A comprehensive safety profile of tafamidis in patients with transthyretin amyloid polyneuropathy

Abstract

Background: Tafamidis is approved in over 40 countries to delay neurologic progression in patients with transthyretin amyloid polyneuropathy (ATTR-PN). A comprehensive, integrated analysis of safety data from interventional, observational and surveillance studies of tafamidis in ATTR-PN patients was conducted. Methods: Safety data from all sponsored, completed, or ongoing, Phase 2/3 studies of tafamidis in ATTR-PN patients as of 3 January 2017 were pooled. Also assessed were safety data from the ongoing Transthyretin Amyloidosis Outcomes Survey (THAOS) as of 3 January 2017 and post-marketing surveillance reports as of 31 March 2017. Results: There were 137 patients in Phase 2/3 studies (mean duration of tafamidis exposure, 44.2 months), with 134 (97.8%) experiencing !1 treatment-emergent adverse event (TEAE) and 46 (33.6%) !1 treatment-emergent serious adverse event (TESAE). The most common TEAEs were diarrhoea (26.3%), urinary tract infection (UTI; 25.5%) and influenza (21.2%). In THAOS, 661 subjects had tafamidis exposure (mean duration, 27.6 months), with 250 (37.8%) experiencing !1 TEAE and 96 (14.5%) !1 TESAE. The most common TEAE was UTI (6.1%). Post-marketing surveillance reports generally reflected the known safety profile of tafamidis. Conclusions: This analysis did not reveal any significant new safety findings; tafamidis was generally safe and well tolerated in ATTR-PN patients.

Real-world outcomes in non-endemic hereditary transthyretin amyloidosis with polyneuropathy: a 20-year German single-referral centre experience

“…Also in line with previous findings, treatment with tafamidis was very well tolerated and no drug-related adverse events were reported in our study [29,30]. Time to neurologic progression was far longer in our patients with PND score I compared to PND score II (Figure 4) confirming that treatment with tafamidis is most efficacious when initiated as early as possible at Coutinho stage 1 ATTR-PN, that is, when the PND score is still I [31,32].…”

A Brief Review of Analytical Methods for the Estimation of TTR Kinetic Stabilizers in Pharmaceutical Formulations and Biological Matrices

“…Comparable to these results are the data obtained with non-Val30Met mutations [26][27][28][29]. An additional evaluation of efficacy and safety in ATTR patients reaffirmed the beneficial effects of TAF during long-term treatment and in the early stages of the disease [24,[34][35][36][37][38][39]. Ongoing open-label studies have found that the progression of neurological disease is more severe in patients with higher baseline neuropathy impairment score (NIS) values (more advanced stages of the disease), which justifies the need for early treatment [40].…”

Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans

“…The pharmacological stabilization of TTR tetramer with tafamidis has been approved by the European Medicines Agency to treat early-stage FAP and is currently available in Japan and Europe ( Bulawa et al, 2012 ). Unfortunately, tafamidis fails to treat advanced TTR amyloidosis and has some adverse effects ( Lozeron et al, 2013 ; Huber et al, 2019 ). With this understanding, we performed in vitro TTR stabilization assay to address whether the TTR inhibitory potential of santalol isomers was mediated through tetramer stabilization.…”