Drug Watch: Ensifentrine for COPD

Educational Objectives

Summary

Drug Watch: Ensifentrine is Newly Approved for Maintenance Treatment in Patients with Chronic Obstructive Pulmonary Disease

Ensifentrine (trade name: Ohtuvayre) is a novel phosphodiesterase 3 and 4 inhibitor — administered by nebulizer — that was approved recently by the U.S. FDA for maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

Background

According to a paper in the International Journal of Chronic Obstructive Pulmonary Disease (https://doi.org/10.2147/COPD.S413436), in vitro and in vivo studies have demonstrated that bronchodilator and anti-inflammatory effects are ensifentrine’s mechanisms of action. Other phosphodiesterase inhibitors that have been used to treat patients with COPD include theophylline (no longer recommended) and roflumilast (trade name: Daliresp), an oral drug that is recommended only for patients with inadequate response to maximal inhaled therapies, according to guidelines from the Global Initiative for Chronic Obstructive Lung Disease (GOLD; https://www.jwatch.org/na56004 and Am J Respir Crit Care Med 2023; 207:819).

The randomized trials that led to FDA approval

In the manufacturer-sponsored ENHANCE-1 and ENHANCE-2 trials published in the American Journal of Respiratory and Critical Care Medicine (https://doi.org/10.1164/rccm.202306-0944OC), ≈1500 patients with moderate-to-severe COPD were randomized to ensifentrine or placebo; treatment duration was 24 weeks for most participants. Forced expiratory volume in 1 second (FEV₁) improved significantly (by ≈91 mL) with ensifentrine compared with placebo, and the proportion of patients with moderate-to-severe exacerbations was lower in the ensifentrine groups (≈8% vs ≈15%). Self-reported daily symptoms improved among ensifentrine recipients, compared with placebo recipients, in only one of the two studies. No important adverse effects were reported.

Notable points from the official prescribing information

Ensifentrine is officially approved for maintenance treatment in adults with COPD, without reference to its specific role among other agents. It is administered as 3-mg vials via standard jet nebulizers twice daily. It is not indicated for managing acute exacerbations of COPD or acute bronchospasm. Because “psychiatric adverse reactions, including suicidality” have been reported, clinicians are advised to “carefully weigh risks and benefits” in patients with histories of depression or suicidal thoughts. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217389s000lbl.pdf)

Having a new treatment for patients with COPD is a welcome development, but several issues are worth noting:

• Ensifentrine has been administered to fewer than 3000 patients worldwide, according to the company (personal communication with Verona spokesperson; Jul 26 2024).

• The nebulized delivery system should minimize systemic side effects that have been seen with oral phosphodiesterase inhibitors, but this issue should be examined in clinical practice.

• Until guidelines (such as GOLD) specify how this drug will fit into treatment algorithms, I believe that ensifentrine will merit consideration as add-on therapy in patients with COPD who are not responding adequately to standard management of COPD.

• As with many new drugs, cost and insurance coverage might be barriers for patients and clinicians.

Steven T. Kariya, MD

Readings

Disclosures

Acknowledgements

CME/CE INFO

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