Phase 3 Trial Tests Ensifentrine for COPD Exacerbation Prevention

The treatment landscape for chronic obstructive pulmonary disease (COPD) continues to grow with Merck's recent announcement of the initiation of its phase 3 clinical trial assessing ensifentrine to prevent COPD exacerbations.¹

Ensifentrine (Ohtuvayre) is the first and only novel inhaled mechanism for the maintenance treatment of COPD in more than 20 years, combining bronchodilation and non-corticosteroid anti-inflammatory effects. A selective dual inhibitor of phosphodiesterase 3 and 4 (PDE3 and PDE4), it was approved by the FDA in June 2024 for the maintenance treatment of COPD in adults; the new trial addresses its potential to prevent COPD exacerbations before they can occur.^1,2 The phase 3 ENHANCE-3 trial (NCT07874815) builds on the ENHANCE-1 (NCT04542057) and ENHANCE-2 (NCT04778397) phase 3 clinical trials that supported the drug's current approval.^1,2 Although originally approved under Verona Pharma, which Merck acquired in October 2025,³ the company continues to invest in research and development to strengthen the evidence supporting ensifentrine and address unmet needs in COPD care.

"Many patients with COPD continue to experience persistent symptoms such as shortness of breath, despite current standard-of-care therapy," Mahesh Patel, MD, vice president of global clinical development at Merck Research Laboratories, said in a press release. "For these patients, exacerbations remain a major driver of disease progression and diminished quality of life."¹

ENHANCE-3 Trial Targets Patients With a History of COPD Exacerbations

The randomized, double-blind, placebo-controlled trial is expected to enroll approximately 2136 patients in 28 countries, with recruitment underway and the first patients enrolling in the US. Participants will be randomized 1:1 to receive ensifentrine twice daily plus standard of care or placebo plus standard of care.¹

Eligible adults are aged 40 to 80 years with a confirmed COPD diagnosis for at least 12 months, a current or former smoking history, and at least 1 moderate or severe exacerbation in the prior year. They must also have been on the same standard of care for at least 2 months, defined as a long-acting muscarinic antagonist (LAMA), a long-acting β2-agonist (LABA), and an inhaled corticosteroid (ICS), or a LAMA and LABA if an ICS is not appropriate.¹

The primary end point will be the annualized rate of adjudicated moderate or severe COPD exacerbations over 52 weeks. The secondary end points will include lung function, health-related quality of life, severe exacerbations, and safety.¹

ENHANCE-1 and ENHANCE-2 Data Point to Ensifentrine's Exacerbation Benefit

As the first inhaled product with a novel mechanism for COPD maintenance in more than 20 years, ensifentrine demonstrated safety and efficacy in the ENHANCE-1 and ENHANCE-2 trials, and their exacerbation findings suggest its promise as a preventive treatment.² However, this must still be confirmed by data from the ENHANCE-3 trial, which has only just begun enrolling.¹

The replicate ENHANCE trials enrolled patients aged 40 to 80 years with moderate to severe symptomatic COPD at 250 research centers in 17 countries, with 760 patients randomized and treated in ENHANCE-1 and 789 in ENHANCE-2.²

Patients randomized to receive ensifentrine experienced a significant improvement in lung function compared with placebo. It improved mean forced expiratory volume in 1 second area under the curve at 0 to 12 hours in both ENHANCE-1 (87 mL; 95% CI, 55-119) and ENHANCE-2 (94 mL; 95% CI, 65-124) (both P < .001).²

Ensifentrine also reduced the rate of moderate or severe exacerbations over 24 weeks vs placebo in ENHANCE-1 (rate ratio [RR], 0.64; 95% CI, 0.40-1.00; P = .050) and ENHANCE-2 (RR, 0.57; 95% CI, 0.38-0.87; P = .009). It also lowered the risk of a first exacerbation in the ENHANCE-1 (HR, 0.62; 95% CI, 0.39-0.97; P = .038) and ENHANCE-2 (HR, 0.58; 95% CI, 0.38-0.87; P = .009) populations.²

Treatment-emergent adverse events were similar between groups, occurring in 38.4% of patients receiving ensifentrine vs 36.4% receiving placebo in ENHANCE-1 and in 35.3% vs 35.4%, respectively, in ENHANCE-2.²

More than 390 million people worldwide were estimated to have COPD as of 2019, and the disease has no cure.¹

"We remain committed to advancing innovative research to help the millions of people impacted by this disease worldwide," Patel said.¹

References

1. Merck initiates phase 3 study evaluating OHTUVAYRE (ensifentrine) for the prevention of COPD exacerbations in adult patients receiving standard of care with a history of exacerbations. Merck. November 3, 2026. Accessed November 12, 2026. https://www.merck.com/news/merck-initiates-phase-3-study-evaluating-ohtuvayre-ensifentrine-for-the-prevention-of-copd-exacerbations-in-adult-patients-receiving-standard-of-care-with-a-history-of-exacerbations/

2. McCormick B. FDA approves ensifentrine for maintenance treatment of adult patients with COPD. AJMC. June 26, 2024. Accessed November 12, 2026. https://www.ajmc.com/view/fda-approves-ensifentrine-for-maintenance-treatment-of-adult-patients-with-copd

3. Merck completes acquisition of Verona Pharma. Merck. October 7, 2025. Accessed November 12, 2026. https://www.merck.com/news/merck-completes-acquisition-of-verona-pharma/