Liver transplant or therapy with Pfizer‘s Vyndaqel (tafamidis) can substantially extend the lives of people with familial amyloid polyneuropathy (FAP) in early stages of the disease, a Portuguese study has shown.
The study, one of the largest done in FAP patients, also showed that mortality still remains high among these patients, highlighting the importance of timely diagnosis and earlier treatment to improve life expectancy, researchers said.
The study, “Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy” was published in the journal Neurology.
FAP is a rare, slowly progressive disease with high prevalence in specific populations, predominantly in Portugal (estimated 22.93 per 100,000 adult inhabitants), Sweden, Japan, and Brazil.
The condition is marked by the buildup of amyloid protein deposits in the body’s organs and tissues, the consequence of a mutated transthyretin (TTR) gene. More than 100 TTR mutations have been associated with FAP, the most frequent being Val30Met.
Few treatment options are available. Routine care consists of orthotopic liver transplant (patient’s liver is replaced by one from a donor) or Vyndaqel (tafamidis), an oral medication designed to delay FAP progression in adults with early-stage disease. It is marketed by Pfizer and approved in the European Union. In the United States, the medicine is still under investigation and has not yet been approved.
Though widely used, the efficacy of such disease-modifying treatments is difficult to access, owing to “disease rareness, clinical heterogeneity [diverse symptoms], incomplete natural history, and uncertain treatment effectiveness,” researchers stated.
Thus, a team led by researchers from Hospital Santo António and Instituto de Medicina Molecular João Lobo Antunes, both in Portugal, performed a study on whether liver transplant or Vyndaqel improved survival among patients with early-stage FAP.
The study included 3,160 patients with Val30Met FAP at an early stage (low polyneuropathy disability score — stage 1), referred to two Portuguese centers. They were grouped into untreated (1,771), liver transplant-treated (957) and Vyndaqel-treated (432).
Within each group, researchers also studied the natural history of the disease and explored prognostic factors for survival, including sex, late-onset status, stage, and disease duration before treatment.
Median follow-up was 10.25 years for untreated patients, 13.67 years in those who had a liver transplant, and 5.45 years in the Vyndaqel-treated group.
A whole population analysis suggested that both liver transplant and treatment with Vyndaqel reduced mortality rates among FAP patients.
The standardized mortality ratios in 1991 (before liver transplant and Vyndaqel become available) indicated that untreated patients had a mortality rate 10 times higher than the general population. But in 2016 (when both treatments were already routinely used), this rate dropped by more than a half, from 10 to 4. The mortality rate was highest in those ages 45-54 and higher for women than men.
Comparisons among each patient group (untreated, liver transplant, Vyndaqel) showed that both treatments were able to improve survival of FAP patients.
Median overall survival of untreated patients was 11.61 years, while in the liver transplant group it was 24.73 years. Median survival could not be determined for those receiving Vyndaqel because of the short follow-up time in this group (maximum 10 years).
In early-onset patients (FAP onset before age 50), the mortality risk was reduced by 91% and 63% by Vyndaqel and liver transplant, respectively, compared with untreated patients.
Among late-onset patients (50 and older), a population with a poorer prognosis and for whom liver transplant is not normally recommended, Vyndaqel led to a clinically relevant survival benefit, reducing mortality risk by 82%.
According to researchers, the study’s main clinical finding is that disease-modifying treatments, in particular liver transplant, “changed dramatically the long-term prognosis for patients with TTR-FAP in the past 25 years, from a progressive, devastating, fatal disease to a more chronic condition with treatment leading to delayed disease progression.”
However, “these treatments have not proven to reverse established damage” and mortality rates still remain high for FAP patients, about four times greater than in the general population, researchers said.
Also, the study showed that patients who went longer without treatment had a poorer prognosis, highlighting the importance of a timely diagnosis and the need to start treatment early.
To confirm the study findings, researchers propose the conduction of prospective clinical registries “as longer follow-up data may facilitate understanding of how clinical practice can reconcile different treatment options, especially as new drugs emerge from Phase 3 clinical trials.”
This evidence, they said, can be a valuable source to inform regulatory agencies and clinical treatment guidelines and recommendations.