What makes Ohtuvayre different from Spiriva or Trelegy? Inside the science of dual inhibition

Merck & Co., Inc.’s $10 billion acquisition of Verona Pharma has made Ohtuvayre® (ensifentrine) one of the most closely watched COPD therapies in years. While Spiriva (tiotropium) and Trelegy Ellipta (fluticasone/umeclidinium/vilanterol) dominate the global COPD market, Ohtuvayre enters with a fundamentally different mechanism—dual phosphodiesterase 3 and 4 (PDE3/PDE4) inhibition. This unique pathway promises to reduce airway inflammation without steroids while simultaneously improving bronchodilation. As Merck integrates Verona’s respiratory portfolio, understanding how this novel approach compares to long-established inhalers is critical for prescribers, payers, and investors assessing whether Ohtuvayre can secure a significant role in COPD care.

How does Ohtuvayre’s dual PDE3/PDE4 inhibition differ mechanistically from existing inhalers like Spiriva or Trelegy?

Spiriva remains a gold-standard LAMA, blocking M3 muscarinic receptors to relax airway smooth muscles, while Trelegy Ellipta combines three classes—an inhaled corticosteroid (ICS), a LAMA, and a LABA—to target both airway constriction and inflammation. These drugs are effective in reducing exacerbations but rely heavily on muscarinic receptor blockade and corticosteroid suppression of inflammatory pathways, which can cause long-term systemic side effects.

Ohtuvayre works differently by inhibiting both PDE3 and PDE4 enzymes, raising cyclic adenosine monophosphate (cAMP) levels in airway smooth muscle and inflammatory cells. PDE3 inhibition results in direct bronchodilation, while PDE4 inhibition suppresses pro-inflammatory cytokines without the need for steroid exposure. This dual-action approach makes Ohtuvayre the first COPD therapy in decades to deliver both bronchodilatory and anti-inflammatory effects in a single molecule.

Clinical trials under Verona’s ENHANCE program showed statistically significant improvements in lung function, with some patients reporting symptomatic relief as early as Day 7. This rapid onset differentiates Ohtuvayre from many standard therapies, where benefits may take weeks to manifest, particularly in patients with high inflammatory burden.

Why does this distinction matter for prescribers and payers evaluating treatment options?

The unique mechanism directly impacts clinical decision-making. Prescribers are likely to consider Ohtuvayre as an add-on or alternative for patients who remain symptomatic despite being on LAMA/LABA or triple-combination regimens. Its non-steroidal anti-inflammatory profile could also make it attractive for patients with comorbidities aggravated by chronic steroid use, such as diabetes or osteoporosis. For payers, the value proposition lies in reducing costly exacerbations and hospitalizations, which represent the bulk of COPD-related healthcare expenditure.

Health economists argue that therapies capable of simultaneously reducing inflammation and improving airflow could significantly lower long-term care costs, especially in severe COPD populations. If real-world data supports these benefits, Ohtuvayre could be placed higher on formularies for high-risk patient groups, even with a premium price tag.

Could Ohtuvayre’s unique mechanism influence future combination therapy strategies?

Merck’s acquisition of Verona Pharma isn’t just about monotherapy potential; it’s also a strategic play for life-cycle expansion. Verona had already initiated development of a fixed-dose combination pairing ensifentrine with glycopyrrolate, a LAMA. If successful, this dual-inhibition + LAMA triple-pathway therapy could directly compete with blockbuster inhalers like Trelegy and Breztri Aerosphere while offering a steroid-sparing alternative.

Beyond COPD, Ohtuvayre’s mechanism may also have applications in overlapping airway diseases such as asthma-COPD overlap syndrome (ACOS) or even rare inflammatory lung conditions like non-cystic fibrosis bronchiectasis. Merck’s R&D infrastructure could accelerate such label expansions, building a multi-indication franchise around ensifentrine.

What challenges could limit Ohtuvayre’s competitive edge despite its novel science?

While the dual-inhibition approach is promising, Ohtuvayre faces hurdles in proving long-term cost-effectiveness compared to cheaper generics dominating the COPD market. Payers will demand robust real-world evidence demonstrating fewer exacerbations and lower hospitalization rates. Moreover, safety concerns—including psychiatric adverse events noted in trials—could limit its use in certain populations or prompt caution among regulators in markets like Japan or the EU.

Competitors are also investing heavily in next-generation inhalers and combination regimens. AstraZeneca and GlaxoSmithKline, for instance, are exploring anti-inflammatory add-ons that could rival Ohtuvayre’s steroid-sparing appeal. Merck must therefore move quickly to secure first-mover advantage, especially in fixed-dose combinations where competition could intensify by 2027–2028.

Could dual inhibition redefine COPD treatment standards?

If Merck successfully scales Ohtuvayre’s adoption and supports it with strong outcomes data, dual inhibition could mark a shift in how COPD is treated, moving away from heavy reliance on ICS-based regimens. Analysts predict that with fixed-dose combinations and additional indications, Ohtuvayre could evolve into a multi-billion-dollar franchise, reshaping the competitive respiratory landscape. For prescribers and payers, the coming years will determine whether this first-in-class therapy becomes a niche add-on for refractory patients or a new standard in COPD maintenance treatment.