An Inhaled PI3Kδ Inhibitor Improves Recovery in Acutely Exacerbating COPD Patients: A Randomized Trial

Abstract

Purpose

This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).

Methods

In this double-blind, placebo-controlled study, 126 patients (40–80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV₁) ≤80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).

Results

A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (−1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was >0% (Pr(θ>0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV₁ (change from baseline, 95% Cr I (−2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).

Conclusion

These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV₁. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.

Keywords:

• acute exacerbation
• COPD
• nemiralisib

Abbreviations

AE, adverse event; AT, air trapping; BVD, blood vessel density; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; Cr I, credible interval; ECG, electrocardiograph; FEV₁, forced expiratory volume in 1 sec; FRC, functional residual capacity; FRI, functional respiratory imaging; FVC, forced vital capacity; IALD, internal airflow lobar distribution; LAS, low attenuation score; LD-HRCT, low dose high resolution computed tomography; mMRC, modified Medical Research Council Dyspnea Scale; PEF, peak expiratory flow; PI3Kδ, phosphoinositide 3-kinase δ; SiRaw, specific imaging airway resistance; SiVaw, specific imaging airway volume; SiVaww, specific imaging airway wall thickness; TLC, total lung capacity.

Data Sharing Statement

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Acknowledgments

DISKUS is owned by/licensed to the GSK group of companies. Editorial support was provided by Kate Hollingworth of Continuous Improvement Ltd and funded by GSK.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

AC, JR, MB, GD, CL, YC, MMiz, MMont and EJ are GSK employees and all hold GSK shares. JNH, RW and EMH were GSK employees at the time of the study conduct, analysis and interpretation, and hold GSK shares. JNH and EMH are named on patents for compound GSK2269557 (nemiralisib). JNH reports patents WO2010125082A1 and WO2012055846A1 issued. EMH has a patent WO2015055691A1 issued. CVH, WV and JDB are employees of FLUIDDA, the company responsible for FRI analysis and interpretation. WV and JDB hold FLUIDDA shares. WDB reports costs from University Hospital Antwerp to perform the study. The current affiliation of JNH is Discovery, Charles River, Chesterford Research Park, Cambridge, UK. The current affiliation of RW is DLRC, Letchworth Garden City, UK. The current affiliation of WV is OncoRadiomics, Liège, Belgium. The current affiliation of EMH is Eligo Bioscience, Paris, France. The authors report no other conflicts of interest in this work.

Additional information

Funding

This study was funded by GlaxoSmithKline (NCT02294734). The sponsor/funder, as described under author contributions, was involved in the study design, data analysis, interpretation of data and writing of the manuscript.