Background: The objective of the present study was to evaluate the long-term safety and efficacy of tafamidis in treating hereditary transthyretin amyloid polyneuropathy. Methods: A prospectively planned interim analysis was conducted on an on-going, phase III, open-label extension study following an 18-month, randomized, controlled study and 12-month, open-label extension study in ATTRV30M patients and a single-arm, open-label study in non-ATTRV30M patients. Thirtyseven ATTRV30M patients received placebo for 18 months, then switched to tafamidis and 38 ATTRV30M patients and 18 non-ATTRV30M patients continuously received tafamidis from day 1, up to 6 years. Results: Long-term tafamidis was associated with a favourable safety/tolerability profile, without any unexpected adverse events. Patients initiating tafamidis at the start of the randomized study had less polyneuropathy progression versus those switching to tafamidis following 18 months of placebo and were less likely to progress to the next ambulatory stage after up to 6 years follow-up. In the patients who switched from placebo to tafamidis, polyneuropathy progression and deterioration in quality of life slowed significantly during long-term tafamidis treatment as compared with the previous placebo treatment. In non-ATTRV30M patients, some polyneuropathy progression was observed across all efficacy measures. Conclusions: These data provide evidence for the long-term (up to 6 years) safety and efficacy of tafamidis. ClinicalTrials.gov: NCT00925002

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44–0.79]; P <0.001). Mortality was also reduced in the continuous tafamidis (versus placebo to tafamidis) subgroups of: variant transthyretin amyloidosis (0.57 [0.33–0.99]; P =0.05) and wild-type transthyretin amyloidosis (0.61 [0.43–0.87]; P =0.006); and baseline New York Heart Association class I and II (0.56 [0.38–0.82]; P =0.003) and class III (0.65 [0.41–1.01]; P =0.06). Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01994889 and NCT02791230.

Introduction: The effects of tafamidis on mortality in Val30Met and non-Val30Met patients with transthyretin amyloidosis with polyneuropathy (ATTR-PN) were evaluated. Methods: The analyses were based on cumulative data from the Val30Met patients in the 18-month double-blind registration study and its 12-month open-label extension study, the non-Val30Met patients of the 12-month openlabel study, and both patient groups in the ongoing 10-year extension study. Kaplan-Meier analyses of time to death from first treatment dose were performed. For the Val30Met group, two treatment groups were analyzed: those who received tafamidis in both the parent and extension studies (T-T) and those who received placebo in the parent study and switched to tafamidis in the extension studies (P-T). Results: Kaplan-Meier estimates (95% confidence interval [CI]) were available up to 9 years for the Val30Met group, at which time 85.9% (53.1-96.4) and 91.1% (77.9-96.6) of the patients in the T-T and P-T groups, respectively, were alive. For the non-Val30Met group, estimates were available up to 8 years from the first dose, and the percentage of patients alive was 75.9% (47.7-90.2). Conclusion: Long-term tafamidis treatment may confer survival benefit in patients with ATTR-PN.

Background Transthyretin amyloid cardiomyopathy (ATTR-CM), is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure. The Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), an international, multi-center, double-blind, placebo-controlled, randomized study, demonstrated the efficacy and safety of tafamidis treatment for patients with ATTR-CM due to variant (ATTRm) or wild-type (ATTRwt) TTR. Purpose This is a pooled analysis of data from ATTR-ACT and interim data from the ongoing, long-term, extension study to evaluate longer term data on the efficacy of tafamidis in patients with ATTR-CM. Methods Patients who completed ATTR-ACT (which had a duration of 30 months) were eligible to be enrolled in a long-term, extension study in which patients either continued to receive tafamidis meglumine at the same dose (the tafamidis/tafamidis [T/T] group) or, for patients previously treated with placebo, were randomised (in a 1:2 ratio) to tafamidis meglumine 20 mg or 80 mg (the placebo/tafamidis [P/T] group) for up to 60 months. The primary efficacy outcome was all-cause mortality. This analysis combined data from the completed ATTR-ACT with interim data from the extension study (cut-off date: 15 Feb, 2018), and included patients treated with tafamidis meglumine across the two studies with a median follow up of 36 months. Results All-cause mortality was significantly lower in the T/T group (n=264; 88 events, 33.3%) compared with the P/T group (n=177; 88 events, 50.3%); hazard ratio (95% CI), 0.64 (0.47, 0.85); P=0.001. In the subgroup of ATTRwt patients, all-cause mortality was significantly reduced in the T/T group (55/201; 27.4%) compared with the P/T group (60/134; 44.8%); 0.64 (0.44, 0.92); P=0.002. In the 106 (24.0%) ATTRm patients, there was a trend towards a reduction in all-cause mortality in the T/T group (33/63; 52.4%) compared with the P/T group (29/43; 67.4%); 0.66 (0.39, 1.09); P=0.17. In patients who were NYHA Class I or II at baseline, all-cause mortality was significantly reduced in the T/T group (38/186; 20.4%) compared with the P/T group (45/114; 39.5%); 0.49 (0.32, 0.75); P=0.001. In those patients with more severe symptoms at baseline (NYHA Class III), there were fewer deaths in the T/T group (50/78; 64.1%) compared with the P/T group (44/63; 69.8%); 0.80 (0.53, 1.21), but this difference was not statistically significant (P=0.50). Conclusions In ATTR-ACT, tafamidis was shown to significantly improve survival, functional capacity, and quality of life in patients with ATTR-CM. This pooled analysis with data from the ongoing extension study further supports the efficacy of tafamidis in patients over a longer period of time and the importance of early diagnosis and treatment. Acknowledgement/Funding This study was sponsored by Pfizer.

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.