The effectiveness and value of ensifentrine for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a group of lung diseases characterized by progressive and persistent airflow obstruction in the lungs. Symptoms include persistent shortness of breath, fatigue, wheezing, chest tightness, sputum production, and cough. In the United States, COPD affects 16 million people and is the sixth leading cause of death.^1,2 Each year, COPD is associated with 1 million emergency department visits and half a million hospitalizations. The annual medical cost of COPD is estimated to be $24 billion among adults aged 45 years and older, with $6.3 billion in inpatient costs and $900 million in emergency department costs.^3,4

The goals of treatment for COPD are to relieve symptoms, improve lung function, and reduce exacerbations.⁵ Treatment may include both nonpharmacologic (eg, pulmonary rehabilitation, smoking cessation) and pharmacologic approaches. The main medications for maintenance treatment are inhaled bronchodilators, specifically long-acting β-2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). The 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines now recommend dual combination therapy of LAMA + LABA therapy for those with moderate to severe COPD. Inhaled corticosteroids (ICS) can be added to the treatment regimen for patients with frequent exacerbations and/or a blood eosinophil count of at least 300 cells/μl. However, despite receiving therapy, around half of patients with COPD continue to report daily symptoms that impact their well-being.^6,7

Ensifentrine (Ohtuvayre, Verona Pharma) is a novel inhaled dual inhibitor of phosphodiesterase (PDE) 3 and PDE4 enzymes that works by relaxing airway smooth muscle, decreasing airway inflammation, and improving ciliary function of the lungs. Ensifentrine received regulatory approval from the US Food and Drug Administration on June 26, 2024, for maintenance treatment of COPD in adults.

The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of ensifentrine for the treatment of moderate to severe COPD.⁸ We present the summary of our findings and highlights of the policy discussion with key stakeholders held at a public meeting of the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC) on June 14, 2024. The report is available on the ICER website: https://icer.org/wp-content/uploads/2023/1/ICER_COPD_Final-Report_For-Publication_071624.pdf.

Summary of Findings

The 2 pivotal trials of ensifentrine (ENHANCE-1 and −2) were phase 3 multicenter, randomized controlled trials that evaluated the efficacy and safety of nebulized ensifentrine 3 mg twice daily vs placebo for 24 weeks, with an additional 24-week safety extension in ENHANCE-1 only.⁹ Participants were aged between 40 and 80 years, were current or former smokers, had symptomatic moderate to severe COPD with an established diagnosis (ie, score of ≥ 2 on the modified Medical Research Council Dyspnea Scale and postbronchodilator forced expiratory volume in 1 second [FEV₁]/forced vital capacity [FVC] < 0.70 and FEV1 ≥ 30% and ≤ 70%), and did not have any other respiratory disorder. Participants were allowed to continue with LAMA or LABA therapy (with or without ICS) if stable for 28 days prior to randomization; however, those on dual LAMA + LABA or triple LAMA + LABA + ICS therapy were excluded. Additionally, between 30% and 45% of patients were on no maintenance therapy at baseline. A total of 1,549 participants (760 in ENHANCE-1 and 789 in ENHANCE-2) took part in the 2 trials.⁹

Treatment with ensifentrine met the primary outcome of change in lung function as measured by average FEV₁ at week 12 in both trials. Given the similar study designs, we conducted meta-analyses of the 2 trials, with a focus on patient-important outcomes at 24 weeks. At week 24, those who received ensifentrine had a 40% decrease in the annualized rate of moderate to severe exacerbation (rate ratio = 0.60; 95% CI = 0.41-0.79; P < 0.0001; I² = 0%). Moderate exacerbation was defined as worsening of COPD symptoms for more than 2 days, requiring a minimum of 3 days of therapy with oral or systemic corticosteroids and/or antibiotics, and severe exacerbation was defined as worsening of symptoms and inpatient hospitalization.⁹ In addition, there was a significantly longer time to first exacerbation compared with placebo (hazard ratio = 0.60; 95% CI = 0.41-0.78; P < 0.0001; I² = 0%). This benefit was maintained at week 48 in the extension phase of ENHANCE-1.

However, data on self-reported symptoms and quality of life were mixed. Specifically, participants who received ensifentrine reported a significant reduction in dyspnea on the Transition Dyspnea Index compared with placebo in both trials at week 24 (mean difference [MD] vs placebo = 1.00; 95% CI = 0.58-1.41; P < 0.001; I² = 0%) and met what is considered as the minimal clinically important difference.¹⁰ However, reported respiratory symptoms using Evaluating-Respiratory Symptoms and overall health on the St. George’s Respiratory Questionnaire at week 24 was significantly improved in participants who received ensifentrine compared with placebo in the ENHANCE-1 trial, but not the ENHANCE-2 trial. Although the pooled estimate for Evaluating-Respiratory Symptoms was statistically significant (MD vs placebo = −0.69; 95% CI = −1.38 to −0.01; P = 0.047; I² = 0%), the pooled estimate for St. George’s Respiratory Questionnaire was not (MD vs placebo = −1.51; 95% CI = −3.13 to 0.12; P = 0.069; I² = 22%) and neither MD met the published minimal clinically important difference.^11-14

Ensifentrine was well tolerated in both trials, with a comparable proportion of serious treatment-emergent adverse events observed across the ensifentrine and placebo groups. Rates of discontinuation because of treatment-emergent adverse events were similar between the groups. Although gastrointestinal issues are common with oral PDE4 therapy, these were infrequent with ensifentrine. There was no observed increase in pneumonia, which has been associated with ICS-containing therapies.¹⁵

LIMITATIONS OF THE CLINICAL EVIDENCE

Participant withdrawal was high (ENHANCE-1 at week 48 = 14.8%; ENHANCE-2 at week 24 = 23.1%). Although this was likely due to the challenges of conducting trials during the COVID-19 pandemic, there were missing outcome data, and because of limited reporting, it is unclear the extent of the missing data. In addition, participants enrolled in the trials were not on dual LAMA + LABA or triple LAMA + LABA + ICS therapy, as these regimens only became standard of care in guidelines published after the initiation of the ENHANCE trials. We also noted that a substantial number of participants in the trials were on no background therapy. These conditions limited our interpretation of ensifentrine’s value when added to current COPD treatments. Both trials were short in duration, measuring primary outcomes at either 12 or 24 weeks. Longer trials are needed to account for any seasonal effects (ie, increased exacerbations during months with higher infectious respiratory illness), to assess the durability of ensifentrine, and to evaluate its benefit when added to the current standard of care.

LONG-TERM COST-EFFECTIVENESS

We developed a de novo decision analytic model, informed by key clinical trials and prior relevant economic models^16-18 to estimate the cost-effectiveness of ensifentrine added on to current maintenance therapy for the treatment of COPD relative to current maintenance therapy alone. The Markov model focused on intention-to-treat analysis and included a hypothetical cohort of patients with moderate to severe COPD at baseline receiving ensifentrine added on to current maintenance therapy or current maintenance therapy alone.

The model consisted of 4 health states (moderate, severe, very severe COPD, and death) and tracked exacerbations within each state. The model cycle length was 1 year, and a lifetime time horizon was used. We performed analyses examining outcomes and costs from a health care sector perspective (ie, focusing on the health care costs) and conducted sensitivity analyses from a modified societal perspective (eg, including patient and caregiver productivity impacts).

Key model assumptions included patients could only transition to more severe health states because of the progressive nature of the disease; the effect on pulmonary function did not result in different health state transition probabilities as ensifentrine was not expected to be disease modifying; and ensifentrine’s effect on pulmonary function testing did not result in improvements in the day-to-day quality of life of patients not experiencing an exacerbation. Full details on ICER’s cost-effectiveness analysis and model are available on the ICER website: https://icer.org/assessment/copd-2024/.

Treatment with ensifentrine resulted in higher intervention costs but slightly lower nonintervention costs (eg, costs associated with exacerbations) and more quality-adjusted life years, equal-value life years, and life years gained compared with current maintenance therapy alone. Model outcomes are shown in Table 1. Incremental results are displayed in Table 2, with incremental cost-effectiveness ratios at $492,000 per quality-adjusted life year gained and $426,000 per equal-value life year gained. From both health care sector and modified societal perspectives, ensifentrine’s price of $2,950 per month (annual price of $35,400) exceeded commonly used cost-effectiveness thresholds. Ensifentrine would meet commonly used cost-effectiveness thresholds at an annual price between $7,500 and $12,700. With the high wholesale acquisition cost of ensifentrine, approximately 0.5% of those with COPD in the United States could be treated within 5 years without crossing the ICER potential budget impact threshold of $735 million per year. Thus, ICER issued an access and affordability alert.⁸

Table 1.

Model Outcomes for the Base Case

Treatment	Intervention cost	Total cost	Total exacerbations	QALYs	evLYs	Life years
Ensifentrine + current maintenance therapy	$284,000	$564,000	8.03	6.25	6.34	8.43
Current maintenance therapy alone	$0	$284,000	12.26	5.68	5.68	7.71

evLY = equal-value life year; QALY = quality-adjusted life year.

Table 2.

Incremental Cost-Effectiveness Ratios Compared With Supportive Care for the Health Care Sector and Modified Societal Perspective

Treatment	Cost per QALY gained	Cost per evLY gained	Cost per life year gained
Health care sector	$492,000	$426,000	$387,000
Societal	$511,000	$442,000	$401,000

evLY = equal-value life year; QALY = quality-adjusted life year.

LIMITATIONS OF THE COST-EFFECTIVENESS MODEL

Because of the lack of data, we assumed that ensifentrine’s impact on improved quality of life was the result of an indirect effect on exacerbations. There were also limited data on caregiver quality of life, and thus, the findings from the modified societal perspective scenario analysis may not fully represent the impact of COPD on patients and caregivers. Finally, although we used the best available source to inform the basket of regimens and treatments within current maintenance therapy, the dates included in this source largely predated LABA + LAMA combination products. To account for this potential limitation, we varied the cost of current maintenance therapy across a very wide range in the sensitivity analyses. The sensitivity analyses showed that variability in the cost of the current maintenance therapy had a very small impact on the overall findings, given that ensifentrine is added to the current maintenance therapy.⁸

POLICY DISCUSSION

The Midwest CEPAC is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on the clinical and cost-effectiveness of health care interventions. The Midwest CEPAC is composed of medical evidence experts, including clinicians, methodologists, and patient advocates. The ICER report on ensifentrine was the subject of a Midwest CEPAC meeting on June 14, 2024. Following the discussion, panel members deliberated on key questions raised by ICER’s report.

A majority of the Midwest CEPAC (11-4) voted that current evidence is adequate to demonstrate that the net health benefit of ensifentrine added to maintenance therapy for COPD is superior to that of maintenance therapy alone (Table 3). The Midwest CEPAC also voted on benefits beyond health and special priorities (Table 4) that should be considered by policymakers as they make judgments regarding the value of ensifentrine. A vote on long-term value for money was not taken as, at the time of voting, a price was not available for ensifentrine.

Table 3.

Votes on Comparative Clinical Effectiveness Questions

Question	Yes	No
Is the current evidence adequate to demonstrate that the net health benefit of ensifentrine added to maintenance therapy is superior to that of maintenance therapy alone?	11	4

Table 4.

Votes on Benefits Beyond Health and Special Ethical Priorities

Benefits beyond health and special ethical priorities	Strongly disagree	Disagree	Neutral	Agree	Strongly agree
To help inform judgments of overall long-term value for money, please indicate your level of agreement with the following statements:
There is substantial unmet need despite currently available treatments	0	2	0	9	4
This condition is of substantial relevance for people from a racial and ethnic group that have not been equitably served by the health care system	0	0	5	8	2
To help inform judgments of overall long-term value for money, please indicate your level of agreement with the following statements based on the relative effects of ensifentrine added to maintenance therapy vs maintenance therapy alone:
The treatment is likely to produce substantial improvement in caregivers’ quality of life and/or ability to pursue their own education, work, and family life	0	2	10	3	0
The treatment offers a substantial opportunity to improve access to effective treatment by means of its mechanism of action or method of delivery	0	4	8	3	0

Following the discussion of the evidence, a policy roundtable was convened to deliberate on how best to apply the evidence on ensifentrine to treatment for moderate to severe COPD. The full set of policy recommendations can be found in the Final Evidence Report on the ICER website: https://icer.org/wp-content/uploads/2023/1/ICER_COPD_Final-Report_For-Publication_071624.pdf. Select key policy recommendations relevant to the potential introduction of ensifentrine into practice are as follows:

1. Because of the high launch price of ensifentrine and the uncertainty around its efficacy in addition to dual or triple therapy, payers may choose to develop prior authorization criteria or other limits on utilization. None of these limits should undermine the tenets of fair access for all patients.

2. Considerations for coverage criteria for ensifentrine:

   1. Diagnosis: Some payers may wish to consider diagnostic spirometry to confirm diagnosis of COPD, in line with GOLD guidelines and clinical trial eligibility criteria.
   2. Severity: Although pivotal trial eligibility criteria included that patients should have a score of at least 2 on the modified Medical Research Council Dyspnea Scale, clinical experts noted that these scales are not necessarily used routinely in clinical practice and did not see a reason to require a measure of severity as a condition of coverage.
   3. Step therapy: The pivotal clinical trial included patients on no maintenance therapy, LAMA or LABA monotherapy, or LAMA or LABA with ICS. However, clinical experts suggested that ensifentrine’s role in therapy would be as an add-on to guideline-based dual LAMA + LABA or triple LAMA + LABA + ICS therapy. Therefore, it is not unreasonable for payers to require patients to be on dual or triple therapy prior to trying ensifentrine. However, payers should be aware that some patients may not be able to tolerate dual or triple therapy because of side effects or difficulties with inhaler use, and thus, there should be a clear and efficient process for requesting exceptions.
   4. Smoking status: Although the ENHANCE trials were restricted to only smokers with COPD, clinical experts did not believe there was any reason to limit the use of ensifentrine to current smokers.

3. Payers should include coverage of effective smoking cessation therapies, including nicotine replacement products, pharmacologic therapies, cognitive behavioral therapy, and combinations thereof, as smoking cessation is a critical part of slowing the progression of COPD.

4. Manufacturers should set prices that will foster affordability and access for all patients by aligning prices with the value of their treatments. The manufacturer of ensifentrine has priced the drug far above this level and missed an opportunity to provide broad access and increased uptake.

Funding Statement

These authors report that other funding came from Abbott, AHIP, Alnylam, Anthem, Astra Zeneca, Bayer Healthcare, Blue Shield of California, Boehringer-Ingelheim, CRISPR Therapeutics, CVS, Envolve Pharmacy Solutions, Express Scripts, Genentech/Roche, GSK, Harvard Pilgrim Healthcare, Health Care Service Corporation, Humana, Kaiser Permanente, Karuna Therapeutics, LEO Pharma, Mallinckrodt, Merck, Novartis, Novo Nordisk, National Pharmaceutical Council, Otsuka, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare outside the submitted work. Dr. Whittington reports funding from the Institute for Clinical and Economic Review for the conduct of the study; and other research support from the National Pharmaceutical Council and from No Patient Center Behind outside the submitted work; and other personal fees from Genentech outside the submitted work.