Two replicate phase 3, double-blind, placebo-controlled RCTs at 250 centres in 17 countries
Treatment
Nebulised ensifentrine, a dual PDE3 and PDE4 inhibitor
Control
Placebo
Population
760 patients in ENHANCE-1 and 789 in ENHANCE-2, aged 40-80 with moderate-to-severe symptomatic COPD
Follow-up
24 weeks (48 weeks in ENHANCE-1)
Primary endpoint
Average FEV1 area under the curve over 0-12 hours
Result
FEV1 AUC0-12 improved by 87 mL (95% CI 55 to 119) in ENHANCE-1 and 94 mL (65 to 124) in ENHANCE-2, both p<0.001. Moderate or severe exacerbations fell over 24 weeks: rate ratio 0.64 (0.40 to 1.00, p=0.050) in ENHANCE-1 and 0.57 (0.38 to 0.87, p=0.009) in ENHANCE-2. Symptom and quality-of-life endpoints improved in ENHANCE-1 but not ENHANCE-2. Adverse event rates matched placebo.
Secondary endpoints
Symptoms (E-RS), St George's Respiratory Questionnaire, exacerbation rate and time to first exacerbation
Ensifentrine significantly improved lung function in both trials, with results supporting exacerbation rate and risk reduction in a broad COPD population and in addition to other classes of maintenance therapies.
The trial authors, in the published abstract
How it has aged
The first genuinely new inhaled drug class in COPD for decades, and notable for being tolerable in a way oral roflumilast is not. The lung function gain is real but modest; the exacerbation signal was significant in only one of the two replicates, so its place in therapy is still being worked out.
Publications
Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials)
Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a Novel Phosphodiesterase 3 and 4 Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease: Randomized, Double-Blind, Placebo-controlled, Multicenter Phase III Trials (the ENHANCE Trials). Am J Respir Crit Care Med 2023 Aug 15;208(4):406-416.
Improved FEV1 AUC0-12 by 87-94 mL versus placebo in both replicate trials
Reduced moderate or severe exacerbations, significantly so in ENHANCE-2