Transthyretin Kinetic Stabilizers for ATTR Amyloidosis

Key Summary Points

Two transthyretin (TTR) stabilizers, tafamidis and acoramidis, are currently approved for transthyretin amyloidosis (ATTR amyloidosis).

Tafamidis and acoramidis share the same mechanism of action, but perceived disparities in their biochemical and pharmacokinetic properties and pivotal clinical trial outcomes have become topics of intense scientific debate.

Tafamidis and acoramidis demonstrate similar TTR stabilization using the subunit exchange assay, the gold standard for evaluating the efficacy of a TTR stabilizer in inhibiting TTR dissociation.

Evidence from pivotal clinical trials support the efficacy, tolerability, and safety of both tafamidis and acoramidis for transthyretin amyloidosis, but major methodological differences preclude meaningful comparisons of the results.

Only tafamidis has demonstrated evidence of long-term and real-world effectiveness and safety, as well as durability of treatment response in clinical practice, whereas long-term and real-world data on acoramidis are still emerging.

Commentary

Current availability of two regulatory-approved transthyretin (TTR) kinetic stabilizers, tafamidis and acoramidis (Table 1), raises questions about how to prioritize these agents in clinical practice. Clinical decision-making requires a thorough understanding of the mechanisms involved in kinetic stabilization in systemic transthyretin amyloidosis (ATTR amyloidosis) as well as of the effects of kinetic stabilizers at both cellular and clinical levels. To address this need, a review appearing in the current issue of Cardiology and Therapy, entitled, “Transthyretin kinetic stabilizers for ATTR amyloidosis: a narrative review of mechanisms and therapeutic benefits,” summarizes the published literature on the mechanisms involved in TTR kinetic stabilization in systemic ATTR amyloidosis, the essential properties of TTR kinetic stabilizers in preclinical testing, and their efficacy and safety profiles in clinical trials. As described in this review, tafamidis and acoramidis share the same mechanism of action, but perceived disparities in their biochemical and pharmacokinetic properties and pivotal clinical trial outcomes have become topics of intense scientific debate.

Table 1.

Key attributes of tafamidis and acoramidis

	Tafamidis	Acoramidis
Terminal half-life [15]	~ 49 h	~ 25 h
TTR stabilization1 [15]	~ 96%	~ 96%
Approved dose for ATTR-CM	Tafamidis meglumine 80 mg or tafamidis free acid 61 mg once daily	Acoramidis 712 mg twice daily
Key efficacy results from registration trials for ATTR-CM
Win ratio for two-component hierarchical primary outcome (all-cause mortality and CV-related hospitalization)	1.7 (95% CI 1.3, 2.3) [1]	1.5 (95% CI 1.1, 2.0) [14]
Key safety results from registration trials for ATTR-CM
Incidence of AEs (treatment vs placebo)	98.5% vs 98.9% [1]	98.1% vs 97.6% [14]

¹At plasma concentrations achieved via approved oral doses

AE adverse event, ATTR-CM transthyretin amyloid cardiomyopathy, CV cardiovascular, TTR transthyretin

Tafamidis was the first pharmacotherapy approved for the treatment of transthyretin amyloid polyneuropathy (ATTR-PN; in the European Union in 2011) and wild-type or variant transthyretin amyloid cardiomyopathy (ATTR-CM; in the United States and Japan in 2019 and the European Union in 2020). Tafamidis is currently approved in more than 40 countries for ATTR-PN and over 50 countries for ATTR-CM. Data from clinical trials (including the pivotal phase 3 ATTR-ACT trial) and real-world studies have confirmed its efficacy and long-term safety and tolerability [1–13]. More recently, acoramidis received approval for the treatment of ATTR-CM (in the United States in November 2024 and the European Union in February 2025) based on positive results from the pivotal phase 3 ATTRibute-CM trial [14]. Long-term and real-world evidence are still emerging for acoramidis.

Although differences in the thermodynamic forces that drive binding to the TTR tetramer by these agents have received considerable attention, no evidence has emerged to support the clinical relevance of such differences. Moreover, despite ongoing dialogue comparing the efficacy findings of these agents’ registration clinical trials in ATTR-CM, critical divergences in the methodology of these trials do not allow an “apples-to-apples” comparison of outcomes.

Kinetic Stabilizer Potency and Binding

Assertions regarding the potential superiority of acoramidis, including its characterization as a “super-stabilizer,” warrant careful scrutiny. These claims can be challenged based on the following three observations (further detailed in the accompanying review article).

First, several investigations of the potency and selectivity of acoramidis were conducted using methods that do not directly measure the tetramer dissociation rate or are conducted under non-physiological conditions [15–18]. For example, methods that assess resistance to denaturing perturbations are commonly used, but these perturbations can alter ligand affinity and TTR stability and may not accurately represent stabilization under physiological conditions. Another commonly used method, fluorescence probe exclusion, is performed under physiological conditions, but the TTR stabilizer is often displaced from the second binding site on TTR, which is essentially irrelevant to kinetic stabilizer activity. Subunit exchange is the only method published thus far in the literature that measures TTR kinetic stabilization under physiological conditions, such as in human plasma [19, 20]. Second, the potency of kinetic stabilizers depends not only on biochemical properties but also on pharmacological properties. Blinded subunit exchange experiments have shown that tafamidis (80 mg once daily) and acoramidis (800 mg twice daily) demonstrate very similar TTR stabilization at plasma concentrations stemming from the administered doses [15]. Although acoramidis was slightly more potent than tafamidis at a plasma concentration of 10 μM, this benefit was offset by less advantageous pharmacological properties, which lead to lower plasma concentrations of acoramidis. The importance of pharmacological properties in drug efficacy is exemplified by diflunisal—it is an effective stabilizer despite its relatively poor binding to TTR because it reaches very high plasma concentrations. Third, increasing the plasma concentration of native TTR via kinetic stabilization is not an intrinsically desirable property, and such increases cannot be used as surrogate measures of the therapeutic efficacy of TTR kinetic stabilizers [21].

Clinical Benefits of Kinetic Stabilizers

In the case of kinetic stabilizer therapies, it may be wise to consider the maxim “only the results matter.” Evidence from pivotal clinical trials conducted in patients with ATTR amyloidosis support the efficacy, tolerability, and safety of both tafamidis and acoramidis [1, 13, 14]. However, as summarized in the accompanying review article, only tafamidis has demonstrated evidence of long-term and real-world effectiveness and safety, as well as durability of treatment response in clinical practice [2, 11]. In the absence of head-to-head clinical trials, little else can be said with certainty, as major differences in the methodology of the tafamidis and acoramidis registration trials preclude meaningful comparison of their primary and secondary outcomes.

In conclusion, the availability of kinetic stabilizers that significantly improve survival and lower hospitalization rates for patients with ATTR amyloidosis represents an important step forward in treating this degenerative disease. Both tafamidis and acoramidis prevent the disease-triggering formation of TTR aggregates and TTR fibrils by targeting the aggregation cascade at its outset. Investigations using state-of-the art methodology such as subunit exchange kinetics have not uncovered substantial disparities in the biochemical binding or potency of the two small molecules at their therapeutic concentrations, and differences perceived with other types of laboratory assays have not translated into clinically relevant differences in kinetic stabilization or therapeutic response. Both tafamidis and the newcomer acoramidis have demonstrated significant efficacy, with acceptable tolerability and safety, in controlled clinical trials. Tafamidis has accumulated long-term clinical trial and real-world evidence supporting its safety, tolerability, and effectiveness in hereditary and sporadic forms of ATTR amyloidosis, whereas the long-term benefits of acoramidis in the clinical trial and practice settings remain to be determined.

Author Contribution

The concept for this commentary was developed by Jeffery Kelly. Jeffery Kelly assisted with drafting the commentary, revised it critically, and takes responsibility for the integrity of the work.

Funding

This work was sponsored by Pfizer. Jeffery W. Kelly acknowledges support by NIH DK46335 to develop tafamidis and an understanding of its function. Pfizer funded the journal’s Rapid Service Fee.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current commentary.

Declarations

Conflict of interest

Jeffery W. Kelly discovered tafamidis and receives sales royalties and sales milestone payments.

Ethical Approval

This commentary is based on previously conducted studies and does not contain any new studies with human participants performed by the author.