A Review on Tafamidis to Treat a Genetic condition that affects Nerves and may lead to High Blood Pressure and Other Heart Problems
Mayur S. Jain*, Shashikant D. Barhate
Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jammer (MH)
*Corresponding Author E-mail: mayurjain176@gmail.com
ABSTRACT:
Tafamidis, available under the brand names Vyndaqel and Vyndamax, is a medication used to help slow the progression of transthyretin amyloidosis in adults. This rare condition can be inherited, as seen in familial amyloid cardiomyopathy and familial amyloid polyneuropathy, or it can occur without a genetic link, such as in wild-type transthyretin amyloidosis (previously called senile systemic amyloidosis). The drug works by binding to the transthyretin protein and stabilizing its structure, which helps prevent it from breaking apart and forming amyloid deposits that can harm organs like the heart and nervous system. Tafamidis has been recognized by the U.S. Food and Drug Administration as a first-in-class therapy due to its novel mechanism of action.
1. INTRODUCTION:
Tafamidis is a prescription drug used to manage transthyretin amyloidosis (ATTR), a rare disorder caused by the buildup of faulty transthyretin proteins in organs such as the heart, nerves, and other tissues. These protein accumulations can lead to serious health complications. Tafamidis helps by binding to the transthyretin protein and stabilizing it, which stops it from breaking apart and forming amyloid fibrils. By doing so, the medication can slow the advancement of the condition, reduce symptoms, and improve overall quality of life. It is sold under brand names like Vyndaqel and Vyndamax and is usually administered as an oral capsule.1,2 Amyloidosis refers to a group of disorders where abnormal protein fragments, called amyloid fibrils, accumulate in tissues and organs.
The condition often presents with general symptoms that are not specific, such as fatigue, swelling in the limbs, unexplained weight loss, difficulty breathing, heart palpitations, and lightheadedness upon standing. Certain forms of amyloidosis have unique features—AL amyloidosis, for instance, may involve an enlarged tongue or bruising around the eyes. In wild-type transthyretin amyloidosis (ATTRwt), non-heart-related symptoms can include carpal tunnel syndrome in both wrists, narrowing of the spinal canal, rupture of the biceps tendon, nerve pain involving small fibers, and issues with autonomic body functions.
There are approximately 36 known forms of amyloidosis, each associated with a specific protein that misfolds and becomes unstable. Of these, 19 are considered localized types, 14 are systemic, and three can manifest in either form. These proteins may become abnormal due to inherited genetic mutations or environmental and acquired factors. The most frequently encountered types of systemic amyloidosis include: AL (associated with abnormal light chains), AA (linked to chronic inflammation), Aβ2M (connected to long-term dialysis), and ATTR, which includes both hereditary and age-related forms.3,4
Fig. 1 Amyloidosis
Symptoms are often vague, mimicking those of other common conditions. Therefore, a multidisciplinary approach among physician specialists is essential for diagnosis. In some cases, Telltale signs of amyloidosis are an enlarged tongue (macroglossia) or bruising around the eyes (periorbital purpura)
There are two types of ATTR:
ATTR-CM (cardiac amyloidosis), which affects the heart.
ATTR-PN (polyneuropathy), which affects the nerves, especially in the peripheral nervous system
Tafamidis, marketed under the names Vyndaqel and Vyndamax, is a prescription medication used to slow the progression of certain types of transthyretin amyloidosis (ATTR) in adults. It is approved for treating both the hereditary forms—such as familial amyloid cardiomyopathy and familial amyloid polyneuropathy—as well as the wild-type form of the disease, which was previously referred to as senile systemic amyloidosis.The drug works by stabilizing the transthyretin protein in its normal, four-part (quaternary) structure. In individuals with ATTR, this protein can break apart and form harmful amyloid deposits that accumulate in various tissues, particularly affecting the heart and nerves. By helping maintain the protein's structure, tafamidis prevents or reduces the formation of these toxic clumps.
IUPAC NAME- 2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Tafamidis is an oral medication prescribed to slow the progression of nerve damage in adults diagnosed with transthyretin amyloidosis accompanied by polyneuropathy. It is also used to manage transthyretin amyloidosis-related cardiomyopathy. Women are advised to avoid pregnancy and breastfeeding while on this treatment. Additionally, it is not recommended for individuals with familial amyloid polyneuropathy who have undergone a liver transplant. An alternative treatment is acoramidis.
Pharmacodynamics:
"Tafamidis works by stabilizing transthyretin tetramers, thereby limiting the breakdown into monomers that can lead to amyloid formation. It is administered once daily due to its prolonged effect and has a broad therapeutic range".
Mechanism of action:
Mutations in the transthyretin (TTR) gene or spontaneous misfolding of the protein can compromise the stability of TTR tetramers. This instability causes the tetramers to break apart into monomers, which can misfold and accumulate in various tissues, impairing their normal function. Tafamidis works by binding to the thyroxine-binding sites on the TTR tetramer, enhancing its stability and thereby limiting the formation of monomers that contribute to amyloid buildup.
Metabolism:
Tafamidis undergoes minimal first-pass or oxidative metabolism, with studies showing that around 90% of the compound remains unchanged in in vitro settings. Preclinical findings indicate that its primary metabolic pathway is glucuronidation, and it is predominantly eliminated via the bile.3,4
Interactions:
Tafamidis does not significantly interact with cytochrome P450 enzymes. However, it is known to inhibit the ATP-binding cassette sub-family G member 2 (ABCG2), which may alter the levels of certain medications such as methotrexate, rosuvastatin, and imatinib. Additionally, tafamidis inhibits organic anion transporters OAT1 and OAT3 (also known as SLC22A8), suggesting a potential for interaction with non-steroidal anti-inflammatory drugs (NSAIDs) and other substances that depend on these transport systems for clearance.3,4
Route of elimination:
Following a 20mg oral dose of tafamidis, around 59% is excreted in the feces, primarily as the unchanged compound. Additionally, approximately 22% of the dose is eliminated through urine, mainly in the form of its glucuronide metabolite.
Toxicity:
Data regarding overdoses of tafamidis are not readily available.7 In a clinical trial, some patients were given up to 6 times the normal dose with one reported case of mild hordeolum.
History:
In the 1990s, Jeffery W. Kelly’s laboratory at The Scripps Research Institute began exploring methods to prevent the formation of transthyretin fibrils. Their efforts led to the discovery of tafamidis through a structure-based drug design approach, with the compound’s chemical structure first disclosed in 2003. That same year, Kelly teamed up with Susan Lindquist from MIT and the Whitehead Institute to establish FoldRx, a company that advanced tafamidis development. FoldRx submitted an application for marketing approval in Europe by early 2010, and later that year, Pfizer acquired the company. In November 2011, the European Medicines Agency approved tafamidis to slow the progression of peripheral nerve damage in adults suffering from hereditary transthyretin amyloidosis. However, the U.S. FDA declined approval in 2012, citing insufficient evidence of clinical benefit based on functional outcomes, and requested additional trials. Eventually, in May 2019, the FDA approved two formulations—Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis)—for treating transthyretin-mediated cardiomyopathy. Japan granted approval for the drug in 2013, contingent on further studies to confirm its efficacy.
The FDA granted approval for tafamidis meglumine based mainly on a clinical trial involving 441 adult participants across 60 sites in countries including Belgium, Brazil, Canada, the Czech Republic, Spain, France, Greece, Italy, Japan, the Netherlands, Sweden, the United Kingdom, and the United States. This study assessed the effects and safety of tafamidis in treating transthyretin amyloidosis with cardiomyopathy. Patients were randomly assigned to receive either tafamidis (at doses of 20mg or 80mg) or a placebo for a duration of 30 months. Approximately 90% of the participants were also on standard heart failure treatments. Additionally, both the European Medicines Agency and the FDA recognized tafamidis as an orphan drug, highlighting its use for a rare condition.4,5
Protein binding:
Tafamidis 99.9% protein bound in plasma, mostly to transthyretin.
Drug Categories:
Anti-Inflammatory Agents, BCRP/ABCG2 Inhibitors, Fused-Ring Compounds, Heterocyclic Compounds, Fused-Ring, Hormones, Hormone Substitutes, and Hormone Antagonists, Immunologic Factors, Miscellaneous, Cardiac Drugs, Nervous System
Legal Status:
Tafamidis was first approved in the European Union in 2011 to treat transthyretin amyloidosis with polyneuropathy, followed by approval in Japan in 2013. However, the U.S. Food and Drug Administration (FDA) initially rejected its use for this condition due to insufficient evidence supporting its effectiveness. Later on, tafamidis gained approval to treat transthyretin amyloidosis with cardiomyopathy, receiving clearance in the U.S. in 2019 and in the EU in 2020. In the United States, two forms of tafamidis are available: tafamidis meglumine (marketed as Vyndaqel) and tafamidis (marketed as Vyndamax). Both contain the same active ingredient but are not interchangeable on a milligram-to-milligram basis. Additionally, both versions were approved for medical use in Australia in March 2020. Overall, tafamidis is now accessible in 64 countries worldwide.5,6
CONCLUSION:
Tafamidis, marketed as Vyndaqel and Vyndamax, is a drug used to slow the progression of certain types of transthyretin amyloidosis in adults. It is effective in treating hereditary forms such as familial amyloid cardiomyopathy and familial amyloid polyneuropathy, as well as the wild-type transthyretin amyloidosis, which was previously known as senile systemic amyloidosis. The medication works by stabilizing the transthyretin protein's structure, preventing it from breaking down. In transthyretin amyloidosis, this protein disintegrates and forms harmful deposits called amyloid, which damage tissues like nerves and the heart. The FDA recognizes tafamidis as a pioneering treatment in its category.
REFERENCES:
1. Coelho T, Merlini G, Bulawa CE, Fleming JA, Judge DP, Kelly JW, Maurer MS, Plante-Bordeneuve V, Labaudiniere R, Mundayat R, Riley S, Lombardo I, Huertas P. Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis. Neurol Ther. 2016 Jun; 5(1): 1-25. doi: 10.1007/s40120-016-0040-x. Epub 2016 Feb 19. [Article]
2. Gurwitz JH, Maurer MS. Tafamidis-A Pricey Therapy for a Not-So-Rare Condition. JAMA Cardiol. 2020 Jan 8. pii: 2758314. doi: 10.1001/jamacardio.2019.5233. [Article]
3. Endo J, Sano M, Izumiya Y, Tsujita K, Nakamura K, Tahara N, Kuwahara K, Inomata T, Ueda M, Sekijima Y, Ando Y, Tsutsui H, Isobe M, Fukuda K. A Statement on the Appropriate Administration of Tafamidis in Patients With Transthyretin Cardiac Amyloidosis. Circ J. 2019 Dec 25; 84(1):15-17. doi: 10.1253/circj.CJ-19-0811. Epub 2019 Nov 16. [Article]
4. Ratner M. Spotlight focuses on protein-misfolding therapies. Nat Biotechnol. 2009 Oct; 27(10): 874. doi: 10.1038/nbt1009-874c.
5. Lee KR, Jeong JW, Hyun HC, Jang E, Ahn S, Choi S, Joo SH, Kim S, Koo TS. Pharmacokinetics of tafamidis, a transthyretin amyloidosis drug, in rats. Xenobiotica. 2018 Aug; 48(8):831-838. doi: 10.1080/00498254.2017.1366575. Epub 2017 Nov 16.
6. Tafamadis SmPC EMA
7. FDA Approved Drug Products: Vyndaqel Tafamidis Meglumine Oral Capsules
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Received on 04.02.2025 Revised on 21.06.2025 Accepted on 26.09.2025 Published on 22.01.2026 Available online from January 29, 2026 Asian J. Pharm. Res. 2026; 16(1):83-86. DOI: 10.52711/2231-5691.2026.00010 ©Asian Pharma Press All Right Reserved
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