Vyndaqel May Help Halt Neurological Disease Progression in Patients With Val30Met Mutation, Study Reveals

Early diagnosis and prompt treatment with Vyndaqel (tafamidis) may help halt neurological disease progression in familial amyloid polyneuropathy (FAP) patients who are positive for the Val30Met mutation, clinical analyses of three trials suggest.

The study “Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy” was published in the journal Orphanet Journal of Rare Diseases.

Mutations in the TTR gene are the underlying cause of the rare genetic disease familial amyloid polyneuropathy, or FAP. The abnormalities lead to the formation of amyloid fibers that damage organs and periphery nerve cells — those outside the brain and spinal cord.

The disease symptoms and its progression depend on the type of mutations. While the most common mutation is the amino acid substitution Val30Met, patients with non-Val30Met mutations have poorer outcomes. This diversity of genetic errors may hinder diagnosis and monitoring of disease progression.

Pfizer’s Vyndaqel (tafamidis) stabilizes the TTR gene’s production of TTR protein, preventing the formation of the potentially toxic fibers and is approved in Europe, parts of Asia, and Latin America as a therapy to delay disease progression and nerve cell’s damage.

To understand how the level of severity in early diagnosis correlates with disease progression in FAP patients with the Val30Met mutation, researchers analysed data from three clinical trials that evaluated the safety and efficacy of Vyndaqel: The placebo-controlled Phase 2/3 trial (NCT00409175) and two follow-up open-label extension trials — the completed NCT00791492, and the ongoing NCT00925002.

They evaluated the initial analysis of the ongoing open-label trial (NCT00925002), and the data from patients who participated in the first trial and who were randomized to 18 months of Vyndaqel or a placebo, followed by 12 months of Vyndaqel (NCT00791492).

In total, 64 patients received Vyndaqel throughout the three studies (T-T group), and 61 patients received first a placebo and were then switched to Vyndaqel in the open-label studies (P-T group).

Both groups had a similar median age (39.8 in the T-T group and 38.4 years in the P-T group) and male ratio (50% in T-T and 43% in P-T).

Patients’ neurologic functioning was measured at the beginning of the trials, and at regular visits using the Neuropathy Impairment Score–Lower Limbs (NIS-LL), and focused on the first 18 months of treatment.

NIS-LL scale ranges between zero (no impairment) and a score of 88 (total impairment). Researchers also measured patients scores in the NIS-LL muscle weakness subscale, which assesses hip, knee, ankle and toe function.

The analysis showed that patients in both groups had signs of neurological symptoms since enrollment. Disease severity at the time of enrollment was a significant, independent predictor of disease progression — patients with a lower score in the NIS-LL scale at baseline showed less progression than those with higher NIS-LL scores.

The rate of disease progression was significantly higher in the P-T group compared with the T-T group, which supports the disease-modifying effects of Vyndaqel, with the separation between both groups increasing over the 18-month period.

Similar results were seen with the NIS-LL muscle weakness subscale.

“This analysis of patients with Val30Met ATTR-PN demonstrates that disease progression strongly depends on baseline neurologic severity and illustrates the disease-modifying effect of tafamidis relative to placebo across a range of baseline levels of neurologic severity and treatment durations,” the researchers wrote.

“These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression,” the study concluded.