Rahway, New Jersey, USA, November 3, 2026
Merck & Co. has initiated a new Phase 3 clinical trial evaluating OHTUVAYRE® (ensifentrine) for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations in adults who continue to experience worsening respiratory symptoms despite receiving standard-of-care treatment. The study, named ENHANCE-3, will investigate whether adding ensifentrine to existing COPD treatment can reduce the frequency of moderate and severe exacerbations among patients with a documented history of these events. Patient recruitment has begun in the United States, marking another important step in Merck’s efforts to expand the clinical evidence supporting this respiratory medicine.
ENHANCE-3 Evaluates OHTUVAYRE in High-Risk COPD Patients
The ENHANCE-3 Phase 3 study is a randomized, double-blind, placebo-controlled clinical trial expected to enroll approximately 2,136 adult patients across 28 countries. It will evaluate OHTUVAYRE in patients who have experienced at least one moderate or severe COPD exacerbation during the previous year despite receiving standard-of-care treatment. Eligible participants will be adults aged 40 to 80 years with a confirmed COPD diagnosis for at least 12 months and a history of current or former smoking. Participants will be randomly assigned in a 1:1 ratio to receive either OHTUVAYRE twice daily alongside standard-of-care therapy or a placebo alongside standard-of-care therapy. Background treatment may include long-acting muscarinic antagonists (LAMA), long-acting beta-agonists (LABA) and inhaled corticosteroids (ICS). Patients who are not suitable for inhaled corticosteroids may receive a combination of LAMA and LABA. The study will assess treatment outcomes over a 52-week period, providing researchers with an opportunity to evaluate the medicine’s potential role in reducing COPD exacerbations in patients who remain at risk despite established therapies.
Primary Endpoints Focus on Reducing COPD Exacerbations
The primary endpoint of ENHANCE-3 is the annualized rate of adjudicated moderate or severe COPD exacerbations over 52 weeks. This measurement will help investigators determine whether adding ensifentrine to existing treatment reduces the frequency of clinically significant worsening episodes. COPD exacerbations can result in increased respiratory symptoms, additional medical interventions, hospitalizations and deterioration in patients’ quality of life. Secondary endpoints will examine several other important aspects of treatment, including changes in lung function, health-related quality of life, severe exacerbation rates and overall safety. Lung function will be assessed using forced expiratory volume in one second (FEV1), including measurements following treatment administration. Health-related quality of life will be evaluated using the St. George’s Respiratory Questionnaire (SGRQ). These measures will provide a broader understanding of the medicine’s potential benefits beyond exacerbation frequency. The study’s findings are expected to contribute additional clinical evidence for healthcare professionals and regulatory authorities assessing treatment strategies for adults with COPD who continue to experience exacerbations while receiving maintenance therapy.
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OHTUVAYRE’s Dual Mechanism Supports Respiratory Research
OHTUVAYRE (ensifentrine) is a first-in-class, selective dual inhibitor of phosphodiesterase 3 and 4 (PDE3 and PDE4). Its mechanism combines bronchodilator and non-corticosteroid anti-inflammatory effects in a single inhaled medicine. By supporting airway relaxation and addressing inflammatory processes, ensifentrine offers a different approach to maintenance treatment for adults with COPD. The U.S. Food and Drug Administration (FDA) approved OHTUVAYRE in June 2024 for the maintenance treatment of COPD in adult patients, based on results from the ENHANCE-1 and ENHANCE-2 Phase 3 clinical trials. Those studies demonstrated statistically significant and clinically meaningful improvements in lung function. The medicine is administered twice daily through oral inhalation using a standard jet nebulizer. The new ENHANCE-3 trial is designed to investigate an additional potential clinical benefit: reducing exacerbations when ensifentrine is used alongside existing standard-of-care therapies. This prevention objective is being evaluated in the new study and should not be confused with a separately approved indication. COPD is a progressive respiratory disease commonly associated with emphysema and chronic bronchitis. It restricts airflow and can cause breathlessness, persistent coughing, wheezing and fatigue. Exacerbations can further worsen symptoms and contribute to disease burden, making the development of effective long-term treatment strategies an important area of respiratory research. Through ENHANCE-3, Merck aims to strengthen the clinical evidence for OHTUVAYRE and investigate its potential contribution to COPD management in patients with a history of exacerbations. The results will help determine whether the medicine can provide an additional treatment benefit when combined with established therapies.
Source: Merck press release
