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: COPD; acute exacerbation; nemiralisib.

Figure 1

Study schematic (Panel A) and trial profile (Panel B).

Figure 2

Median % change from baseline in distal region siVaw at FRC after 28 days.

Figure 3

Placebo-corrected change in siVaw at FRC after 12 and 28 days of treatment with nemiralisib.

Figure 4

Change from baseline in FEV₁ (Panel A) and sGaw (Panel B) in relation to the severity of the index exacerbation (FEV₁ and sGaw measured at clinical visits at baseline, Day 28 and Day 84). Data presented as median ± 95% Cr I. Analyses of FEV₁ data excludes data for one subject (281) due to erroneously large FEV₁ recorded at baseline.

Figure 5

Number of patients (out of 63 per arm) with any new exacerbation events^a during treatment and of the observed total number of severe exacerbations^b (28 in the placebo arm and 21 in the nemiralisib arm) the proportion requiring hospitalization. ^aNew exacerbation event based on observed treatment for an exacerbation; a new prescription for corticosteroids and/or antibiotics. ^bSevere exacerbations based on investigator-reported exacerbations resulting in hospitalization.