Vyndaqel (Tafamidis)

Vyndaqel (tafamidis) is an investigational treatment being developed by Pfizer for the treatment of patients with familial amyloid polyneuropathy (FAP), a neurodegenerative disease caused by mutations in the gene that encodes for the transthyretin (TTR) protein. The TTR protein transports thyroid hormones and vitamin A in the human body.

Vyndaqel has been approved as an oral treatment for FAP patients in Europe since 2011. It received approval from the U.S. Food and Drug Administration (FDA) in May 2019 for the treatment of cardiomyopathy in adults with wild-type or hereditary TTR cardiac amyloidosis, which is a cardiac disease caused by mutations in the TTR gene. However, the FDA has not approved the treatment for FAP patients in the U.S., as clinical trials testing its long-term efficacy are still underway.

How Vyndaqel works

The functional TTR protein is a tetrameric complex made up of four identical transthyretin protein molecules. Mutations in the TTR gene destabilize the soluble tetrameric complex and cause the accumulation of monomeric TTR proteins as amyloid fibrils in various organs, including the brain and heart, thereby disrupting their normal functions. In the brain of FAP patients, these amyloid deposits are commonly found around nerve cells. They block normal signal transmission and result in neurodegeneration or nerve cell death.

Vyndaqel acts as a transthyretin stabilizer. It binds to the unstable tetrameric transthyretin complex and prevents it from breaking down into monomeric TTR molecules. This process may prevent the formation and buildup of amyloid deposits, thereby reducing nerve cell damage and slowing down disease progression. However, Vyndaqel does not reverse the nerve damage that has been caused by amyloid deposits nor can it remove the deposits that are already present.

Vyndaqel in clinical trials

The European Commission approved Vyndaqel for marketing in Europe based on the results of Pfizer’s double-blind, randomized, multicenter, placebo-controlled Phase 2/3 clinical trial (NCT00409175) called Fx-005. The trial enrolled 128 FAP patients with a particular type of mutation (called V30M) in the TTR gene. The primary outcome measures included neuropathy impairment scores in the lower limbs (NIS-LL) and quality of life scores based on the Norfolk quality of life–diabetic neuropathy questionnaire (Norfolk QOL-DN). These parameters were compared for patients taking Vyndaqel once daily against those treated with a placebo. The trial took place at locations in the U.S, South America, and Europe.

The results published in the journal Neurology showed that the primary outcome measures were comparatively similar between patients in the Vyndaqel- and the placebo-treated groups. However, analysis of secondary outcome measures showed significant evidence that Vyndaqel slowed the progression of neurological damage. Furthermore, TTR protein was successfully stabilized in 98% of Vyndaqel-treated patients, compared with none in the placebo group. Vyndaqel was found to be well-tolerated by the patients.

An extension study (NCT00791492) called Fx-006 assessed the long-term safety and benefits of Vyndaqel treatment in 86 participants previously enrolled in the Fx-005 study. Patients who chose to enroll in this trial continued taking Vyndaqel, or switched to Vyndaqel from a placebo immediately after the end of the first trial, for 12 more months. The results were published in the Journal of Neurology and showed that Vyndaqel slowed disease progression in patients for at least 30 months. Disease progression was reduced to a lesser degree in patients who switched from a placebo to Vyndaqel than patients who received the treatment earlier. None of the patients enrolled in both the Fx-005 and Fx-006 trials discontinued treatment due to side effects, which suggests that Vyndaqel was well-tolerated.

A Phase 2 clinical trial (NCT00630864) called FX1A-201 enrolled 21 FAP patients with non-V30M mutations in the TTR gene to evaluate the safety and efficacy of Vyndaqel treatment as well as its effect on the stabilization of the TTR protein complex. The results published in the Journal of Cardiovascular Translational Research suggested that by six months of treatment, Vyndaqel successfully stabilized the TTR protein in all patients with eight different mutations. The study also showed that Vyndaqel was safe and well-tolerated.

A Phase 3 open-label extension study (NCT00925002) is underway to monitor the long-term safety and efficacy of Vyndaqel in 93 FAP patients who completed the Fx-006 or FX1A-201 trials. This study will evaluate patients for up to 10 years and is expected to be completed in December 2021. The results of this study will determine whether the FDA will approve Vyndaqel for treatment in FAP patients. In a letter to Pfizer in 2012, the FDA had required further efficacy studies before granting approval.

Further evaluation of data from the Fx-005, Fx-006, and the Phase 3 open-label extension study revealed that early treatment with Vyndaqel resulted in a sustained delay in neurologic disease progression and long-term preservation of nutritional status. These results were published in the journal Amyloid.

In a report published in the European Journal of Neurology in 2018, a statistical analysis compared the neurological results obtained from the FX1A-201 study against the results obtained from the Fx-005 study at month 12. This baseline-adjusted analysis showed that Vyndaqel treatment delayed neurological progression comparably in patients with Val30Met and non-Val30Met mutations, suggesting that the two groups may be clinically more similar than previously thought.

A study published in 2018 in the New England Journal of Medicine reported the results of a multicenter, international, double-blind, placebo-controlled, Phase 3 trial (NCT01994889) in which 441 patients with transthyretin amyloid cardiomyopathy were randomly assigned in a 2:1:2 ratio to receive 80 mg of Vyndaqel, 20 mg of Vyndaqel, or a placebo for 30 months. The study showed that Vyndaqel reduced the decline in functional capacity and in quality of life compared with a placebo. Overall, patients experienced reduced mortality and cardiovascular-related hospitalizations. Based on these findings, the FDA then approved Vyndaqel for the treatment of patients with TTR-related cardiac amyloidosis.

Other details

The most common adverse reactions caused by Vyndaqel treatment include diarrhea, stomach aches, and urinary tract and vaginal infections.


Last updated: 07/10/2019


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