Long-term treatment with Vyndaqel (tafamidis) is safe and well-tolerated by patients with transthyretin familial amyloid polyneuropathy (TTR-FAP) caused by Val30Met and other mutations, but does not prevent progression of nerve damage, or neuropathy, in most patients, a three-year follow-up study reported.
However, in patients with early-onset FAP-associated Val30Met mutations, the medicine may lead to significant clinical benefit. In contrast, efficacy seems limited for older patients with more advanced disease; thus, other therapies should be considered for them.
Pivotal studies on Vyndaqel have reported encouraging short-term results in patients carrying Val30Met mutations — the most common transthyretin (TTR) gene causing FAP — when given at an early stage of the disease.
But the medicine’s potential benefits are less known at a more advanced stage of the disease and in the long term, and particularly in non-Val30Met patients.
A team of physicians and researchers at France’s Henri Mondor University sought to address this knowledge gap by carrying out a study examining a group of 43 FAP patients who had initiated treatment with Vyndaqel.
Patients carried a variety of TTR mutations, including non-Val30Met (53%), and were at early or more advanced stages of neuropathy.
Ile107Val, Ser77Tyr, and Ser77Phe were the three non-Val30-Met variants most frequently found among this sample of patients. These are associated with a more rapid and severe disease progression.
Patients were taking 20 mg a day of Vyndaqel and followed for a mean of 2.1 years, and up to three years.
Every six to 12 months, clinical assessments, including neuropathy, walking capacity and global health scores, were performed, along with neurophysiological tests (e.g. nerve conduction and sensory function).
The results showed that during the three years of follow-up, Vyndaqel was generally safe and well-tolerated. There were no serious adverse events reported.
But overall, there was significant worsening of clinical signs of neuropathy and patients’ global condition, although some neurophysiological scores seemed to remain stable for the first two years.
At the end of follow-up, 10% of the patients had lost their ability to walk and 26% had “frankly altered global health status.”
Patients gained considerable weight, as evidenced by an increase in body mass index (BMI) over time. However, these results should be interpreted with caution, as in later stages of the disease a BMI increase can be caused in part by body swelling.
Three variables were significant predictors of a better response and slower progression of neuropathy: younger age at disease onset or treatment start, higher BMI, and little advanced disease at treatment initiation.
In addition, most patients who responded to Vyndaqel at two years after treatment were those of Portuguese origin who had the early-onset Val30Met.
This suggests the medicine is more effective in those with this type of TTR-FAP, which may also explain the association of a younger age with a better response.
“These data are in line with the results of the follow-up studies on tafamidis mentioned … and could be of practical help for the management of patients,” researchers said.
There were patients who preserved their walking capacity or a good clinical condition, suggesting the treatment can be beneficial for some in the long term. What makes these patients respond is unknown, but suggests that individual factors likely play a role.
“In older patients with a more advanced disease, the value of tafamidis is probably more limited and other anti-amyloid therapeutic strategies are needed.” researchers said.
They added that “a regular monitoring of neuropathic and cardiac parameters is recommended in patients treated by tafamidis, to [promptly] consider other available therapeutic options.”
Vyndaqel is an investigational treatment being developed by Pfizer for FAP. It has been approved for marketing as an oral treatment 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.