Vyndaqel effective for hATTR-CM patients with A97S mutation

Studies supporting approval lacked disease's most common mutation in Taiwan

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with Vyndaqel (tafamidis) reduces signs of heart damage for most people with hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM) associated with the A97S mutation, the most common cause of the disease in Taiwan, a study in that country shows.

Notably, improvements in heart health were most pronounced among patients with more severe heart damage prior to treatment.

The study, “Efficacy of Tafamidis in Patients with Ala97Ser Hereditary Transthyretin Cardiac Amyloidosis: A Six-Month Follow-Up Study,” was published in Acta Cardiologica Sinica.

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Vyndaqel helps to prevent clumping of the transthyretin protein

Hereditary ATTR amyloidosis is a group of disorders in which a protein called transthyretin forms toxic clumps in body tissues due to mutations in the TTR gene. hATTR-CM is a subtype marked by the accumulation of these toxic clumps mostly in heart tissue, leading to cardiomyopathy, or heart damage.

When these protein aggregates accumulate mostly on nerve cells outside the brain and spinal cord, it is called familial amyloid polyneuropathy or hereditary transthyretin polyneuropathy.

Vyndaqel, by Pfizer, works to stabilize the transthyretin protein so that it doesn’t form toxic clumps. It is approved in the U.S. and other countries to treat cardiomyopathy associated with both hereditary and nonhereditary, or wild type, forms of amyloidosis. In Europe, the oral therapy also is available to treat the initial stages of FAP.

While Vyndaqel was proven in clinical trials to be effective in treating ATTR amyloidosis-associated cardiomyopathy, these studies mainly enrolled white patients, and none carried A97S, the most common TTR mutation in Taiwan.

More than 80% of people with this mutation develop cardiomyopathy, though ATTR amyloidosis symptoms usually develop later in life than in those carrying V30M, the most common disease-causing TTR mutation worldwide.

Scientists in Taiwan evaluated how Vyndaqel’s use affected the heart health of 20 people with hATTR-CM associated with the A97S mutation. All received the therapy for at least six months; 10 were part of a Pfizer-sponsored long-term clinical trial (NCT02791230) and the other 10 were treated under a compassionate use program before the therapy’s approval.

Patients’ mean age was 63, and three-quarters were men. Most had notable heart muscle enlargement (hypertrophy), which develops when the heart is overly strained.

With the exception of one patient, all were classified as New York Heart Association (NYHA) functional class 2, meaning they had mild symptoms that were noticeable, but caused only slight problems during typical activities.

Vyndaqel stabilized or eased disease symptoms in patients with A97S mutation

After six months on Vyndaqel, none of the patients experienced a worsening in NYHA functional class, results showed. Three patients moved from class 2 to class 1, meaning they no longer had noticeable symptoms.

Measures of heart hypertrophy tended to reduce, and life quality tended to improve, over six months on Vyndaqel. However, these differences did not reach statistical significance, which the researchers said is probably attributable to the small number of patients in this study.

Average blood levels of NT-proBNP, a well-established marker of heart damage, decreased significantly following six months of treatment. Most patients (70%) experienced a notable decline in NT-proBNP levels, while the remaining six showed an increase in these levels.

Those who experienced a drop in NT-proBNP levels had significantly more heart hypertrophy and numerically higher NT-proBNP levels before treatment, suggesting they had more severe heart disease.

Vyndaqel also led to an increase in transthyretin levels in the blood, which the researchers said is consistent with the therapy’s known mechanism of action. By stabilizing the protein and stopping it from forming clumps, more of the protein ends up freely flowing in blood, rather than building up in the heart and other organs.

“This study is the first to demonstrate the short-term treatment effects of [Vyndaqel] in patients with A97S hereditary ATTR-CM,” the scientists wrote.

“Our results showed that the NT-proBNP level significantly improved after 6 months of [Vyndaqel] treatment. … In addition, we found that the patients with more severe [heart] involvement were more likely to have an improvement in NT-proBNP level,” they added.

The scientists suggested that a longer, larger study might be necessary to identify meaningful changes among patients who start on treatment with less severe heart disease.

“This study only provided 6 months of follow-up data. Consequently, the long-term effects of [Vyndaqel] on patients with A97S ATTR-CM cannot be demonstrated, and further studies with longer follow-up are needed,” the team wrote.