Objectives:To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods:In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo.Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (Ͻ2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n ϭ 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n ϭ 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population.Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p ϭ 0.068) and change in TQOL (2.0 vs 7.2; p ϭ 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p ϭ 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p ϭ 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p Ͻ 0.0001). Adverse events were similar between groups. Conclusions:Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence:This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months. Neurology® 2012;79:785-792 GLOSSARY AE ϭ adverse event; ANCOVA ϭ analysis of covariance; ARR ϭ absolute risk reduction; CI ϭ confidence interval; DPN ϭ diabetic polyneuropathy; EE ϭ efficacy-evaluable; ITT ϭ intent-to-treat; LS Mean ϭ least-squares mean; mBMI ϭ modified body mass index; NIS-LL ϭ Neuropathy Impairment Score-Lower Limbs; NNT ϭ number needed to treat; QOL ϭ quality of life; QOL-DN ϭ Quality of Life-Diabetic Neuropathy Questionnaire; TQOL ϭ total quality of life; TTR-FAP ϭ transthyretin familial amyloid polyneuropathy.

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.

The study demonstrated a PVT prevalence of 8.7%, a higher incidence of partial thrombosis (grade 1), and successful management of PVT grade 4 with thrombectomy. Liver transplant in PVT patients was associated with an increased operative time, transfusion requirements, re-interventions, and lower survival rate according to PVT extension.

Variant forms and post-translational modifications of transthyretin (TTR) can be identified by electrospray ionisation mass spectrometry (ESI-MS). The aim of the present study was to investigate thiol conjugation of transthyretin and it's relation to age and symptomatic amyloid disease in different populations of variant TTR carriers. Plasma samples from 70 individuals from Denmark, Argentina, Sweden and Japan, with 2 different TTR mutations were analysed. The percentage cysteine (Cys) conjugated wild and variant TTR were calculated from the corresponding peaks of the spectra, and multiple regression analysis was employed to disclose relationships between age, symptomatic amyloid disease and origin. Age, origin and presence of symptomatic disease, were found to be independent factors related to transthyretin conjugation. A higher percentage of conjugated to unconjugated TTR was disclosed in symptomatic, but not in asymptomatic carriers. In summary: Thiol conjugation of TTR is dependent on age and presence of symptomatic amyloid disease. Furthermore, it varies between different populations. Variant TTR is more susceptible to thiol conjugation than the wild type. Post-translational factors may be related to amyloid formation and/or toxicity.

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