Vyndaqel found most effective in early-stage FAP in real world: Study

Therapy approved in EU for patients with most-common mutation Val30Met

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Among familial amyloid polyneuropathy (FAP) patients carrying the most common FAP-causing mutation Val30Met, treatment with Vyndaqel (tafamidis meglumine) is most effective when given at the very early stages of the disease.

That’s according to the findings of a real-world study in Spain, which linked a cutoff value of 15 or higher in the Neuropathy Impairment Score (NIS) — a score indicating worse disability — to a 60% probability of failing to respond to Vyndaqel. The oral therapy is approved for treating FAP in Europe, but not in the U.S.

“Our results reinforce the [Vyndaqel] efficacy to treat [FAP] if started early in the disease course,” the researchers wrote, noting, however, that “treatment failure may occur” if the therapy is started late.

“In our analysis of real-world experience with [Vyndaqel] 20 mg … we showed that early treatment … was associated with a better response,” the team wrote.

The study, “Real life experience of tafamidis for the treatment of Spanish patients with Val30Met transthyretin amyloidosis with polyneuropathy,” was published in the journal Medicina Clínica.

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FAP, also known as hereditary transthyretin amyloidosis with polyneuropathy, is caused by mutations in the TTR gene, which contains instructions for the production of a protein called transthyretin (TTR). As a result of this mutation, toxic clumps of mutated TTR accumulate mainly in the nerves outside the brain and spinal cord, and, less commonly, in the heart.

Vyndaqel, developed by Pfizer, works by stabilizing the altered TTR, which is expected to halt the formation of toxic clumps. The oral therapy is approved in the U.S. and Europe to treat transthyretin amyloid cardiomyopathy (ATTR-CM), an FAP-related disease characterized by toxic TTR clumps in the heart instead of the nerves.

In Europe, but not in the U.S., Vyndaqel also is cleared to treat adults with FAP who have Coutinho stage 1, or early-stage, polyneuropathy. Polyneuropathy refers to damage to several nerves.

Clinical trial data supported the therapy’s safety and efficacy in this patient population, the researchers noted. However, according to the team, based in Spain, “there is limited real-life experience” with Vyndaqel in FAP caused by the Val30Met mutation — “particularly outside of Portugal,” they noted.

To learn more, the researchers assessed the therapy’s real-world safety and effectiveness in 100 FAP patients carrying Val30Met who received Vyndaqel for at least a year.

Patients were followed at seven main referral centers for the disease in Spain between January 2012 and December 2022.

More than half of the patients (56%) were men. At diagnosis and treatment start, their median age was 65, and their median NIS was 6 on a scale ranging from 0 to 96, where a higher score reflects a greater FAP-related disability burden. Most patients (83%) had very early-stage disease.

All were treated with Vyndaqel, for a median of 35 months or nearly three years (range, 1-10.6 years).

Nearly half of the patients (47%) were classified as complete responders, meaning they showed no symptom progression. A total of 21% were deemed non-responders, with symptoms that continued to rapidly worsen. Patients outside of these two groups — 32% in all — were deemed as partial responders.

Vyndaqel treatment was discontinued by almost half of the patients (48%). The main reason given was a progression of neurological symptoms, which occurred in 21 non-responders and 21 partial responders.

Of these 42 patients showing disease progression, half switched to Onpattro (patisiran) and 12 (28.6%) to Tegsedi (inotersen), two FAP treatments. Six patients (14.3%) joined clinical trials and three (7.1%) underwent a liver transplant. Because TTR is produced in the liver, a liver transplant can slow FAP progression and improve survival.

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Overall, the findings showed that individuals at the very early stages of FAP — defined as Polyneuropathy disability (PND) stage 1 — were significantly more likely to respond to Vyndaqel treatment. Patients classified as PND stage 1 have noticeable symptoms, such as abnormal sensations, but no difficulty walking.

Importantly, according to the researchers, “walking ability, measured by both PND and Coutinho stages, remained stable in the vast majority of the population (80%), even in cases where clinical progression was considered.”

Compared with non-responders, those with a response to Vyndaqel also had significantly lower NIS (median of 3 vs. 14) and significantly higher Compound Muscle Action Potential, the muscle response to nerve fiber stimulation (median of 11.3 vs. 8.4).

Lab results showed that higher blood levels of the albumin protein and lower levels of NT-proBNP, a heart damage marker, were significantly associated with better treatment responses.

[Those at early disease stages] are the most appropriate subjects for this treatment, and treatment alternatives should be considered in more advanced disease.

Following this, the researchers assessed whether NIS at Vyndaqel initiation was able to discriminate responders, complete and partial, from non-responders. They found that using a NIS cutoff of 15 or higher was able to do so with a sensitivity of 50% and a specificity of 82%. In this case, a test’s sensitivity is its ability to correctly identify responders, while specificity refers to accurately identifying non-responders.

Further, the team noted that a patient with an NIS of 10 or higher at treatment start had a 33% probability of being a non-responder. This probability rose to 60% if a patient had a NIS of 15 or higher.

These findings suggest that among FAP patients with a Val30Met mutation, those at early disease stages and with a NIS below 15 “are the most appropriate subjects for this treatment, and treatment alternatives should be considered in more advanced disease,” the researchers concluded.