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Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy. | LitMetric

AI Article Synopsis

Article Abstract

Background: Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN.

Methods: A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score-Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment.

Results: The T-T (n = 64) and P-T (n = 61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p < 0.0001). Neurologic progression in the T-T group was less than in the P-T group across all levels of baseline NIS-LL (p = 0.0088), and the degree of separation increased over the 18-month period. Similar results were seen with the NIS-LL muscle weakness subscale.

Conclusions: This analysis of patients with Val30Met ATTR-PN demonstrates that neurologic 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. These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression in ATTR-PN.

Trial Registration: NCT00409175 , NCT00791492 and NCT00925002 registered 08 December 2006, 14 November 2008 (retrospectively registered), and 19 June 2009, respectively.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296038PMC
http://dx.doi.org/10.1186/s13023-018-0947-7DOI Listing

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