Ensifentrine improves outcomes in COPD, but unlikely to be cost effective
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Key takeaways:
- Ensifentrine plus maintenance therapy yielded multiple benefits in patients with moderate to severe COPD.
- If priced at $18,000 a year, it would go over common cost-effectiveness thresholds.
When added to maintenance therapy for moderate to severe COPD, ensifentrine improves lung function and exacerbation rate vs. placebo, according to a draft evidence report by the Institute for Clinical and Economic Review.
However, models in the Institute for Clinical and Economic Review (ICER) draft evidence report suggested ensifentrine (Verona Pharma), a novel inhaled dual PDE-3 and PDE-4 inhibitor, would exceed typical cost-effective thresholds.
“We heard a lot of interest in ensifentrine from clinical experts as it has a different mechanism of action from other inhalers without the gastrointestinal side effects of the related oral drug roflumilast,” David M. Rind, MD, MSc, chief medical officer at ICER, told Healio.
“There was disagreement about whether there would be interest in using it early in treatment or only as an add-on to LAMA/LABA or triple therapy,” he continued. “There was recognition, though, that pricing may determine whether patients will be able to receive it as a first-line treatment.”
Ensifentrine is nebulized, administered as 3 mg twice a day and under review by the FDA, according to the ICER report.
Clinical data
ICER’s draft evidence report considered the use of ensifentrine added to maintenance therapy among patients with moderate to severe COPD vs. maintenance therapy alone.
As Healio previously reported, results from two phase 3 trials (ENHANCE-1 and ENHANCE-2) showed improved measures of lung function, exacerbation rate and quality of life with ensifentrine at 12 or 24 weeks compared with placebo.
The pooled cohort included 62% on LABA or LAMA and 18% on LABA or LAMA plus inhaled corticosteroids.
In both trials, patients receiving ensifentrine vs. placebo showed a significant increase in average FEV1 area under the curve over 12 hours (ENHANCE-1, +87 mL; ENHANCE-2, +94 mL; P < .001 for both).
At week 24, patients receiving ensifentrine had a 36% (P = .0503) reduction in moderate/severe COPD exacerbation rate in ENHANCE-1, with an even greater reduction rate in ENHANCE-2 at 43% (P = .009).
Researchers also found a delay in time to first exacerbation with receipt of ensifentrine, with a 38% (P = .0382) risk reduction in ENHANCE-1 and a 42% (P = .0089) risk reduction in ENHANCE-2, according to the ATS 2023 presentation on these trials.
Further, patients receiving ensifentrine had significant improvements in:
- Evaluating Respiratory Symptoms scores at week 6 and week 12 in ENHANCE-1 and -2 and week 24 in ENHANCE-1;
- St. George’s Respiratory Questionnaire scores at week 6, week 12 and week 24 in ENHANCE-1; and
- Transition Dyspnea Index scores at week 6, week 12 and week 24 in ENHANCE-1 and -2.
In terms of safety, researchers noted comparable incidences of serious treatment-emergent adverse events in the ensifentrine groups and the placebo groups in both trials.
Overall, the ICER report gave ensifentrine a B+ evidence rating, and this grade indicates that there is high certainty of “at least a small net health benefit, and may result in substantial net health benefit” compared with maintenance therapy alone.
“[This] is a strong rating for a new therapy. ICER always considers the possibility of uncommon long-term harms which won’t be apparent in clinical trials,” Rind said. “That said, we would have preferred if the ENHANCE trials included patients on background LAMA/LABA and background triple therapy. We have some uncertainties around benefits in patients on those very common regimens.”
Rind added that the number of withdrawals in these trials was concerning.
“The ENHANCE trials had a lot more patients withdrawing than is typical, and this could lead to biased estimates of effect,” he said. “The high rate of withdrawals was almost certainly because of the pandemic, so this wasn’t a design issue, but it still creates uncertainties.”
Cost
ICER noted that ensifentrine’s pricing is not yet known, but a placeholder price indicates that it will go over thresholds that are traditionally considered cost effective.
Using a placeholder price of $18,000 per year for ensifentrine, economic models showed that ensifentrine plus maintenance therapy conferred more quality-adjusted life-years (QALYs; 6.25 years vs. 5.68 years), equal value life-years (6.34 years vs. 5.68 years) and life-years (8.43 years vs. 7.71 years) vs. maintenance therapy alone.
Use of ensifentrine plus maintenance therapy also resulted in a lower number of total exacerbations (8.03 vs. 12.26), according to the draft evidence report.
Further, the ICER report estimated a cost of $248,000 per QALY gained, $214,000 per equal value of life years gained and $195,000 per life year gained with ensifentrine plus maintenance therapy.
According to the report, ensifentrine plus maintenance therapy priced at $18,000 would still go over thresholds traditionally considered cost effective even if it raises quality of life beyond improvements linked to fewer exacerbations among patients with COPD.
“These results are preliminary and could change after we receive public comment,” Rind told Healio.
Perspective
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The ICER report on ensifentrine provides some much-needed excitement in the world of COPD management. Ensifentrine’s novel mechanism of action (dual PDE3 and PDE4 inhibition) represents a new strategy to manage bronchospasm and inflammation, two primary drivers of COPD symptoms, simultaneously. Administration via the inhalation route will likely reduce the frequency of adverse effects reported by people with COPD using the previously approved PDE4 inhibitor, roflumilast. Twice-daily dosing using nebulizer equipment that many in the COPD community already have will go far in reducing barriers to adherence and, in some cases, access. Many people will be able to use their Medicare Part B benefits along with a supplemental plan to minimize cost sharing, making this a very appealing option for them.
Of course, symptom burden is only one facet of optimal COPD management. Reducing exacerbations, often the key driver of both health care costs and disease progression, is also critically important. This is another area where ensifentrine shows promise, reducing the frequency of these events and extending the time between therapy initiation and the first flare. In this ICER report, the analysis assumed that this effect was the main cause of quality of life (QOL) improvements reported by many study participants, especially as those QOL improvements were inconsistent between ensifentrine’s two phase 3 trials.
While it is certainly true that people tend to prefer staying out of the hospital, I would argue that assumption is somewhat flawed, at least conceptually. COPD is an incredibly heterogeneous condition with symptom burdens that are quite subjective and can vary widely even among common study subgroups (such as those defined by age or sex at birth), making improvements in these burdens very difficult to capture in the best of circumstances. Ensifentrine’s studies were conducted at the height of the COVID-19 pandemic, introducing myriad confounding factors.
This was not the only assumption in the report that I would argue is partially flawed, or at least imprecise. To create their cost-effectiveness model, the ICER team also assumed that people with COPD only progress to more severe disease states, defined by decreases in FEV1. While this was the historical model to determine COPD severity, it has been found lacking in prognostic value in a study by Pandey and colleagues. Current models place more emphasis on disease burden and 12-month exacerbation history to define severity. With this model, subjective disease severity may advance or retreat based on response to one’s current therapy.
ICER also works to identify “benefits beyond health” and “special ethical priorities” as part of their reports. One of those is “improved access to effective treatment by means of its mechanism of action or method of delivery.” In the case of ensifentrine, the ICER team assumed that the drug’s delivery via standard nebulizer would likely have no effect on access. However, this does not account for differences in reimbursement based on one’s insurance (for example, having Traditional Medicare and a supplement vs. a Medicare Advantage plan). In addition, most current bronchodilator and inhaled corticosteroid formulations are delivered via a metered-dose inhaler, dry-powder inhaler or soft mist inhaler. All these devices require some form of coordination and/or inspiratory technique to deliver the appropriate dose of medication. These factors are rarely evaluated or instructed, leading to a high degree of inadvertent nonadherence, according to Bosnic-Anticevich and colleagues. Nebulizers require no such special technique or ability, thus making it more likely an effective dose will be delivered to the lung tissue.
To be clear, some of these arguments are inherently subjective and challenging to prove (or disprove) objectively. The ICER team did acknowledge a fair degree of uncertainty based on the many changing paradigms in the world of COPD. Future real-world studies should provide more definitive answers about its impact on QOL outside of exacerbation counts and spirometry measurements, as well as its long-term cost-effectiveness. However, the ultimate takeaway from this report (that ensifentrine is well-tolerated, likely has at least mild additive therapeutic benefit when prescribed with standard maintenance medications and may well have significant benefits) is very encouraging.
References:
Bosnic-Anticevich S, et al. J Allergy Clin Immunol Pract. 2023;doi:10.1016/j.jaip.2023.04.031.
Pandey AK, et al. Cureus. 2022;doi:10.7759/cureus.32116.
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