Ensifentrine improves lung function, cuts exacerbations in COPD

The novel, selective, dual PDE*3 and PDE4 inhibitor ensifentrine improved lung function and reduced exacerbations in individuals with chronic obstructive pulmonary disease (COPD), findings from the ENHANCE**-1 and ENHANCE-2 trials have shown.

“In these phase III trials [evaluating the effect of] ensifentrine 3 mg BID in symptomatic, predominantly GOLD*** group B patients with moderate-to-severe COPD, the primary endpoint was met,” said the researchers.

Compared with placebo, ensifentrine improved week-12 average FEV₁ AUC^#_{0–12 hours} from baseline (87 mL; p<0.001 [ENHANCE-1] and 94 mL; p<0.001 [ENHANCE-2]), as well as the key secondary endpoints of week-12 peak FEV₁ (147 mL and 146 mL, respectively; p<0.001 for both) and morning trough FEV₁ from baseline (35 mL; p=0.041 and 49 mL; p=0.002). [Am J Respir Crit Care Med 2023;208:406-416]

There were also significant improvements in mean E-RS^## and SGRQ^## total scores with ensifentrine vs placebo at week 24 in ENHANCE-1 (-1.0; p=0.011 [E-RS] and -2.3; p=0.025 [SGRQ]) but not in ENHANCE-2 (-0.6; p=0.134 and -0.5; p=0.669, respectively).

Week 24 also saw reductions in mean daily rescue medication use with ensifentrine vs placebo in ENHANCE-1 (-0.45 puffs/day; p<0.001) and ENHANCE-2 (-0.14 puffs/day; p=0.320), as well as improvements in dyspnoea as measured by TDI^## (1.0 and 0.9; p<0.001 for both).

Overall, there were similar rates of any treatment-emergent adverse events (TEAEs; 35.3–38.4 percent) and serious TEAEs (5.6–6.7 percent) across both studies over 24 weeks. Treatment cessations owing to TEAEs were low (6.1–10.0 percent), as were the overall incidences of pneumonia events (0.7–1.7 percent).

COPD exacerbations

In ENHANCE-1, annualized moderate or severe exacerbation rate dropped with ensifentrine by 36 percent at week 24 (rate ratio [RR], 0.64; p=0.050) and by 44 percent at week 48 (RR, 0.56; p=0.052). There was also a longer time to first event with ensifentrine vs placebo at both timepoints (hazard ratio [HR], 0.62; p=0.038 [24 weeks] and HR, 0.48; p=0.007 [48 weeks]).

A similar effect in favour of ensifentrine was seen in ENHANCE-2 in terms of annualized exacerbation rate (RR, 0.57; p=0.009) and time to first event (HR, 0.58; p=0.009).

“[These rates align with previous evidence. As such,] the overall impact on the healthcare system may be substantial, given the consistent effect identified in a broad COPD population in replicate trials,” the researchers noted.

Synergistic effects with dual inhibition

The modified intention-to-treat cohorts (n=760 [ENHANCE-1] and n=789 [ENHANCE-2]) were treated over 24 weeks; ENHANCE-1 had a subgroup treated for 48 weeks. After a 28-day run-in phase to ensure stable background^### medication use, eligible participants were randomized 5:3 to ensifentrine 3 mg or placebo BID.

A substantial proportion of COPD patients report a significant symptom burden on daily living and emotional well-being, as well as persistent exacerbations, despite being on dual or triple therapy. [Int J Chron Obstruct Pulmon Dis 2018;13:1365-1376]

“The results indicate that ensifentrine, with a novel [dual] inhibition mechanism, would be a valuable and complementary addition to the limited available treatment mechanisms for patients with COPD,” the researchers said.

Dual PDE3 and PDE4 inhibition has shown synergistic effects on airway smooth muscle contraction and inflammatory response suppression compared with inhibition of PDE3 or PDE4 alone. [Br J Pharmacol 2000;131:1607-1618; Clin Exp Allergy 2011;41:535-546] “[T]his dual mechanism of action [appears] a promising strategy for the treatment of obstructive and inflammatory diseases of the respiratory tract,” said the researchers.

A new treatment option has arrived

“[The findings] are almost overwhelmingly positive, showing that ensifentrine provides bronchodilation associated with meaningful clinical benefits,” commented Dr Dave Singh from the University of Manchester in the UK, in a separate editorial. [Am J Respir Crit Care Med 2023;208:344-346]

“Despite these impressive results, the discussion will quickly move to questions and comparisons that the trials did not investigate,” he noted. “[Nonetheless,] a novel bronchodilator mechanism of action in COPD had arrived.”