Hereditary Transthyretin Amyloidosis (hATTR)

Vyndaqel^® (tafamidis meglumine) and Vyndamax^® (tafamidis) belong to the class of drugs known as transthyretin stabilizers. They are given to adults who have cardiomyopathy associated with wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) to prevent cardiovascular mortality and hospitalization due to cardiovascular disease.¹ The active ingredient in Vyndaqel is tafamidis meglumine, a salt form of tafamidis, and tafamidis is the active ingredient in Vyndamax.The suggested doses of Vyndamax and Vyndaqel differ because they are absorbed differently by the body. These drugs cannot be substituted for each other on a 1:1 basis.² The recommended dose of Vyndaqel is 80 mg (a total of four 20-mg capsules) taken orally once daily. The recommended dose of Vyndamax is 61 mg (one 61-mg capsule) taken orally once daily.¹ 

Vyndaqel was originally licensed in the European Union in 2011 as a treatment to delay the onset of peripheral neurologic impairment in adult patients with symptomatic, early-stage transthyretin amyloidosis-associated polyneuropathy (ATTR-PN). Presently, it has received approval for the treatment of ATTR-PN in 40 nations, including South Korea, Brazil, Mexico, Argentina, Israel, Russia, and several European nations. The treatment of ATTR-PN with Vyndaqel or Vyndamax is not authorized in the United States. Vyndaqel received an Orphan Drug Designation for the treatment of ATTR-CM in the European Union and the United States in 2012 and in Japan in 2018. The US Food and Drug Administration (FDA) granted Vyndaqel Fast Track and Breakthrough Therapy designations for the treatment of ATTR-CM in June 2017 and May 2018, respectively, and Priority Review for a New Drug Application in November 2018. Vindaqel was approved by the Ministry of Labor Health and Welfare in Japan under Sakigake designation in March 2019 for the treatment of patients with wild-type and variant or hereditary forms of ATTR-CM. In May 2019, Vyndaqel received FDA approval for the treatment of ATTR-CM. The medication is supplied as oblong, opaque, yellow-colored capsules that contain 20 mg of drug.^3,4 The capsules are taken orally.

Mechanism of Action

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare disease characterized by an abnormal accumulation of amyloid deposits, derived from misfolded transthyretin (TTR) protein, in organs and tissues.⁵ The heart is affected in hereditary or variant forms of ATTR-CM. Wild-type ATTR-CM is not caused by a mutation and is usually associated with aging. ATTR-CM is characterized by restrictive cardiomyopathy and progressive heart failure. Frequently, it is not diagnosed until severe symptoms develop. Depending on the subtype, patients with ATTR-CM have a median life expectancy of 2 to 3.5 years after diagnosis.⁴

Read more about hATTR therapies

In ATTR-CM, tetramers of TTR protein are destabilized as a consequence of genetic mutations or natural misfolding of the protein and dissociate. The resulting monomers accumulate in tissues, so that the tissues cannot function normally. The active salt in Vyndaqel, tafamidis meglumine, is a selective TTR stabilizer that decreases the number of monomers available for amyloidogenesis as it attaches to TTR protein at thyroxine binding sites.The half-life of tafamidis meglumine is 49 hours.^1,6 

Efficacy in Trials and Trial Results

FDA approval was based on a pivotal phase 3 clinical trial, Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy (ATTR-ACT). This was a multicenter, international, randomized, double-blind, placebo-controlled study (NCT01994889) of 441 patients with wild-type or hereditary ATTR-CM. Patients were randomized in a 1:2:2 ratio to receive 20 mg of Vyndaqel, 80 mg of Vyndaqel (four 20-mg capsules), or placebo once daily for 30 months, in addition to standard of care. The study results showed a significant reduction in the hierarchical combination of all-cause mortality and cardiovascular-related hospitalizations in the pooled arms receiving 20 or 80 mg of Vyndaqel versus placebo. Further examination of the individual components in the primary analysis (all-cause mortality and cardiovascular-related hospitalizations) also showed significant reductions for Vyndaqel versus placebo.^4,7 

After completion of the ATTR-ACT trial, participants were eligible to enroll in a long-term extension study (NCT02791230). Tafamidis meglumine at a dose of 20 or 80 mg (or 61 mg when available) was tested in this ongoing global, open-label, 60-month phase 3 trial, which will continue to treat enrolled participants with tafamidis for up to 60 months or until they have access to tafamidis via prescription, whichever happens first. The extension trial is emphasizing the need for early treatment of ATTR-CM and has demonstrated a long-term decrease in mortality with tafamidis use.^8,9

Warnings, Precautions, and Adverse Reactions

In clinical trials, the frequency of adverse events in patients treated with Vyndaqel has been similar to that in patients treated with placebo.⁷ 

It is important that patients inform treating health care providers about any liver diseases they may have before starting this medication.¹⁰ According to results from animal research, Vyndaqel may harm an unborn child if given to a pregnant woman. Breastfeeding is also not recommended during treatment with this drug.¹¹ 

Upon starting treatment with Vyndaqel, patients should enroll in a registry called the Transthyretin Amyloidosis Outcome Survey (THAOS). THAOS is a global disease registry created to evaluate the effect of therapies such as Vyndaqel and Vyndamax on the course of disease, as well as the association between genotype and phenotype. Participation is voluntary.¹¹ The details are available at ClinicalTrials.gov (NCT00628745). 

Get full prescribing information for Vyndaqel at MPR

References

1. VYNDAQEL and VYNDAMAX. Highlights of prescribing information. Pfizer. Revised May 2019. Accessed July 20, 2022. 
2. Vyndamax (tafamidis) Vyndaqel (tafamidis meglumine). Medical News Today. Accessed July 20, 2022. 
3. Vyndaqel (tafamidis) – treatment for transthyretin familial amyloid polyneuropathy. January 17, 2012. Accessed July 20, 2022. 
4. U.S. FDA approves VYNDAQEL® and VYNDAMAX™ for use in patients with transthyretin amyloid cardiomyopathy, a rare and fatal disease. News release. Pfizer. May 6, 2019. 
5. Transthyretin amyloidosis (ATTR). Pfizer. Accessed July 20, 2022. 
6. Tafamidis.Drugbank Online. Accessed July 20, 2022. 
7. Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis). Centerwatch. Updated May 1, 2019. Accessed July 20, 2022. 
8. Long-term safety of tafamidis in subjects with transthyretin cardiomyopathy. ClinicalTrials.gov. Updated December 7, 2021. Accessed July 20, 2022.
9. 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
10. Vyndaqel and Vyndamax. Rxlist.com. Accessed July 20, 2022. 
11. VYNDAQEL- tafamidis meglumine capsule, liquid filled. VYNDAMAX- tafamidis capsule, liquid filled. Pfizer Laboratories Div Pfizer Inc. Revised June 2021. Accessed July 20, 2022. 

Reviewed by Kyle Habet, MD, on 7/23/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.