Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy

Abstract

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.

Trial registration: ClinicalTrials.gov NCT00791492.

Fig. 1

Patient disposition and analysis populations

Fig. 2

Sustainability of the treatment effect, as measured by the mean rate of change per month for each efficacy measure in the tafamidis–tafamidis ITT population. a NIS-LL. b Σ7 NTs nds score. c Σ3 NTSF nds. d TQOL. e mBMI. For comparison, the 30-month rate of change from Fx-005 baseline for the tafamidis–tafamidis group (n = 38) is also displayed for each endpoint. Σ7 NTs nds summated 7 nerve tests normal deviate score, Σ3 NTSF nds summated 3 nerve tests (small fiber) normal deviate score, mBMI modified body mass index, NIS-LL Neuropathy Impairment Score in the Lower Limbs, TQOL total quality of life

Fig. 3

Efficacy of tafamidis in slowing disease progression in 33 patients from study Fx-006 previously given placebo in study Fx-005, as measured by the mean rate of change per month for each efficacy measure in the placebo−tafamidis ITT population. a NIS-LL. b Σ7 NTs nds score. c Σ3 NTSF nds. d Norfolk TQOL. e mBMI. For comparison, rate of disease progression in 64 patients treated with tafamidis in study Fx-005 is also displayed for each endpoint. Σ7 NTs nds summated 7 nerve tests normal deviate score, Σ3 NTSF nds summated 3 nerve tests (small fiber) normal deviate score, mBMI modified body mass index, NIS-LL Neuropathy Impairment Score in the Lower Limbs, TQOL total quality of life

Fig. 4

Effect of tafamidis on disease progression over 30 months as measured by the mean change from study Fx-005 baseline in efficacy measures in the ITT population. a NIS-LL. b NIS-LL muscle weakness subscale. c Σ7 NTs nds. d Σ3 NTSF nds. e TQOL. f mBMI. Σ7 NTs nds summated 7 nerve tests normal deviate score, Σ3 NTSF nds summated 3 nerve tests (small fiber) normal deviate score, mBMI modified body mass index, NIS-LL Neuropathy Impairment Score in the Lower Limbs, TQOL total quality of life

Fig. 5

Early-start treatment effect (tafamidis–tafamidis group) vs. late-start treatment effect (placebo–tafamidis group) as measured by the mean (±SEM) change from baseline at 30 months in efficacy measures in the ITT population. a NIS-LL and muscle weakness subscale. b Σ7 NTs nds and Σ3 NTSF nds scores. c TQOL. d mBMI. p-Values are based on Wilcoxon’s rank sum test. Σ7 NTs nds summated 7 nerve tests normal deviate score, Σ3 NTSF nds summated 3 nerve tests (small fiber) normal deviate score, mBMI modified body mass index, NIS-LL Neuropathy Impairment Score in the Lower Limbs, TQOL total quality of life