Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis

Abstract

This phase II, open-label, single-treatment arm study evaluated the pharmacodynamics, efficacy, and safety of tafamidis in patients with non-Val30Met transthyretin (TTR) amyloidosis. Twenty-one patients with eight different non-Val30Met mutations received 20 mg QD of tafamidis meglumine for 12 months. The primary outcome, TTR stabilization at Week 6, was achieved in 18 (94.7%) of 19 patients with evaluable data. TTR was stabilized in 100% of patients with non-missing data at Months 6 (n = 18) and 12 (n = 17). Exploratory efficacy measures demonstrated some worsening of neurological function. However, health-related quality of life, cardiac biomarker N-terminal pro-hormone brain natriuretic peptide, echocardiographic parameters, and modified body mass index did not demonstrate clinically relevant worsening during the 12 months of treatment. Tafamidis was well tolerated. In conclusion, our findings suggest that tafamidis 20 mg QD effectively stabilized TTR associated with several non-Val30Met variants.

Trial registration: ClinicalTrials.gov NCT00630864.

Fig. 1

Change from baseline in NIS, NIS-LL, and NIS-UL scores in the intent-to-treat population. While the baseline scores in the NIS (mean ± SEM, 48.7 ± 9.7; median, 45.0), NIS-LL (mean ± SEM, 27.6 ± 5.4; median, 18.0), and NIS-UL (mean ± SEM, 21.1 ± 4.7; median, 13.0) indicated the presence of significant neurological impairment affecting both lower and upper limbs, mean and median changes from baseline to Months 6 and 12 in NIS, NIS-LL, and NIS-UL presented in this figure increased marginally, with the maximal mean change from baseline being an increase of 5.3 (SEM = 3.0) in the NIS total score at Month 12. This suggests that neuropathy progressed minimally during tafamidis treatment. This is an observed cases analysis including the values of those patients for whom both baseline and Month 6 or baseline and Month 12 data were available. Bars indicate the range of scores; boxes span from the 25th to the 75th percentiles; the horizontal line within the box indicates the median change; plus sign indicates the mean change. SEM standard error of the mean, NIS Neuropathy Impairment Score, NIS-LL NIS of the lower limbs, NIS-UL NIS of the upper limbs

Fig. 2

Change from baseline in Norfolk QOL-DN (TQOL) scores in the intent-to-treat population. While the baseline TQOL score (mean ± SEM, 47.8 ± 7.7; median, 38.0) indicated impaired quality of life, this figure shows that mean and median changes from baseline in TQOL at Months 6 and 12 were negligible, indicating that overall quality of life was maintained during 12 months of tafamidis treatment. This is an observed cases analysis. Bars indicate the range of scores; boxes span from the 25th to the 75th percentiles; the horizontal line within the box indicates the median change; plus sign indicates the mean change. SEM standard error of the mean, QOL-DN quality of life–diabetic neuropathy, TQOL total quality of life, CI confidence interval

Fig. 3

Change from baseline in mBMI scores (expressed as kilograms per square meter × grams per liter) in the intent-to-treat population. Starting with a relatively normal mBMI at baseline (mean ± SEM, 1,052.5 ± 46.2; median, 1,047.8), the mBMI decreased slightly from baseline to Month 6 (mean change ± SEM, –22.4 ± 18.7; median change, –26.7) and subsequently increased, producing a small positive overall change from baseline to Month 12 (mean change ± SEM, 16.6 ± 22.3; median change, 8.3), indicating that the overall nutritional status was maintained after 12 months of tafamidis treatment. The mBMI has been adapted as a measure of nutritional status in TTR amyloidosis patients, as multiplying the BMI (kilograms per square meter) by serum albumin level (grams per liter) corrects for weight gains due to swelling and edema formation frequently associated with TTR amyloidosis. Bars indicate the range of scores; boxes span from the 25th to the 75th percentiles; the horizontal line within the box indicates the median change; plus sign indicates the mean change. SEM standard error of the mean, mBMI modified body mass index

Fig. 4

Median and median change from baseline/screening in NT-pro-BNP levels in patients with a high likelihood of heart failure (baseline NT-pro-BNP >1,000 pg/mL) and b low likelihood of heart failure (baseline NT-pro-BNP <300 pg/mL). Based on their highest NT-pro-BNP level at baseline/screening, ten patients with values >1,000 pg/mL were categorized as having a high likelihood, and nine patients with levels <300 pg/mL were classified as having a low likelihood of congestive heart failure, where the normal range is <160 pg/mL. The median NT-pro-BNP level in patients with high likelihood of heart failure increased by 521 pg/mL at Month 12. In contrast, the median NT-pro-BNP level in patients with low likelihood of heart failure increased only marginally by 47 pg/mL at Month 12. NT-pro-BNP N-terminal pro-hormone brain natriuretic peptide