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

Figures & data

Figure 1 Simplified view of the main cellular targets of dual PDE3/4 inhibition relevant to COPD.

Table 1 Summary of Clinical Studies Assessing the Efficacy of the Dual Phosphodiesterase 3 and 4 Inhibitor RPL554/Ensifentrine

First Author	Patient Groups/Disease	Study Design	n	Study Duration	RPL554/Other Drugs	Outcomes	Results
Franciosi^Citation67	Men with mild allergic asthma	Double-blind, crossover, placebo-controlled, randomised	10	Single dose	RPL 0.018 mg/kg Placebo	Other outcomes Change in FEV1 PC20 MCh	FEV1 increase at 1h of 520 mL (+14%) Increase in the PC20MCh by 1·5 doubling doses compared with placebo
	Men with clinically stable asthma	Single-blind (patients were masked), nonrandomised, single arm, placebo (day –1) followed by RPL554	12	Six days	RPL554 0.018 mg/kg Placebo	Primary outcome maximum mean increase in FEV1 during 6h after dosing vs placebo	FEV1 increased in asthmatics Day 1: +555mL Day 3: +505 mL Day 6: +485 mL
	Men with mild to moderate COPD	Open label, randomized placebo- controlled crossover	12	Single dose	RPL554 0.018 mg/kg Placebo	Other outcomes Increase from baseline in FEV1	Increase in FEV1 by 194 mL at 60 min
	Healthy men	Double-blind randomized placebo-controlled crossover	21	Single dose	RPL554 0.018 mg/kg Placebo	Primary outcome LPS-induced inflammatory cell infiltration in induced sputum (% neutrophils in sputum)	Did not reduce %neutrophils in sputum but reduced neutrophil numbers (p=0·002) and total cell numbers (p=0·002)
Singh^Citation68	COPD with short acting bronchodilator reversibility ≥150 mL increase in FEV1	Six-way, placebo-controlled crossover study	36	Single dose	RPL554 6 mg Salbutamol 200µg Ipratropium 40 µg RPL554+salbutamol RPL554+ipratropium RPL554+placebo	Primary outcome: change from baseline in peak and average FEV1 over 8 h comparing RPL554+salbutamol vs salbutamol and RPL554+ipratropium vs ipratropium Other outcomes onset of action forced vital capacity (FVC), body plethysmography measurements (lung volumes and sGaw)	Improvement in peak FEV1 comparable between salbutamol, ipratropium and RPL Peak FEV1 higher for RPL+ipratropium vs ipratropium and for RPL+salbutamol vs salbutamol Lung volumes and sGaw showed greater RPL554 combination treatment effects versus monotherapy
	COPD with short acting bronchodilator reversibility ≥150 mL increase in FEV1	Three-way crossover study	30	3 days	Tiotropium 18 µg +RPL554 1.5 mg or RPL554 3 mg or Placebo	Primary outcome: Change from baseline (pre-dose day 1) in peak and average FEV1 over 12 h on day 3 comparing RPL554 versus placebo Other outcomes onset of action forced vital capacity (FVC), body plethysmography measurements (lung volumes and sGaw)	Both RPL554 doses caused greater peak FEV1 effects than placebo. Average FEV1 (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^Citation70 Watz^Citation71	COPD ppFEV1 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 FEV1 (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 FEV1 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^Citation72	COPD ppFEV1 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 FEV1 from baseline to Week 4 Other outcomes average FEV1 (0–12h) at week four SGRQ-C	Increase in peak FEV1: +77.5 mL (0.375mg) +129 mL (3 mg) Average FEV1 (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^Citation73	Asthma Pre BD ppFEV1 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 FEV1 over 12 h for ensifentrine vs placebo and salbutamol.	Improvement in peak and average FEV1 vs placebo for all doses Effects on FEV1 were less than with both doses of salbutamol except at 24 mg

Abbreviations: COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 sec; ppFEV₁, percent predicted forced expiratory volume in 1 sec; sGaw, specific airway conductance; LPS, lipopolysaccharide; PC₂₀MCh, provocative concentration of methacholine causing a 20% fall in FEV₁; SGRQ-C, St George Respiratory Questionnaire COPD; TDI, transitional dyspnea index.

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