Rationale and design of ACO-SWITCH - a phase 4 study evaluating serum transthyretin levels in patients with ATTR-CM who switched from tafamidis to acoramidis

Background/Introduction

Acoramidis is a transthyretin (TTR) stabiliser approved for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM) by regulatory authorities in the United States, Europe, Japan, and the UK, based on improved survival and cardiovascular hospitalisations versus placebo in the phase 3 ATTRibute-CM study. Acoramidis is one of two TTR stabilisers for the treatment of ATTR-CM in Europe, along with tafamidis. Serum TTR (sTTR) has been proposed as a surrogate marker of ATTR-CM disease activity and as an indicator of response to TTR stabiliser treatment. While tafamidis stabilises TTR via predominantly entropic binding, acoramidis achieves near-complete (>90%) stabilisation through strong, enthalpically driven interactions with TTR, forming hydrogen bonds at the T4 binding site that mimic the stabilising effects of the disease-protective T119M variant of TTR. This efficient stabilisation with acoramidis may result in higher sTTR levels than with tafamidis.

Purpose

ACO-SWITCH will evaluate the change in sTTR levels in acoramidis-treated adult patients with ATTR-CM who were previously treated with tafamidis.

Methods

ACO-SWITCH is a prospective, open-label, single-arm, multicentre, phase 4 low intervention study planned in 50 participants who have used tafamidis for ≥3 months prior to study start (Figure 1). It will be conducted in up to 20 study sites in Austria, Germany, and Italy. Eligible participants will have a previous diagnosis of variant or wild-type ATTR-CM, New York Heart Association class II or less, estimated glomerular filtration rate ≥30 mL/min/1.73 m², N-terminal pro-B-type natriuretic peptide >300 pg/mL and ≤7000 pg/mL, and stable disease for ≥3 months. Participants will be switched from tafamidis to acoramidis after a 21-day run-in period. To minimise the burden for participants, study visits will be conducted at the participants’ homes by a study nurse, whenever possible.

The primary objective is to evaluate the mean change in sTTR level from baseline to month 6 or at the time of premature discontinuation of treatment, using a one-sided paired Wilcoxon Signed-Rank test. Secondary objectives include: sTTR levels at baseline, Weeks 1, 2, 3, 4, and Month 3; biomarkers and functional capacity; laboratory parameters related to kidney and thyroid function; quality of life; and safety (Table 1).

Conclusions

ACO-SWITCH is a prospective study in adults with ATTR-CM who are treated with tafamidis at study entry but then switched to acoramidis for up to 6 months. It aims to determine whether acoramidis induces a further increase in sTTR concentration over those observed under tafamidis and may provide evidence to support clinical decision-making.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.