Merck initiates Phase 3 ENHANCE-3 trial to evaluate Ohtuvayre (ensifentrine) for reducing COPD exacerbations in 2,136 patients.
Written By: Charvi Kalal, PharmD
Reviewed By: Pharmacally Editorial Team
Merck announced on November 3, 2026, the initiation of ENHANCE-3 (NCT07874815), a Phase 3 clinical trial evaluating Ohtuvayre (ensifentrine) for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations in adults receiving standard-of-care (SOC) treatment. Recruitment has begun, with the first patients enrolling in the United States. Merck acquired Verona Pharma, the original developer of ensifentrine, in October 2025, bringing the medicine and its ongoing clinical development programme under its ownership.
The study will investigate whether adding ensifentrine to existing maintenance therapy can provide additional clinical benefit by reducing COPD exacerbations. No efficacy or safety results from ENHANCE-3 are available yet.
Ohtuvayre: Mechanism and Existing Clinical Evidence
Ohtuvayre (ensifentrine) was developed by Verona Pharma and received FDA approval on June 26, 2024, for the maintenance treatment of COPD in adults. Merck subsequently completed its acquisition of Verona Pharma in October 2025, bringing Ohtuvayre into its respiratory disease portfolio.
Ohtuvayre is a selective dual inhibitor of phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4), combining bronchodilator and non-corticosteroid anti-inflammatory effects. Its initial approval was supported by the Phase 3 ENHANCE-1 and ENHANCE-2 studies, which demonstrated significant improvements in lung function. The approved dosage is 3 mg twice daily through oral inhalation using a standard jet nebulizer with a mouthpiece.
ENHANCE-3 Study Design and Endpoints
ENHANCE-3 is a randomized, double-blind, placebo-controlled Phase 3 study planning to enroll approximately 2,136 adults across 28 countries. Participants will be randomized 1:1 to receive twice-daily Ohtuvayre or placebo, both alongside background SOC therapy.
SOC comprises a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS), or LAMA plus LABA when ICS is not appropriate.
Eligible participants include adults aged 40–80 years with a confirmed COPD diagnosis for at least 12 months, a current or former smoking history, stable SOC treatment for at least two months and at least one documented moderate or severe COPD exacerbation during the preceding year.
The primary endpoint is the annualized rate of adjudicated moderate or severe COPD exacerbations over 52 weeks.
Secondary endpoints include change from baseline in forced expiratory volume in one second (FEV1) area under the curve over 0–4 hours after dosing (AUC0–4h) at week 12, St. George’s Respiratory Questionnaire (SGRQ) responder status at week 24, annualized severe exacerbation rates and overall safety.
Safety Considerations
The available safety information comes from the existing prescribing information, not ENHANCE-3. Ohtuvayre is contraindicated in patients with hypersensitivity to ensifentrine or its components. It is not intended for acute bronchospasm and carries a warning for paradoxical bronchospasm and psychiatric adverse reactions.
In the pooled 24-week safety population, insomnia occurred in 0.6% of ensifentrine-treated patients versus 0.3% receiving placebo, while depression-related reactions occurred in 0.4% versus none. Clinical studies also reported one suicide attempt and one suicide among patients receiving ensifentrine. These events warrant careful consideration when evaluating the existing safety profile.
Other common adverse reactions included back pain, hypertension, urinary tract infection and diarrhea. Ensifentrine exposure was 2.3-fold higher in patients with moderate or severe hepatic impairment, requiring caution in this population.
Clinical Significance and Development Outlook
ENHANCE-3 addresses an important evidence gap in ensifentrine’s clinical development. While ENHANCE-1 and ENHANCE-2 established improvements in lung function, the new study is designed to determine whether those effects translate into fewer clinically significant exacerbations.
Its large planned enrollment, 52-week treatment period and adjudicated exacerbation endpoint provide a framework for evaluating this question. Importantly, maintaining background SOC allows investigators to assess the potential incremental benefit of ensifentrine rather than its effectiveness as a replacement for established maintenance therapies.
However, the announcement provides no efficacy evidence, expected completion date, assumed treatment effect or statistical power. It also does not disclose the investigational dose. The company has not reported results demonstrating that ensifentrine prevents exacerbations in this patient population.
Merck’s Dr. Mahesh Patel, vice president of global clinical development at Merck Research Laboratories, described exacerbations as an important contributor to disease progression and reduced quality of life, highlighting the need for additional treatment options.
The initiation of ENHANCE-3 therefore represents an expansion of the clinical evidence being generated for Ohtuvayre, rather than a new established treatment benefit. Its eventual results will determine whether ensifentrine can extend its clinical value beyond lung-function improvement to exacerbation prevention in adults with COPD receiving maintenance therapy.
Reference
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, 03 November 2026
Ensifentrine (MK-5884) Study for the Prevention of Chronic Obstructive Pulmonary Disease (COPD) Exacerbations in Adults with a History of Moderate or Severe Exacerbations While Receiving Standard of Care (SOC) (MK-5884-031/RPL554/ENHANCE-3) (ENHANCE-3), ClinicalTrials.gov ID NCT07874815
About the Writer
Charvi Kalal (LinkedIn) is a Pharm.D intern and aspiring medical writer with hands-on experience in medical writing, clinical research, pharmacovigilance, and clinical pharmacy. She has experience in medical content writing through CliMed, along with exposure to ADR monitoring, prescription analysis, patient counselling, literature review, and research documentation. Her research focuses on ADR monitoring and reporting in breast cancer patients receiving targeted therapy. With certifications in GCP, biomedical research, scientific writing, and clinical research, she is passionate about transforming scientific evidence into accurate, engaging, and accessible healthcare content.