Key Information
Source
Year
2025
summary/abstract
INTRODUCTION
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a chronic disease caused by transthyretin (TTR) tetramer destabilization and subsequent TTR amyloid fibril deposition in the myocardium, leading to progressive heart failure, impaired quality of life, hospitalization, and death.1external link, opens in a new tab,2external link, opens in a new tab
Untreated patients with ATTR-CM have a median survival of 2.5 to 3.6 years depending on disease stage, making early diagnosis and treatment initiation essential.1external link, opens in a new tab,2external link, opens in a new tab Tafamidis, a TTR stabilizer, was the first FDA-approved therapy for ATTR-CM.1external link, opens in a new tab,3external link, opens in a new tab,4external link, opens in a new tab Acoramidis (AG10) is an oral, potent, selective, small molecule that offers near-complete (≥ 90%) TTR stabilization, which mimics the stabilizing properties of the naturally occurring protective TTR variant, T119M; is FDA-approved to reduce the risk of cardiovascular death and cardiovascular hospitalization in patients with ATTR-CM; and is approved in Europe for the treatment of wild-type and variant ATTR-CM in adults.4external link, opens in a new tab, 5external link, opens in a new tab, 6external link, opens in a new tab, 7external link, opens in a new tab The T119M variant protects against disease in carriers of a pathogenic variant, while preserving normal biologic TTR functions.4external link, opens in a new tab,6external link, opens in a new tab
In the phase 2, randomized, double-blind, placebo-controlled, 28-day AG10-201 study (NCT03458130), which evaluated the safety and tolerability of acoramidis in participants with symptomatic ATTR-CM, acoramidis was well tolerated and achieved target plasma TTR levels and near-complete TTR stabilization.6external link, opens in a new tab Participants who completed AG10-201 could enroll in this phase 2 open-label-extension (OLE) study evaluating long-term treatment with acoramidis (NCT03536767). Herein, we report a 45-month update of OLE safety and pharmacodynamic data.
METHODS
Study Information
The final protocol, amendments, and informed consent documentation were approved by the institutional review boards at each of the investigational centers participating in the study. All participants provided written informed consent for participation in the study. This study was conducted in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines.6external link, opens in a new tab
Patient Population
Eligibility criteria for the AG10-201 study have previously been reported; key eligibility criteria for the present study were: age 18 to 90 years, established diagnosis of ATTR-CM, New York Heart Association (NYHA) class II or III heart failure, and ≥ 1 prior hospitalization for heart failure or clinical evidence of heart failure.6external link, opens in a new tab To be eligible for this OLE study, patients had to complete the AG10-201 study.
Intervention
Participants received oral acoramidis HCl 800 mg twice daily during their participation in the study.
Assessments
The primary endpoints were long-term safety and tolerability. Safety evaluations included vital signs, physical examination, clinical laboratory tests, electrocardiography, and assessment of adverse events (AEs). On days 1, 14, and 45, and at 3-month intervals thereafter, data were collected for clinical, safety, laboratory, and pharmacodynamic assessments. All participants receiving ≥ 1 dose of acoramidis were included in the safety analysis.
Secondary endpoints included pharmacodynamic assessments of TTR stabilization. Serum TTR concentration was measured as a surrogate for in vivo protein level, whereas percentage TTR stabilization and percentage TTR engagement (a surrogate for TTR stabilization) were measured through western blot and fluorescent probe exclusion (FPE) ex vivo assays, respectively. The N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP) levels, elevated in ATTR-CM owing to hemodynamic stress and effects of TTR amyloid fibrils on cardiomyocytes,8external link, opens in a new tab were measured using the Roche Cobas proBNP II e601 assay.6external link, opens in a new tab All laboratory tests were conducted by a central laboratory.