Treatment with 20 mg a day of oral Vyndaqel (tafamidis) is enough for the therapy to reach the central nervous system (CNS) and eyes of familial amyloid polyneuropathy (FAP) patients with a Val30Met mutation, a small study from Portugal found.
Results also showed the treatment was associated with an increased stabilization of the transthyretin protein, the underlying cause of the disease. This supports additional research into the potential for increasing the dose of Vyndaqel as a way to improve clinical manifestations affecting the brain and eyes.
The study, “Cerebrospinal fluid and vitreous body exposure to orally administered tafamidis in hereditary ATTRV30M (p.TTRV50M) amyloidosis patients” was published in the journal Amyloid.
FAP, also known as hereditary transthyretin (TTR) amyloidosis, is a rare progressive disease caused by genetic mutations in the TTR gene, which provides instructions to make a protein called transthyretin.
The mutations alter the structure of transthyretin, which starts to accumulate and form deposits in several tissues, including the nerves, heart, kidneys, and eyes.
While more than 130 different TTR gene mutations have been associated with FAP, the most frequent mutation — affecting up to 50 percent of FAP patients worldwide — is known as Val30Met.
In the last decade, several therapeutic strategies have been developed for Val30Met FAP patients that have slowed down disease progression. These include liver transplantation, and treatment with medicines that stabilize the transthyretin protein, like Pfizer’s Vyndaqel (tafamidis).
However, liver-transplanted patients often still produce the abnormal transthyretin protein in the brain and eyes. Whether Vyndaqel is capable of halting disease manifestations in the CNS and eyes remains unknown.
Researchers analyzed the cerebrospinal fluid content — the fluid bathing the brain and spinal cord of a small group of patients with the Val30Met mutation — five patients had been taking Vyndaqel orally (20 mg per day) and four patients had never received the therapy. They also included three controls without the disease.
They also analyzed the contents of the fluid that fills our eyes, specifically the space between the lens and the retina — called vitreous body — in eight patients treated with Vyndaqel and compared it to those not treated with the therapy (19 patients).
The analysis showed that Vyndaqel administered orally is found in both the cerebrospinal fluid (CSF) and the vitreous body, although at a lower concentration in the latter in this study.
These results “suggest that [Vyndaqel] can cross the CSF-blood and eye-blood barriers,” researchers wrote. The blood-cerebrospinal fluid and the eye-blood barriers are two physical entities separating the contents of the brain and the eye from the general blood circulation.
The data also showed that the transthyretin protein is more stable in patients treated with Vyndaqel compared to healthy controls. However, despite a positive tendency there was no statistical significant difference between the levels of stabilized transthyretin protein between Vyndaqel-treated and nontreated patients.
Overall, these results suggest that Vyndaqel can reach both the central nervous system and the eye, highlighting its potential for easing disease manifestations in these areas.
However, additional studies are essential to “determine whether increasing the daily [Vyndaqel] dosage or altering the dosing regimen would lead to an increase in CNS and eye exposure, and consequently to better clinical outcomes in the brain and in the eye,” the study concluded.