Vyndaqel Likely to Treat FAP Linked to Mutation Common in Asians, Lab Study Suggests

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by Catarina Silva |

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transthyrretin, FAP

Kate Stringaris, a researcher with the NIH's National Heart, Lung and Blood Institute in Bethesda, Maryland, separates lymphocytes from a blood sample as part of an investigation into natural killer immune cells.

Vyndaqel (tafamidis) increases the stability of the transthyretin protein and may help people with familial amyloidosis polyneuropathy (FAP) carrying a TTR gene mutation common in Asian populations, an early study  from Taiwan suggests. 

The research, “Biophysical characterization and modulation of Transthyretin Ala97Ser,” was published in the Annals of Clinical and Translational Neurology.

TTR mutations, the cause of FAP, lead to unstable transthyretin, meaning the protein has a different molecular structure compared to its usual 3D arrangement. This abnormality leaves the protein prone to breaking into smaller pieces that accumulate as amyloid deposits around peripheral nerves and in various tissues, including the heart and kidneys. 

Vyndaqel is approved to treat stage 1 (mild) FAP patients in Europe (marketed by Pfizer) to delay peripheral neurologic impairment. In the U.S., it is approved for cardiomyopathy (heart disease) in adults with wild-type or hereditary TTR cardiac amyloidosis. The therapy acts as a stabilizer, meaning that it prevents unstable transthyretin from breaking into smaller units to ultimately reduce nerve cell damage and slow disease progression.

More than 150 disease-causing mutations are known in TTR, including Ala97Ser (A97S). This mutation is a substitution of alanine by serine (two types of amino acids, the building blocks of proteins) in position 97 of the TTR gene sequence. 

Patients with it typically have late‐onset but rapidly progressive neuropathy (nerve damage) and heart disease.

Because of its late-onset, few FAP patients with the A97S mutation have been included in clinical trials of Vyndaqel, limiting information on whether they would benefit from this medication. 

Among FAP patients in Taiwan, A97S is also the most prevalent disease-causing mutation.

Researchers in that country for these reasons used analytical techniques to assess the stability of the A97S mutant protein and how tightly it binds to Vyndaqel’s active compound (tafamidis) in vitro (in a lab dish).

Results showed that the A97S mutation destabilizes the transthyretin protein. Compared to two other TTR mutations that are linked with early-onset FAP, the A97S mutant showed slightly lower stability.

Tafamidis binds to exactly same spot on A97S transthyretin as it does on the normal protein, the so-called thyroxine binding pocket. Importantly, these experiments also showed that tafamidis binds tightly to the mutated protein, effectively stabilizing it.

“This study confirmed the structural modulation effect of tafamidis [Vyndaqel] on A97S‐TTR and implied the potential therapeutic benefit of tafamidis for A97S TTR‐FAP,” the researchers wrote.

“This approach can be applied to investigate the modulation effect of tafamidis on other rare TTR variants, and help to make individualized choices of available treatments for FAP patients,” they added.

“These [results] deepened our understanding of the pathogenesis [development] of A97S TTR‐FAP. We hope this study pave a road with stone leading to precision medicine of TTR amyloidosis,” the study concluded.