Long term treatment with tafamidis in ATTR-CM: 7.5 year outcomes from the phase 3 open label long-term extension study

Background

Tafamidis is a near-complete transthyretin kinetic stabiliser for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). It is administered orally, once daily, and has demonstrated a statistically significant reduction in mortality at 30 months vs placebo.

Purpose

Report findings from patients who received up to 7.5 years treatment with tafamidis in the phase 3 trial and its long-term extension (LTE) study.

Methods

In ATTR-ACT, patients were randomised (2:1:2) to blinded tafamidis meglumine 80 mg, 20 mg, or placebo for 30 months. Patients continued their blinded tafamidis dose into the up to 60-month LTE study, until commercial prescription availability, or study termination. Those who received placebo in ATTR-ACT were randomized (2:1) to blinded tafamidis meglumine 80 mg or 20 mg in the LTE study. All patients were subsequently switched to open label tafamidis free acid 61 mg (bioequivalent to meglumine 80 mg). Outcomes were assessed over the entire 90-month follow-up.

Results

Of the 264 patients randomised to tafamidis in ATTR-ACT, 173 completed the trial and 170 continued to receive tafamidis the LTE study (Taf/Taf group). Of 177 patients randomised to placebo in ATTR-ACT, 85 completed the trial and 82 initiated tafamidis in the LTE study (Pbo/Taf group). Over a median follow-up of 54.2 months in the Taf/Taf group and 30.5 months in the Pbo/Taf group, incidence of all-cause mortality (ACM) was 54.5% and 71.2%. Median time to ACM was 47.5 and 30.3 months, resulting in a hazard ratio of 0.62 (95% CI: 0.49-0.79; P=0.0001; Figure). Incidence of cardiovascular-related mortality (CVM) was 42.0% and 57.1% in the Taf/Taf and Pbo/Taf groups. Median time to CVM was 47.6 and 30.3 months, resulting in a hazard ratio of 0.61 (0.47-0.81; P=0.0005). The total annual rate of all-cause hospitalisation in the LTE study was 0.69 in the Taf/Taf group and 1.14 in the Pbo/Taf group, and the total annual rate of cardiovascular-related hospitalisation was 0.36 and 0.63. Among patients remaining at each LTE study visit and with available data, improvement in New York Heart Association functional classification was more commonly seen in the Taf/Taf vs Pbo/Taf group. Mean observed reduction from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary score was significantly smaller in the Taf/Taf vs Pbo/Taf group at most LTE study visits. Treatment-related adverse events occurred in 11.2% of the Taf/Taf and 23.2% of the Pbo/Taf groups during the LTE study and were consistent with the known safety profile of tafamidis.

Conclusions

With up to 7.5 years of follow-up data, this analysis of ATTR-ACT trial and its LTE study is the longest reported to date for an ATTR-CM population treated with disease-modifying therapy. Findings demonstrate better long-term outcomes including survival, hospitalisation rates, quality of life, and heart failure symptoms with long-term tafamidis treatment.

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