A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

Inhaled Dual Phosphodiesterase 3/4 Inhibitors for the Treatment of Patients with COPD: A Short Review

“…All RPL554/ensifentrine doses produced a significant and dose-dependent increase in peak FEV 1 from baseline to Week 4, 72 indicating an additive bronchodilator effects. Clinically meaningful and statistically significant improvements in the SGRQ-C additive to tiotropium were observed at Week 4, exceeding the minimally clinically important difference of 4 units with the 1.5 and 3 mg doses, 72 indicating symptom improvement. A phase III randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of ensifentrine (3mg BID) over 24 weeks (with a 48-week safety subset) in subjects with moderate to severe COPD has been started with a target enrolment of 800 patients (NCT04535986).…”

“…Effects on lung function, symptoms and quality of life (QoL) were assessed over 4 weeks. All RPL554/ensifentrine doses produced a significant and dose-dependent increase in peak FEV 1 from baseline to Week 4, 72 indicating an additive bronchodilator effects. Clinically meaningful and statistically significant improvements in the SGRQ-C additive to tiotropium were observed at Week 4, exceeding the minimally clinically important difference of 4 units with the 1.5 and 3 mg doses, 72 73 although the program appears less advanced.…”

“… Average FEV 1 (0–12 h) increase was greater with RPL554 6 mg only versus placebo (+65 mL) Lung volumes and sGaw showed greater RPL554 combination treatment effects versus monotherapy Singh 70 Watz 71 COPD ppFEV 1 40–80 Randomized, double-blind, placebo-controlled, parallel-group study 405 4 weeks Nebulized ensifentrine 0.75 to 6mg twice daily Primary outcome placebo-adjusted difference in peak FEV 1 (assessed over 3 h) at Week 4. Other outcomes E-RS™:COPD total score and subscores SGRQ-C TDI focal score Statistically significant increase in peak FEV 1 for all doses: +146 mL (0.75 mg) +153 mL (1.5 mg) +200mL (3mg) +139mL (6 mg) Improvement in symptoms: E-RS™: COPD total score and subscores for dyspnea and cough and sputum TDI focal score: improvement≥1 point with all doses at week 2 and 4 SGRQ-C: numerical improvement at week 4 (not statistically significant) Ferguson 72 COPD ppFEV 1 30–70 Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study 416 4 weeks Open-label tiotropium once daily (QD) (+) blinded escalating doses of nebulized ensifentrine (0.375 mg to 3 mg) or placebo twice daily (BID). Primary outcome peak FEV 1 from baseline to Week 4 Other outcomes average FEV 1 (0–12h) at week four SGRQ-C Increase in peak FEV 1 : +77.5 mL (0.375mg) +129 mL (3 mg) Average FEV 1 (0–12h) at week four +87.5mL (3mg) Improvements in SGRQ-C≥ 4 points at week 4 for 1.5 mg and 3 mg Bjermer 73 Asthma Pre BD ppFEV 1 60–90 and increase ≥15 following inhalation of salbutamol Randomised, placebo-controlled, double-blind crossover study 29 Single dose Single nebulised doses of ensifentrine 0.4, 1.5, 6 and 24 mg, salbutamol 2.5 and 7.5 mg, and placebo Co-primary outcomes: peak and average FEV 1 over 12 h for ensifentrine vs placebo and salbutamol.…”

“…Ferguson et al recently reported the results from a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study in patients with moderate-to-severe COPD. 72 Patients were randomized to open-label tiotropium once daily (QD) plus blinded escalating doses of RPL554/ensifentrine or placebo twice daily (BID). Effects on lung function, symptoms and quality of life (QoL) were assessed over 4 weeks.…”

“…Adverse effects were generally mild and not increased compared to placebo. 67 , 68 , 70 , 72 This promising safety profile appears likely related to the inhaled nature of RPL554/ensifentrine, which likely limits the occurrence of systemic adverse effects. Of note, in the study by Bjermer et al that compared single doses of RPL554/ensifentrine (form 0.4 mg to 24 mg) to nebulized salbutamol 2.5 mg and 7.5 mg or placebo, salbutamol resulted in dose-dependent increase in heart rate and fall in blood pressure and decreases in serum potassium, all of which were milder for heart rate and blood pressure and not observed for potassium with RPL554/ensifentrine.…”