

Consent for publication

Not applicable.

Competing interests

PMAC has received grants from MedImmune, GlaxoSmithKline and Takeda, personal fees from GlaxoSmithKline, AstraZeneca, Takeda, Boehringer-Ingelheim and Novartis, and non-financial support from Boehringer-Ingelheim. SS has received grants from MedImmune, AstraZeneca, Mylan and Pearl, and personal fees from MedImmune, AstraZeneca, Boehringer-Ingelheim, Novartis, GlaxoSmithKline, Sunovion, Forest, Pearl, CSL Behring, Pulmonx, Bayer, Merck and Reckitt Benckiser. MD was an employee of MedImmune at the time of the study and holds AstraZeneca shares. CKW was an employee of MedImmune at the time of the study and is currently an employee of Bristol-Myers Squibb. DKF is an employee of MedImmune and holds AstraZeneca shares. MP was an employee of MedImmune at the time of the study and is currently an employee of UCB Pharma. PN is an employee of MedImmune and holds AstraZeneca shares. RvdM is an employee of MedImmune and holds AstraZeneca shares.

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Figures

Fig. 1

Subject disposition *Due to metastatic lung cancer, cardiopulmonary failure and cardiac failure. †Due to pneumonia, metastatic neoplasm, necrotising pancreatitis, cerebral haemorrhage, dyspnoea and pulmonary embolism

Fig. 2

Kaplan-Meier plot of time to first moderate or severe AECOPD (mITT population). Kaplan-Meier method used to estimate the percentage of subjects with a moderate/severe AECOPD AECOPD acute exacerbations of chronic obstructive pulmonary disease, mITT modified intention-to-treat

Fig. 3

Kaplan-Meier plot of time to first severe AECOPD (mITT population). Kaplan-Meier method used to estimate the percentage of subjects with a severe AECOPD AECOPD acute exacerbations of chronic obstructive pulmonary disease, mITT modified intention-to-treat

Fig. 4

Forest plot of treatment ratio (90% CI) by subgroup (mITT population). Values AECOPD acute exacerbations of chronic obstructive pulmonary disease, BMI body mass index, CI confidence interval, CRP C-reactive protein, CV cardiovascular, FEV1 forced expiratory volume in 1 s, GOLD Global Initiative for Chronic Obstructive Lung Disease, mITT modified intention-to-treat, MMRC Modified Medical Research Council dyspnoea scale

Fig. 5

a Circulating neutrophil count, (b) serum CRP and (c) serum fibrinogen over time (safety population). Raw mean and standard errors estimated at each visit (neutrophils, panel a; fibrinogen, panel c). Raw geometric mean and standard errors estimated at each visit (CRP, panel b); the geometric mean was used as the distribution of the CRP data was skewed, thus requiring log transformation prior to calculation of the mean CRP C-reactive protein, SE standard error

Fig. 6

Treatment effect on rate of AECOPD by baseline neutrophil count (mITT population). Exacerbation rate ratio and 90% confidence interval estimated by bisecting the data at each value of the baseline blood neutrophils and analysing the data above and below the cut point using a negative binomial regression adjusting for treatment, background therapy and history of exacerbations AECOPD acute exacerbations of chronic obstructive pulmonary disease, CI confidence interval, mITT modified intention-to-treat, SE standard error