The Institute for Clinical and Economic Review (ICER) granted the therapy Trikafta the highest evidence rating (an “A”) for the treatment of cystic fibrosis (CF) in patients with either two copies the F508del mutation, or with one copy of the F508del mutation and a minimal function mutation in the CFTR gene (the gene defective in CF).
ICER compared the efficacy and value of Trikafta (elexacaftor, tezacaftor, and ivacaftor), the most recent approved CF therapy marketed by Vertex Pharmaceuticals, and found that it “provides a substantial (moderate-large) net health benefit” compared to other approaches.
However, in its recent evidence report, ICER states that the price set by Vertex for Trikafta needs to be reduced significantly to be in line with the benefits it provides.
The report is titled “Modulator Treatments for Cystic Fibrosis: Effectiveness and Value.”
Trikafta was approved in October by the U.S. Food and Drug Administration (FDA) for treating CF in patients 12 and older with at least one copy of the F508del mutation in the CFTR gene, found in an estimated 90% of all CF patients.
The triple combination therapy is a CFTR modulator that helps the defective CFTR protein to work more effectively. While elexacaftor and tezacaftor both work as correctors — increasing the amount of functional CFTR that reaches the cell surface by helping the F508del mutated protein fold correctly — ivacaftor (also marketed independently as Kalydeco) is a potentiator that improves the flow of chloride molecules through the CFTR channel.
Trikafta has the potential to improve the lives of patients, not only because its triple combination could have a superior efficacy compared to dual combination therapies like Symdeko (tezacaftor/ivacaftor combo) or Orkambi (lumacaftor/ivacaftor), but also because it is available for patients who were not eligible for prior CFTR modulator therapies.
ICER reviewed the benefits and long-term cost effectiveness of Trikafta in CF patients. It also examined the most recent real-world data of Vertex’s other CFTR modulators — namely Kalydeco, Orkambi, and Symdeko.
According to ICER’s review, patients who have taken Trikafta reported substantial and rapid improvements in their health, including elimination of cough, a decrease in some supportive treatments, fewer pulmonary events requiring medical attention, and a greater ability to participate in activities such as exercise, social events, and planning for the future.
Trikafta has been tested in two pivotal Phase 3 clinical trials (NCT03525444 and NCT03525548), in which it significantly improved measures of lung function in CF patients with either two F508del mutations or one F508del and one minimal function mutation.
Results from these trials, along with a meta-analysis comparing the outcomes of patients treated with multiple CFTR modulators, have led ICER to consider with “high certainty” that Trikafta has a substantial benefit over best supportive care and Symdeko treatment in people with two F508del mutations.
The report also states that Trikafta provides a substantial benefit over best supportive care in people with one F508del and one minimal function mutation, and suggest that “it should be at least as effective” as Symdeko for this patient population.
For the other three treatments — Symdeko, Orkambi, and Kalydeco — ICER’s review of new data confirmed the prior evidence ratings granted in 2018. The report states that compared to best supportive care, evidence provides high certainty that Kalydeco offers a substantial net health benefit, while Orkambi provides a small net health benefit. In turn, Symdeko is said to provide at least a small net health benefit, but with the potential for a substantial benefit.
“CF is a devastating disease that affects the lungs and other organ systems, typically requires substantial medical care, and robs patients and families of hours each day, before taking away full years of life,” David Rind, MD, ICER’s chief medical officer, said in a press release.
“Kalydeco was a great advance for a small segment of the CF population, and Trikafta appears to be an even more remarkable advance for a much larger segment of the population,” Rind said. “Trikafta is likely to alter the course of disease for the majority of patients with CF, transforming their lives and the lives of caregivers.”
Regarding cost-effectiveness, ICER emphasized that CFTR modulator therapies dramatically improve the longevity and quality of life of CF patients, in a way that “had been unthinkable due to the dire prognosis of the disease” a few years ago, but their high cost and need for lifetime use lead to a $1.1 to $1.5 million cost per quality-adjusted life year (QALY), which is well above commonly accepted cost-effectiveness thresholds.
For Trikafta, for example, an appropriate health-benefit price would range from $67,900-$85,500 per year, which would require at least a 73% discount off the therapy’s list price.
“Despite being transformative therapies, the prices set by the manufacturer — costing many millions of dollars over the lifetime of an average patient — are out of proportion to their substantial benefits,” Rind said.
“When a manufacturer has a monopoly on treatments and is aware that insurers will be unable to refuse coverage, the lack of usual counterbalancing forces can lead to excessive prices,” Rind said. “Patients who receive the treatments will benefit, but unaligned prices will cause significant negative health consequences for many unseen individuals — those throughout society who will experience financial toxicity and may have to delay care, forego care, or even abandon insurance as their out of pocket costs and premiums are driven upward.”
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