Biopsy-free test, new drug change course for transthyretin cardiac amyloidosis

Transthyretin cardiac amyloidosis is a rare disease that affects older adults with or without specific genetic mutations that increase risk for disease. In the past, diagnosis required a cardiac biopsy, but there was little incentive perform one as there was no effective treatment. The development of a non-invasive diagnostic modality and the recent approval of an effective but expensive drug provide an optimistic future for patients.

Dhruv S. Kazi, MD, cardiologist and cardiovascular health economist at the Smith Center for Outcomes Research, Beth Israel Deaconess Medical Center, spoke with Healio about how tafamidis (Vyndamax, FoldRx/Pfizer) has changed the outlook of amyloidosis, but cost may remain a substantial barrier to access.

Healio: What factors, other than genetics, can contribute to the development of transthyretin amyloidosis, and how would this help shape the diagnosis?

Kazi: Transthyretin is a tetrameric circulating protein that is synthesized in the liver and transports thyroxine and retinol-binding protein-retinol complex. When destabilized, its component monomers deposit as sheets of amyloid fibrils in the myocardium, causing transthyretin amyloidosis. This may be genetic (3%-4% of African Americans carry the Val122Ile mutation that causes the disease) or age-related. It typically presents as heart failure among adults 70 years or older. In 2019, the FDA approved tafamidis, a drug that stabilizes transthyretin and slows the clinical progression of cardiac amyloidosis.

Healio: What do you think are overlooked factors that might contribute to the development of amyloidosis? Is there any new information on how common amyloidosis is?

Kazi: Non-genetic factors that increase the risk for cardiac transthyretin amyloidosis are not well understood. What we do know is that it is more common than was previously suspected. Now that the 99m-Technetium Pyrophosphate scan can diagnose transthyretin amyloidosis accurately and non-invasively, we are discovering that it is a common condition among older adults with heart failure with preserved ejection fraction, and even among adults presenting with valvular heart disease. Our best estimate based on current data is that between 120,000 to 200,000 adults in the U.S. are affected by amyloidosis, but these may be substantial underestimates.

Healio: Do alternative therapies or treatments exist that could help patients manage their symptoms or stop the progression of the disease?

Kazi: There are off-label uses of a handful of medications that have been tried, but tafamidis is the first approved drug for transthyretin cardiomyopathy – both hereditary and wild-type transthyretin cardiomyopathy. Because of its high price tag, a lot of cardiomyopathy clinics have had to explore the use of less expensive alternatives like diflunisal for patients without insurance or with prohibitively high out-of-pocket costs, but tafamidis is the only drug that carries an FDA indication.

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Healio: How cost-effective is the use of tafamidis for the treatment of transthyretic cardiac amyloidosis?

Kazi: In the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial, treatment with tafamidis among patients with transthyretin amyloid cardiomyopathy and clinical evidence of heart failure resulted in prolonged survival, fewer cardiovascular hospitalizations, and a slower decline in quality-of-life compared with treatment with placebo. Our research group synthesized data from this trial, and from other trials, surveys, epidemiologic studies, and registries to extrapolate the long-term benefits and costs of tafamidis in this population. What we showed was that if trial results were reproduced in the real world, tafamidis would be very effective in improving survival and quality-of-life. But at an annual cost of $225,000 per year, tafamidis is the most expensive oral cardiovascular medication ever launched in the U.S., and cost would be a huge barrier to access. The price would have to decline more than 90% for the drug to meet conventional cost-effectiveness thresholds. And based on the recent experience with other high-cost cardiovascular medications, cost is likely to be a huge barrier to access among fixed-income seniors most likely to benefit from treatment. Thus, tafamidis highlights the challenges with precision medicine for rare diseases – here we have a drug that is effective, safe and unaffordable.

Healio: What should physicians be aware of when diagnosing and treating amyloidosis?

Kazi: To the extent feasible, cardiac amyloidosis is best managed in high volume centers with an amyloidosis specialty clinic. Given the cost of tafamidis therapy, physicians should have regular conversations about out-of-pocket costs with patients, both at the time of initiating therapy and periodically thereafter. Even among fully insured patients, the out-of-pocket costs may be several thousand dollars, though the patient support program may be able to offset some of these costs for select patients.

References:

• FDA. FDA approves new treatments for heart disease caused by a serious rare disease, transthyretin mediated amyloidosis. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatments-heart-disease-caused-serious-rare-disease-transthyretin-mediated. Accessed on February 11, 2020.

• Kazi DS, et al. Circulation. 2020; doi:10.1161/CIRCULATIONAHA.119.045093.