Effect of Tafamidis on Serum Transthyretin Levels in Non-Trial Patients With Transthyretin Amyloid Cardiomyopathy

Abstract

Background Transthyretin amyloid (ATTR) cardiomyopathy is slowed by tafamidis, which stabilizes the TTR molecule and reduces the formation of amyloidogenic oligomers. Stabilizers in clinical doses raise serum TTR, which may be a surrogate for the degree of stabilization. Objectives This study aims to determine, in a non-trial, unselected population of patients with ATTR cardiomyopathy, the effect of tafamidis on serum levels of TTR, and to compare these with published data of changes in TTR. Methods TTR levels were measured before therapy and 3 to 12 months following initiation of tafamidis therapy in all patients seen between May 20, 2019, and March 1, 2021, who had a follow-up visits within 12 months of therapy initiation. Results Among 72 patients with ATTR cardiomyopathy (67 patients with wild-type and 5 patients with variant TTR), administration of tafamidis increased serum TTR from 21.8 mg ± 0.7 mg/dL to 29.3 ± 0.86 mg/dL, an increase of 34.5%. In 5 patients with variant TTR, the increase was 70.9%, compared to 32.0% in the wild-type patients. Mean N-terminal pro-brain natriuretic peptide increased over a mean follow-up of 21 ± 1.2 weeks, but the change was not statistically significant. Over the same period there was a small increase in high-sensitivity troponin T that was of borderline statistical significance (P = 0.057). Conclusions Tafamidis consistently increases serum TTR levels in patients with ATTR cardiomyopathy, consistent with its effect on stabilizing TTR. Measurement of TTR level change post-TTR stabilizing therapy might be a surrogate for stabilization and could be a more accurate measure of drug efficacy than an in vitro nonphysiologic test of stabilization.

Cardiac Amyloidosis Due to Transthyretin Protein

“…Prealbumin may be a useful marker to assess treatment efficacy. Compared with baseline, increased prealbumin concentration of a median of 7.5 mg/dL is observed with stabilizer drug therapy (mean increases from baseline of 50% with tafamidis-free salt and 53% with acoramidis) and on average a more than 80% reduction in prealbumin is observed following TTR-suppressing drug therapy (such as patisiran, vutrisiran, and eplontersen) . There are established staging systems for ATTR cardiomyopathy that incorporate cardiac biomarkers including troponin and natriuretic peptide levels (Mayo), estimated glomerular filtration rate and natriuretic peptides (National Amyloidosis Centre), or biomarker plus NYHA class and daily dose of loop diuretics expressed in furosemide equivalents in milligrams per kilogram (Columbia University) (Table 5).…”

A study protocol for an observational cohort investigating cardiac transthyretin amyloidosis flow reserve before and after Tafamidis treatment: The AMYTRE study

“…Plasma Tafamidis concentration after 12 months of therapy was also a predictor of response for male patients. Falk et al suggested that measurement of TTR level change post-Tafamidis might be a surrogate for stabilization and could be an accurate measure of drug efficacy ( 32 ). Other treatments such as RNA interference therapeutics are developing rapidly in this indication with, it seems for the moment, great efficacy ( 17 ).…”

Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?

“…One obvious difference that might account for the more rapid cardiac progression of patients with TTR variants is the instability of the mutant TTR molecule, leading to a greater degree of breakdown and to a more amyloidogenic product. This hypothesis is supported by the lower levels of circulating TTR protein observed in patients with the familial TTR gene mutation, with a reversion to normal levels following therapy with a TTR stabilizer 4 . Nevertheless, while more rapid TTR breakdown may account for a more rapid disease progression in ATTRv compared to ATTRwt, it does not account for the fact that ATTRv is often associated with neuropathy, whereas proven amyloid neuropathy in ATTRwt is very uncommon.…”

“…This hypothesis is supported by the lower levels of circulating TTR protein observed in patients with the familial TTR gene mutation, with a reversion to normal levels following therapy with a TTR stabilizer. 4 Nevertheless, while more rapid TTR breakdown may account for a more rapid disease progression in ATTRv compared to ATTRwt, it does not account for the fact that ATTRv is often associated with neuropathy, whereas proven amyloid neuropathy in ATTRwt is very uncommon. There is no doubt that the clinical development of heart failure in ATTR cardiomyopathy of either form is due to massive myocardial amyloid infiltration, but neuronal amyloid infiltration is probably not the major underlying pathophysiologic mechanism for early symptomatic ATTRv neuropathy.…”