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

Int J Chron Obstruct Pulmon Dis. 2021 Jun 3:16:1637-1646. doi: 10.2147/COPD.S309320. eCollection 2021.

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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Bronchodilator Agents / therapeutic use
  • Double-Blind Method
  • Forced Expiratory Volume
  • Humans
  • Indazoles
  • Indoles
  • Oxazoles / pharmacology
  • Oxazoles / therapeutic use
  • Phosphatidylinositol 3-Kinases* / pharmacology
  • Phosphatidylinositol 3-Kinases* / therapeutic use
  • Piperazines
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / drug therapy

Substances

  • Bronchodilator Agents
  • Indazoles
  • Indoles
  • Oxazoles
  • Piperazines
  • Nemiralisib

Grants and funding

This study was funded by GlaxoSmithKline (NCT03345407). The sponsor/funder, as described under author contributions, was involved in the study design, data analysis, interpretation of data and writing of the manuscript.