FDA Approves Ensifentrine, Novel Treatment for Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease characterized by chronic respiratory symptoms that cause progressive airflow obstruction.¹ Current treatment for COPD recommended in clinical guidelines includes bronchodilators, long-acting muscarinic antagonists, long-acting β-agonists, and inhaled corticosteroids.

3D rendered image of bronchi / Sebastian Kaulitzki - stock.adobe.com

On June 26, 2024, the FDA approved ensifentrine (Ohtuvayre) for the treatment of COPD.² Ensifentrine is notable for its novel mechanism, inhibiting phosphodiesterase-3 and phosphodiesterase-4 enzymes, which results in various downstream signaling effects and is theorized to reduce inflammation and relax airway smooth muscle.

Efficacy

Two phase 3 clinical trials (ENHANCE-1, NCT04535986; ENHANCE-2, NCT04542057) evaluated ensifentrine efficacy. Trials were conducted from September 2020 to December 2022 and enrolled 1553 patients aged 40 to 80 years with moderate to severe symptomatic COPD. Demographic and baseline disease characteristics were similar across both treatment groups and included patients using concomitant maintenance therapy (69% and 55%, respectively) and those using no other therapies.

Efficacy and safety data utilized a modified intention-to-treat population that included all patients randomly assigned and dosed. The primary end point for both trials was the change from baseline in forced expiratory volume in the first second area under the curve at 0 to 12 hours (FEV₁, AUC_0-12h) post dose at week 12. Both trials achieved statistically significant primary end points (ENHANCE-1: 87 mL; 95% CI, 55-118; ENHANCE-2: 94 mL; 95% CI, 65-124).³ Secondary end points included health-related quality of life, rate of exacerbations, and time to first exacerbation.

Safety

Ensifentrine should not be used for acute episodes of bronchospasm and can cause paradoxical bronchospasm. Treatment with ensifentrine was associated with a rare but notable increase in psychiatric adverse reactions (<1%), including insomnia, anxiety, depression, and suicide-related adverse reactions. Other common adverse events included back pain, hypertension, urinary tract infection, and diarrhea. Adverse events leading to treatment withdrawal occurred similarly across treatment groups.

There are no available human data on ensifentrine use in pregnant or breastfeeding women, and safety and effectiveness have not been established in pediatric patients. No differences in safety or effectiveness were observed in clinical trials for those 65 years or older (n = 852), but greater sensitivity cannot be ruled out.

Dosing and Administration

Ensifentrine is available in 3-mg/2.5-mL ampules and is dosed twice daily via oral inhalation using a jet nebulizer. No dosage adjustments are required in those with renal impairment. Caution is advised in those with moderate to severe hepatic impairment; increased systemic exposure in this population was seen in clinical trials. Store ensifentrine away from direct sunlight and excessive heat, and open drug foil pouches only immediately before use. Ampules must be shaken vigorously to ensure contents are thoroughly mixed and will appear cloudy and yellow to pale yellow.

Cost

Ensifentrine has a wholesale acquisition cost of $35,400 per year, which is above most commonly used cost-effectiveness thresholds.⁴ The Institute for Clinical and Economic Review issued an access and affordability alert for ensifentrine, signaling to stakeholders and policy makers that added health care costs associated with this medication may displace other needed services at the current price point.⁴

It is unclear where payers will place ensifentrine on the formulary and where it will fall in therapy.

Molly Csere, PharmD, is a PGY-1 pharmacy resident at UConn John Dempsey Hospital in Farmington, Connecticut.

Kevin Chamberlin, PharmD, FASCP, is associate vice president and chief pharmacy officer at UConn Health in Farmington, Connecticut.

READ MORE: Respiratory Resource Center

References

1. Patel N. An update on COPD prevention, diagnosis, and management: the 2024 GOLD Report. Nurse Pract. 2024;49(6):29-36. doi:10.1097/01.NPR.0000000000000180

2. Ohtuvayre. Prescribing information. Verona Pharma Inc; 2024. Accessed September 10, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217389s000lbl.pdf

3. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE Trials). Am J Respir Crit Care Med. 2023;208(4):406-416. doi:10.1164/rccm.202306-0944OC

4. Lin GA, Whittington MD, Wright A, McKenna A, Richardson M, Rind DM. Ensifentrine for the treatment of chronic obstructive pulmonary disease: effectiveness and value. Institute for Clinical and Economic Review. July 16, 2024. Accessed September 9, 2024. https://icer.org/assessment/copd-2024/