Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy

Abstract

Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and -7.8 (-44.3, 28.8) kg/m2 × g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis.

Trial registration: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002.

Keywords: ATTRV30M; Amyloidosis; TTR Val30Met; disease modification; transthyretin amyloidosis.

Figures

Figure 1.

Analysis population and patient disposition. *All randomized patients who received at least one dose of study medication and had at least one follow-up assessment. †One patient who completed the tafamidis arm of the double-blind trial did not enroll in the open-label extension study, as he/she wanted to become pregnant. NIS-LL: Neuropathy Impairment Score for the Lower Limbs.

Figure 2.

Absolute NIS-LL total scores throughout long-term tafamidis treatment for each of the 71 patients with baseline NIS-LL ≤ 10 at the last assessment before the first dose of tafamidis. NIS-LL: Neuropathy Impairment Score for the Lower Limbs.

Figure 3.

Mean (95% CI) change from baseline in NIS-LL throughout 5.5 years of tafamidis treatment among 71 patients with baseline NIS-LL ≤ 10 at last assessment before first dose of tafamidis. Analyses were performed using observed cases. Year 5 data were excluded due to limited data (n = 2). Mean change in NIS-LL total score (Panel A). Mean change in three NIS-LL subscale scores, muscle weakness, sensation, and reflexes (Panel B). The subscales range from 0 to 64 (muscle weakness), 0 to 16 (sensation), or 0 to 8 (reflexes), with higher values indicating greater neurologic deficit. Mean (95% CI) baseline NIS-LL sub-scores in the analysis population were 0.2 (0.0–0.4) for muscle weakness, 3.4 (2.8–4.0) for sensation, and 0.5 (0.2–0.8) for reflexes. Subgroup analysis of the mean change in NIS-LL total score in patients with baseline NIS-LL score of 0–5 (n = 50) versus those with a baseline NIS-LL score of >5–10 (n = 21) (Panel C). Mean (95% CI) baseline NIS-LL total scores were 2.5 (2.0–2.9) and 8.1 (7.4–8.8) for the two subgroups. CI: confidence interval; NIS-LL: Neuropathy Impairment Score for the Lower Limbs.

Figure 4.

Mean (95% CI) change from baseline in mBMI throughout 5.5 years of tafamidis treatment among 71 patients with baseline NIS-LL ≤ 10 at last assessment before first dose of tafamidis. Analyses were performed using observed cases. Year 5 data were excluded due to limited data (n = 2). CI: confidence interval; mBMI: modified body mass index.