Hereditary Transthyretin Amyloidosis (hATTR)

Vyndamax™ (tafamidis) is an oral prescription medication developed by Pfizer that is indicated for the treatment of cardiomyopathy in adults with wild-type or hereditary transthyretin amyloidosis (hATTR) to reduce cardiovascular mortality and hospitalization.¹ Initial US approval of Vyndamax for transthyretin amyloidosis cardiomyopathy (ATTR-CM) was granted by the US Food and Drug Administration (FDA) in May 2019.^1,2

Hereditary transthyretin amyloidosis is a genetic condition characterized by the abnormal deposition of amyloid in different tissues and organs due to mutations in the gene coding for transthyretin (TTR) protein. The heart and nerves are the main targets of this excessive TTR protein accumulation.³ Cardiomyopathy is also observed in the wild-type form of disease, which is associated with aging.⁴ Protein deposition in the heart may result in congestive heart failure, and the median survival time of patients with ATTR-CM is 2 to 5 years.^3,5

Read more about hATTR therapies

Vyndamax Mechanism of Action and Usage

The active ingredient of Vyndamax is tafamidis, a selective TTR stabilizer.¹ TTR stabilizers stabilize the structure of circulating TTR protein and prevent its conformational change, which would allow the protein to aggregate as amyloid.³ Tafamidis is a TTR-tetramer stabilizer that binds to the thyroxine (T4) binding sites of TTR protein, decreasing protein dissociation.^1,6 This drug is now approved in 55 countries, including the United States.⁷

The recommended dose of Vyndamax is 61 mg once a day. Pregnant women should be advised that Vyndamax treatment may carry risks to the fetus and that they should not breastfeed while undergoing treatment. There are no known side effects associated with Vyndamax treatment.¹

Vyndamax in Clinical Trials

The safety and efficacy of tafamidis in patients with ATTR-CM have been supported by a phase 3 trial, ATTR-ACT (NCT01994889), involving Vyndaqel^®, a prescription medicine containing tafamidis meglumine.^8,9 In this multicenter, international, 3-arm, placebo-controlled, double-blind, and randomized trial, 441 patients aged 18 to 90 years were enrolled and randomized in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or a placebo, respectively.^1,9 The study had a duration of 30 months and included 335 patients with the wild-type form of the disease and 106 patients with hATTR.⁹ The results obtained after pooling the data of both tafamidis doses have shown that the drug was associated with lower all-cause mortality and a lower rate of cardiovascular-related hospitalizations when compared to the placebo. These effects were observed after about 18 months of treatment. Additionally, tafamidis reduced loss of function (determined by the 6-minute walk test) and improved quality of life (evaluated using the Kansas City Cardiomyopathy Questionnaire–Overall Summary, KCCQ-OS).⁹ 

The safety profiles of the 2 tested doses of tafamidis were similar to each other and the placebo, with events of mild to moderate intensity reported. The most frequent adverse events observed during this trial included gastrointestinal disorders, fatigue, and cardiac disorders.⁹

Following the completion of the ATTR-ACT trial, patients were eligible to enroll in a long-term extension study (NCT02791230).^10,11 This is an ongoing open-label, 60-month trial to evaluate additional safety data for tafamidis at 20 mg or 80 mg and to allow patients to continue treatment until the drug is available in their locations. In this study, the protocol was amended so that patients could receive a single Vyndamax capsule containing 61 mg instead of Vyndaqel at 20 mg or 80 mg. Vyndamax at 61 mg is bioequivalent to Vyndaqel at 80 mg.¹¹ This extension study highlighted that early treatment is important in patients with ATTR-CM and showed a long-term reduction in mortality with tafamidis use.¹¹

Get full prescribing information for Vyndamax at MPR

References

1. Vyndaqel and Vyndamax. Prescribing information. Pfizer Inc; 2021. Accessed July 14, 2022.

2. U.S. FDA Approves VYNDAQEL® and VYNDAMAX™ for Use in Patients with Transthyretin Amyloid Cardiomyopathy, a Rare and Fatal Disease. News Release. May 06, 2019

3. Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979

4. What is ATTR-CM? Pfizer Inc. Accessed July 14, 2022.

5. Lane T, Fontana M, Martinez-Naharro A, et al. Natural history, quality of life, and outcome in cardiac transthyretin amyloidosis. Circulation. 2019;140(1):16-26. doi:10.1161/CIRCULATIONAHA.118.038169

6. Carroll A, Dyck PJ, de Carvalho M, et al. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis. J Neurol Neurosurg Psychiatry. 2022;93(6):668-678. doi:10.1136/jnnp-2021-327909

7. Pfizer’s Vyndaqel®/Vyndamax® reduced the risk of all-cause mortality by 41% among patients with transthyretin amyloid cardiomyopathy, five-year follow-up data demonstrate. News release. Pfizer Inc; December 20, 2021.

8. Safety and efficacy of tafamidis in patients with transthyretin cardiomyopathy (ATTR-ACT). ClinicalTrials.gov. November 26, 2013. Updated April 24, 2019. Accessed July 14, 2022.

9. Maurer MS, Schwartz JH, Gundapaneni B, et al; ATTR-ACT Study Investigators. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689

10. Long-term safety of tafamidis in subjects with transthyretin cardiomyopathy. ClinicalTrials.gov. June 6, 2016. Updated December 7, 2021. Accessed July 14, 2022.

11. Elliott P, Drachman BM, Gottlieb SS, et al. Long-term survival with tafamidis in patients with transthyretin amyloid cardiomyopathy. Circ Heart Fail. 2022;15(1):e008193. doi:10.1161/CIRCHEARTFAILURE.120.008193

Reviewed by Harshi Dhingra, MD, on 7/20/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.