The European Commission (EC) has approved the once-daily oral medication Vyndaqel (tafamidis) for the treatment of cardiomyopathy — a disease of the heart muscle that makes it harder for the heart to pump blood to the rest of the body — in adults with transthyretin amyloidosis.
Vyndaqel is now the first and only approved treatment for cardiomyopathy (ATTR-CM) associated with both forms of amyloidosis in the European Union.
“Until today, there were no approved medicines to treat patients with ATTR-CM in the EU,” Paul Levesque, global president of Pfizer Rare Disease, said in press release. “Today’s approval represents incredible progress for these patients and reflects our steadfast commitment to delivering breakthrough medicines to rare disease patients.”
ATTR-CM is caused by the buildup of misfolded transthyretin protein deposits — called amyloids — in the heart, which lead to progressive heart failure, and ultimately death.
In the case of hereditary transthyretin amyloidosis, also known as familial amyloid polyneuropathy or FAP, the accumulation of the misfolded protein is caused by mutations in the TTR gene. This gene provides the instructions for producing transthyretin. In contrast, in the wild-type form of the disease, the production of the abnormal protein occurs in the absence of any genetic mutation.
Regardless of the cause, in both forms of the disease problems arise when transthyretin falls out of its normal tetramer structure — a unit made of four individual proteins chains. When it’s outside this four-fold structure, the protein starts to fold irregularly, forming aggregates or clumps — technically called amyloid fibrils — that accumulate and damage tissues and organs.
Vyndaqel is a transthyretin stabilizer that works by binding to the protein and keeping it in its tetramer form. A different therapy formulation — 20 mg capsule of tafamidis meglumine — is already approved in the EU for the treatment of stage 1 symptomatic polyneuropathy (ATTR-PN). That medication was approved for use by adults with FAP in 2011.
“With today’s milestone, Vyndaqel is now the first treatment to have two formulations approved in the EU to treat manifestations of transthyretin amyloidosis: one for cardiomyopathy, and one for stage 1 polyneuropathy,” Levesque said.
The approval of Vyndaqel for the treatment of ATTR-CM was based on data from the Phase 3 ATTR-ACT study (NCT01994889). ATTR-ACT is the first and only completed, global, double-blind, randomized, placebo-controlled trial to investigate the safety and efficacy of a pharmacologic therapy for ATTR-CM.
The 30-month (2.5-year) study enrolled 441 people with ATTR-CM. From these, 264 were treated with Vyndaqel, at a daily dose of 20 mg (176 patients) or 80 mg (88 participants). The remaining 177 participants received a placebo. Most patients were men (about 90%) and white (about 80%), and 106 (24%) had FAP.
The results showed that Vyndaqel reduced the all-cause mortality rate by approximately 30% (29.5% versus 42.9%) compared with treatment with the placebo. It also lowered the rate of heart-related annual hospitalizations by 32% (0.48 versus 0.70 hospitalizations per year), in comparison with the placebo.
“Vyndaqel represents a major advance for patients, as it can significantly reduce all-cause mortality and the frequency of cardiovascular-related hospitalizations in patients with wild-type or hereditary ATTR-CM,” said Thibaud Damy, MD, coordinator of the French referral centers for cardiac amyloidosis, and former president of the French heart failure and cardiomyopathy group of the French Society of Cardiology.
Treatment also reduced the decline of patients’ functional capacity, as assessed by the Six-Minute Walk Test, and overall health status — assessed by the Kansas City Cardiomyopathy Questionnaire–Overall Summary — compared with the placebo.
Vyndaqel was generally well-tolerated and showed a favorable safety profile in the trial. The frequency of adverse events reported in the Vyndaqel and placebo groups was similar, with most events being only mild or moderate in severity.
The approval also was based on an analysis that showed that one 61 mg capsule of free acid tafamidis was functionally equivalent to the 80 mg dose of tafamidis meglumine tested in the trial. According to Pfizer, the 61 mg formulation, which was not used in ATTR-ACT, “was developed for patient convenience to enable a single capsule for daily administration.”
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