Nemiralisib in Patients with an Acute Exacerbation of COPD: Placebo-Controlled, Dose-Ranging Study

William A Fahy, Farshid Homayoun-Valiani, Anthony Cahn, Jon Robertson, Alison Templeton, Wilhelmine H Meeraus, Robert Wilson, Mike Lowings, Miriam Marotti, Sarah L West, Maggie Tabberer, Edith M Hessel, William A Fahy, Farshid Homayoun-Valiani, Anthony Cahn, Jon Robertson, Alison Templeton, Wilhelmine H Meeraus, Robert Wilson, Mike Lowings, Miriam Marotti, Sarah L West, Maggie Tabberer, Edith M Hessel

Abstract

Background: Management of acute exacerbations of chronic obstructive pulmonary disease (COPD) is sometimes inadequate leading to either prolonged duration and/or an increased risk of recurrent exacerbations in the period following the initial event.

Objective: To evaluate the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ inhibitor, in patients experiencing an acute exacerbation of COPD.

Patients and methods: In this double-blind, placebo-controlled study, COPD patients (40-80 years, ≥10 pack-year smoking history, current moderate/severe acute exacerbation of COPD requiring standard-of-care treatment) were randomized to placebo or nemiralisib 12.5 µg, 50 µg, 100 µg, 250 µg, 500 µg, or 750 µg (ratio of 3:1:1:1:1:1:3; N=938) for 12 weeks with an exploratory 12-week follow-up period. The primary endpoint was change from baseline in post-bronchodilator FEV1 at week 12. Key secondary endpoints were rate of re-exacerbations, patient-reported outcomes (Exacerbations of Chronic Pulmonary Disease Tool, COPD Assessment Test, St George's Respiratory Questionnaire-COPD), plasma pharmacokinetics (PK) and safety/tolerability.

Results: There was no difference in change from baseline FEV1 at week 12 between the nemiralisib and placebo treatment groups (posterior adjusted median difference, nemiralisib 750 µg and placebo: -0.004L (95% CrI: -0.051L to 0.042L)). Overall, there were also no differences between nemiralisib and placebo in secondary endpoints, including re-exacerbations. Plasma PK increased in a dose proportional manner. The most common adverse event for nemiralisib was post-inhalation cough which appeared to be dose-related.

Conclusion: The addition of nemiralisib to standard-of-care treatment for 12 weeks did not improve lung function or re-exacerbations in patients with, and following an acute exacerbation of COPD. However, this study demonstrated that large clinical trials recruiting acutely exacerbating patients can successfully be conducted.

Keywords: COPD; acute exacerbation; dose-ranging; nemiralisib.

Conflict of interest statement

WAF, FHV, AC, JR, WHM, and SW are employees of and hold shares in GlaxoSmithKline. AT, MM, RW, ML, MT and EMH are former employees of and hold shares in GlaxoSmithKline. EMH is named on patents for compound GSK2269557 (nemiralisib). The current affiliation of AT and MM is AstraZeneca, Cambridge, United Kingdom. The current affiliation of RW is DLRC Ltd, Letchworth garden City, United Kingdom. The current affiliation of EMH is Eligo Bioscience, Paris, France. The authors report no other conflicts of interest in this work.

© 2021 Fahy et al.

Figures

Figure 1
Figure 1
Patient flow through the study.

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