key: cord-1046394-6btozt5r
authors: Falk, Rodney H.; Haddad, Mia; Walker, Crystal R.; Dorbala, Sharmila; Cuddy, Sarah A.M.
title: Effect of Tafamidis on Serum Transthyretin Levels in Non-Trial Patients With Transthyretin Amyloid Cardiomyopathy
date: 2021-10-19
journal: JACC CardioOncol
DOI: 10.1016/j.jaccao.2021.08.007
sha: 48c530759261a65fb116da59440db50953097813
doc_id: 1046394
cord_uid: 6btozt5r

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.

T ransthyretin (TTR), a 55-kDa homotetramer is the second most ubiquitous protein, after albumin, in the body. In normal human serum it is found in a level of 20 to 40 mg/dL and has a half-life of approximately 48 hours. TTRderived amyloid (ATTR) cardiomyopathy is an increasingly recognized disease characterized by infiltration of the myocardium with either variant or wild-type amyloid derived from transthyretin. One method of treatment is to use small molecules that stabilize TTR, thereby lessening breakdown into amyloidogenic monomers. To date, 3 main stabilizing drugs have been used in the treatment of either ATTR cardiomyopathy or neuropathy; diflunisal, tafamidis, and acoramidis (AG10) (1) (2) (3) (4) (5) . Of these, only the first 2 are clinically available, and AG10 is still undergoing evaluation in a pivotal trial. Tafamidis binds to the thyroxine-binding site of the TTR tetramer and inhibits is dissociation into monomers. By doing so, the cascade leading to amyloid formation in susceptible patients is inhibited (3, 6) . The ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) trial showed the efficacy of tafamidis in slowing the progression of amyloid cardiomyopathy, with decreased 30-month hospitalizations for congestive heart failure and decreased mortality in tafamidis-treated patients compared to placebo (4) . There was a decrement in 6-minute walk test over time in both the placebo and treated group, but with a lesser decrement in the patients treated with tafamidis. N-terminal pro-brain natriuretic peptide (NT-proBNP) increased in both treated and placebo patients but with a statistically significant lower increase among patients receiving tafamidis than among those receiving placebo. Thus, although tafamidis slowed disease progression as measured by morbidity and mortality, it did not stop it. Two explanations may be given for the continued deterioration in clinical status among tafamidis-treated patients. One possibility is that tafamidis fails to fully stabilize the TTR molecule and therefore permits ongoing amyloid deposition in the heart, albeit at a slower rate than among untreated patients. Alternatively, decreased exercise tolerance and increasing NT-proBNP in the tafamidis-treated group may simply represent the natural progression of heart failure in a severely damaged ventricle, despite the absence of further amyloid deposition (7) .

The argument that a greater drug-induced TTR stability may improve outcomes seen with has tafamidis has prompted interest in AG10, currently being evaluated in clinical trials (5, 8) . AG10 has a somewhat different mechanism of stabilization from tafamidis in that it was designed to mimic the structural form of the TTR "superstabilizer" variant, T119M. AG10 forms hydrogen bonds with serine residues at the same site as the T119M variant and, based on assays of stabilization, it is believed to be a more potent stabilizer of TTR than is tafamidis (9,10). However, a major problem in theorizing improved efficacy of TTR stabilizers based on assays of stabilization is that there are several assays and all are performed under nonphysiologic conditions. In addition, even if a specific drug produces more stabilization in vitro than another, the efficacy in a human or animal model will depend upon the half-life of the drug and its degree of absorption.

As TTR stabilizers do not appear to affect the rate of production of TTR by the liver, an increase in TTR levels after tafamidis use most likely represents a greater half-life of TTR. The 48-hour half-life of TTR in the human is similar to the half-life of tafamidis, and maximal stabilization of TTR after initiation of the bioequivalent formulations tafamidis meglumine 80 mg daily or tafamidis 61 mg daily occurs by 4 weeks after drug initiation (3, 11) . Therefore, it would seem reasonable that measurement of TTR levels before and after initiation of a clinically effective TTR stabilizer would be a consistent, even if indirect, measure of drug efficacy that potentially overcomes the problems of different in vitro nonphysiologic assays of stabilization. Here, we report the effect of tafamidis meglumine 80 mg or tafamidis 61 mg on TTR levels in an unselected group of patients with amyloid cardiomyopathy seen since the release of tafamidis for general clinical use in the United States.

The records of all patients seen at our institution who were prescribed tafamidis since its approval by the The key data are summarized in Table 1 . Mean baseline TTR levels were 21.8 AE 0.7 mg/dL for the whole group of whom 27 (37.0%) had levels ranging from 11 to 19 mg/dL, which is below the lower limit of normal for our laboratory (20 mg/dL). After a mean of 21.0 AE 1.2 weeks therapy, the mean TTR levels for the whole group had increased to 29.3 AE 0.8 mg/dL, a mean increase of 34.5% (P < 0.0001). Twenty-three of 27 patients (85.2%) who fell <20 mg/dL normalized their TTR levels. After exclusion of the 5 patients with variant TTR, the mean baseline TTR in the wild-type TTR patients was 21.9 AE 0.7 mg/dL, increasing to 28.9 AE 0.8 mg/dL, a mean increase of 32.0%. In contrast, the 5 patients with variant ATTR cardiomyopathy had a baseline TTR level of 20.6 AE 2.9 mg/dL but a mean increase of 70.9% to 35.2 AE 3.20 mg/dL.

The absolute and percentage changes of TTR levels are graphically shown in the Central Illustration.

To determine the stability of TTR levels in the absence of treatment with TTR stabilizers, 55 patients from the study group were identified who had had TTR levels drawn 3 to 6 months before the level immediately preceding the initiation of tafamidis.

The mean TTR level for this group was 22.00 mg/dL immediately before initiating tafamidis compared to 22.04 mg/dL 3 to 6 months earlier (P ¼ 0.95). There were 28 patients who had a second TTR level drawn after starting tafamidis, a mean of 20.5 weeks after We have postulated that elevation of TTR levels is a marker for TTR stabilization of TTR and that it reflects the mechanism responsible for a positive outcome of tafamidis in the ATTR-ACT trial.

Although it might be argued that tafamidis could have a nonstabilizing positive effect on outcome (and thus that changes in levels are merely a bystander phenomenon), we believe this to be very unlikely, as tafamidis was specifically designed to stabilize the TTR molecule and has no known or likely off-target effects that could affect the outcome of a heart failure trial.

In summary, in a non-trial, consecutive, unselected population of patients with ATTR cardiomyopathy predominantly caused by wild-type amyloid deposition, tafamidis had a consistent effect on increasing TTR levels by a mean of 34.5%, or 31.1% when 5 variant TTR patients were removed from analysis. This is virtually identical to the 33% increase seen in as study of AG10, even though those 32 patients were slightly younger and, by virtue of being in a clinical trial, were more highly selected (5 We believe that the jury is still out as to whether a greater stabilization of TTR than that achieved by tafamidis will improve clinical outcomes. Forthcoming data from a randomized trial of AG10 will likely give further insight into the clinical benefit of a potentially more potent stabilizer, although the argument is unlikely ever to be resolved without the unlikely study of a direct comparison of stabilizers (8) . In the interim, we believe that measurement of TTR levels before and after treatment is a simple and reasonable surrogate for TTR stabilization, and is useful to assure patients that, at least on the biochemical level, tafamidis is effective in its desired action. Because there is no current marker to determine the efficacy of tafamidis, measurement of TTR levels offers reassurance to the patient and clinician that the drug is having the desired biochemical effect of stabilization.

TRANSLATIONAL OUTLOOK: Future studies should evaluate various TTR stabilizers to determine whether there is a relationship between the degree of biochemical stabilization, the resultant increase in TTR levels, and the clinical outcome.

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