Vyndaqel (tafamidis) is an investigational treatment being developed by Pfizer for familial amyloid polyneuropathy (FAP). It has been approved for marketing as an oral treatment for FAP in Europe since 2011, but is still under investigation in the U.S. It also is being investigated as a therapy for TTR cardiac amyloidosis.

How Vyndaqel works

FAP is an inherited condition caused by a mutation, or defect, in the transthyretin (TTR) gene, which produces transthyretin, a protein that is involved in transporting hormones and vitamins around the body. Normally four transthyretin proteins bind together to form a functioning protein complex. The mutation causes transthyretin to become unstable, resulting in it being broken down into fibrous proteins called amyloid, which build up as clumps in various organs and disrupt normal functions. These amyloid deposits commonly form around nerve cells, preventing normal signal transmission, and can lead to neurodegeneration, or nerve cell death.

Vyndaqel acts as a transthyretin stabilizer. By attaching to the unstable transthyretin, Vyndaqel prevents the protein from breaking down as easily. This should stop the excess buildup of amyloids, reduce nerve cell damage and slow the progression of the disease. However, Vyndaqel cannot reverse nerve damage already caused by the amyloid deposits or remove the deposits that already are present.

Vyndaqel in clinical trials

The pivotal study leading to the European Commission approving Vyndaqel was a double-blind, randomized, multicenter, placebo-controlled Phase 2/3 clinical trial (NCT00409175) called Fx-005, which compared the effect of Vyndaqel taken once daily to that of placebo in 128 people with FAP. Patients enrolled in the trial primarily had a particular type of mutation (called V30M) in the TTR gene. The trial took place at locations in the U.S, South America, and Europe. The results, published in the journal, Neurology, suggested that while there was no significant improvement in neurological function between patients in the Vyndaqel and the placebo-treated groups, there was significant evidence to suggest that Vyndaqel could slow the progression of neurological damage. Furthermore, TTR protein was successfully stabilized in 98 percent of Vyndaqel-treated patients, compared to none in the placebo group.

An extension study of the Fx-005 study, called Fx-006 (NCT00791492), enrolled 86 participants from the first study to identify the long-term safety of the treatment and to assess the ongoing benefit of Vyndaqel. Patients who chose to enroll in the trial continued taking Vyndaqel, or switched to Vyndaqel from placebo immediately after the end of the first trial, for 12 more months. The results, published in the Journal of Neurology, demonstrated that Vyndaqel could slow disease progression in patients for at least 30 months. Disease progression in patients who switched from placebo to Vyndaqel was reduced, but to a lesser degree than if the treatment was started earlier. Both trials suggested that Vyndaqel was safe, and no patients discontinued treatment due to side effects.

A Phase 2 trial (NCT00630864) called FX1A-201 that enrolled 21 FAP patients with different mutations (other than V30M), also has been completed. The results, published in the Journal of Cardiovascular Translational Research, suggested that Vyndaqel successfully stabilized TTR protein with eight different mutations in 100 percent of patients by six months of treatment.

A second Phase 3 long-term extension study (NCT00925002), which enrolled patients who have completed Fx-006 or FX1A-201 is ongoing. The trial aims to monitor 93 patients on Vyndaqel for up to 10 years.

Combined results from these trials have been published in the scientific journal Amyloid and suggest that Vyndaqel can sustain a reduction in disease progression for up to 5.5 years if treatment is started early.

Other details

The most common adverse reactions caused by the treatment include diarrhea, upper abdominal pain (stomach ache), urinary tract infection, and vaginal infection.

Vyndaqel was first approved in 2011 in the European Union for the treatment of FAP in people with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment.

The U.S. Food and Drug Administration (FDA) has not approved Vyndaqel for the treatment of FAP. In the complete response letter issued to Pfizer in June 2012, the FDA requested further efficacy studies before approval could be granted.

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