Tafamidis reduces disease progression in patients with transthyretin familial amyloid polyneuropathy: supportive post-hoc analyses of a pivotal trial

Abstract

Background and aims: Safety and efficacy of once-daily 20 mg tafamidis, a transthyretin (TTR) stabilizer, was evaluated in an 18-month, multicenter, randomized, doubleblind, placebo-controlled study in 128 patients with early symptomatic V30M TTR familial amyloid polyneuropathy (TTR-FAP). In the intent-to-treat population, a responder analysis for Neuropathy Impairment Score-Lower Limb (NIS-LL) (co-primary with Norfolk Quality of Life-Diabetic Neuropathy) favored tafamidis (p=0.07). A prespecified, key secondary analysis of change from baseline to Month 18 in NIS-LL continuous scores was significant (p=0.04). Additional post-hoc analyses supporting tafamidis for delaying progression of TTR-FAP are reported here. Methods: Change from baseline in NIS-LL over time was analyzed with the addition of baseline as a covariate in a repeated measures model. A sensitivity multiple imputation analysis with imputed values based on assigned treatment group was also performed. Additionally, change in NISLL+ &Sgr;7 (neurophysiological function composite endpoint) over time was assessed. Results: When adjusted for baseline NIS-LL disease severity, statistical significance in change from baseline to Month 18 NIS-LL was retained. The magnitude of separation between placebo and tafamidis was consistent across the full range of baseline values (Figure 1). Treatment effect estimates from the multiple imputation analysis, although reduced, were similar to those from the analysis of change from baseline to Month 18 as a continuous variable, and remained significant (Table 1). Significant differences between treatment groups were observed for NIS-LL+&Sgr;7 at Months 12 and 18 Conclusion: The beneficial effects of tafamidis in delaying neurological impairment in TTR-FAP are further supported by these post-hoc analyses. (Figure Presented).