A dose-ranging study of the inhaled dual phosphodiesterase 3 and 4 inhibitor ensifentrine in COPD

Abstract

Background: Many patients with chronic obstructive pulmonary disease (COPD) still experience daily symptoms, exacerbations, and accelerated lung function decline, even when receiving maximal combined treatment with inhaled long-acting bronchodilators and corticosteroids. Novel treatment options are needed for these patients. Phosphodiesterases (PDEs) are enzymes that impact a range of cellular functions by modulating levels of cyclic nucleotides, and there is evidence to suggest that combined inhibition of PDE3 and PDE4 can have additive (or perhaps synergistic) effects. This study investigated the efficacy and safety of ensifentrine, a first-in-class dual inhibitor of PDE 3 and 4, in patients with COPD.Methods: This randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 40-80% predicted and FEV 1 /forced vital capacity ratio ≤ 0.7. Patients were randomised equally to inhale nebulised ensifentrine 0.75, 1.5, 3 or 6 mg or placebo, all twice daily. Primary outcome: placebo-adjusted difference in peak FEV 1 (assessed over 3 h) at Week 4. Results: The study took place between July 2017 and February 2018. Of 405 patients randomly assigned to medication, 375 (92.6%) completed the study. For peak FEV 1 at Week 4, all four ensifentrine doses were superior to placebo (p ≤ 0.0001) with least squares mean differences of 146 (95% CI 75-216), 153 (83-222), 200 (131-270) and 139 (69-210) mL for ensifentrine 0.75, 1.5, 3 and 6 mg, respectively. Respiratory symptoms (assessed using the Evaluating Respiratory Symptoms questionnaire) were also significantly improved with all ensifentrine doses at Week 4. Adverse events were reported by 33.3, 44.4, 35.4 and 36.3% patients with ensifentrine 0.75, 1.5, 3 and 6 mg, respectively, and 39.2% with placebo. Conclusions:In this four-week Phase IIb study, all four ensifentrine doses significantly improved bronchodilation and symptoms, with a dose-ranging effect from 0.75 to 3 mg twice daily, and all doses well tolerated. The study supports the continuing development of ensifentrine in COPD.

<p>Symptom Improvement Following Treatment with the Inhaled Dual Phosphodiesterase 3 and 4 Inhibitor Ensifentrine in Patients with Moderate to Severe COPD – A Detailed Analysis</p>

“…We previously reported the results for mean E-RS™:COPD total score, in which there was a progressive improvement over the duration of the study for all four ensifentrine doses compared to placebo ( Figure 1A ). 11 Consistent with these total score results, in the full analysis set there was a gradual increase in all mean ensifentrine versus placebo differences for all three subscales from Week 1 to Week 4 – in other words, a relative improvement in symptoms in the ensifentrine groups ( Figure 1B to D ). The greatest ensifentrine effect was on the breathlessness subscale (indicating a relative improvement in dyspnea), for which the mean differences versus placebo were statistically significant for all four doses from Week 2 onwards, reaching an effect size of approximately –1 by Week 4.…”

“…16 The previously published primary and secondary analyses, which focused on lung function, confirmed the bronchodilator effect of ensifentrine, which was apparent from the first dose, with a more gradual effect on symptoms (as assessed using the E-RS™:COPD total score). 11 In the current analyses, the effect of ensifentrine on all three of the E-RS™:COPD subscales showed a similar pattern to the total score with gradual improvement over the study period. Whereas many questionnaires only have defined MCIDs for their total scores, the E-RS™:COPD has recognized MCID values for the total score (-2.0) and for each of the subscales.…”

“…The design of the study (including full inclusion and exclusion criteria) has been previously reported in detail. 11 In brief, eligible patients were males or females aged 40–75 years with a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 second (FEV 1 ) 40–80% predicted normal. Other than requiring all patients to be clinically stable for at least four weeks prior to entry, there were no symptomatic inclusion or exclusion criteria.…”

“…[7][8][9][10] In particular, in a four-week randomized, double-blind, placebo-controlled, parallel-group Phase IIb study in patients with COPD, ensifentrine 0.75 to 6 mg twice daily (BID) significantly improved bronchodilation and symptoms, with all doses being well tolerated. 11 In the current manuscript, we used data from this study to further profile the effect of ensifentrine on symptoms by evaluating the individual domains of the patient reported outcome instruments used. This included prespecified exploratory endpoints describing the effect of ensifentrine on the Evaluating Respiratory Symptoms (E-RS™:COPD) questionnaire subscales and St George's Respiratory Questionnaire -COPD Specific (SGRQ-C) questionnaire domains, and post hoc analyses of E-RS™:COPD and Transition Dyspnea Index (TDI) responders.…”

Chronic obstructive pulmonary disease - diagnosis and management of stable disease; a personalized approach to care, using the treatable traits concept based on clinical phenotypes. Position paper of the Czech Pneumological and Phthisiological Society

“…In terms of treatment, a completely new class of inhaled drugs (PDE3/4 inhibitors -ensifentrine, and PDE4 inhibitors) are expected to enter clinical practice soon 240,241 . Bifunctional bronchodilator molecules with concurrent LABA and LAMA activity are already tested in clinical trials 242 .…”