The ACT-EARLY clinical trial
The ACT-EARLY clinical trial (NCT06563895) has dosed its first participant: an asymptomatic individual who carries a pathogenic variant in the transthyretin (TTR) gene.1,2 This inherited genetic mutation has been linked to variant transthyretin amyloidosis (ATTRv), a rare, progressive disease that can cause serious complications such as cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN).3 The trial is investigating acoramidis, a selective, orally administered, small molecule TTR stabilizer as a preventive therapy to delay or prevent disease onset in at-risk individuals.
Understanding the importance of early intervention
Pathogenic mutations in the TTR gene can cause the production of misfolded TTR proteins that accumulate as amyloid deposits in various organs.3 While carriers of these mutations may remain asymptomatic for years, they are at risk of developing the disease later in life.
Research indicates that more than one-third of asymptomatic TTR gene carriers developed ATTRv within a median of approximately 2 years of enrollment in the transthyretin amyloidosis outcomes survey (THAOS), highlighting the critical need for early detection and intervention.4
The role of acoramidis in disease prevention
Acoramidis is an investigational small molecule designed to stabilize the TTR protein, preventing misfolding and subsequent amyloid deposition. By targeting the root cause of ATTRv, acoramidis aims to delay or even prevent the onset of disease in genetically predisposed individuals.
The ACT-EARLY study is the first primary prevention trial for ATTRv, enrolling approximately 600 asymptomatic carriers of pathogenic TTR variants. The primary efficacy endpoint is the time to development of ATTR-CM and/or ATTR-PN.2 Secondary endpoints include safety and tolerability assessments, as well as effects on cardiac imaging parameters, nerve conduction and neurofilament light chain levels.2
Approval of acoramidis and clinical trial data
Acoramidis has received regulatory approval in multiple regions, including the USA, EU, UK and Japan, for the treatment of adult patients with ATTR-CM.
The approval has been supported by the positive 30-month results from the phase III ATTRibute-CM study (NCT03860935) published in May 2025 in the Journal of the American College of Cardiology.5,6 The study demonstrated that acoramidis significantly improved survival and reduced hospitalizations in patients with ATTR-CM. Key findings from the study include:
- acoramidis caused rapid increases in serum TTR within 28 days, which was sustained over 30 to 42 months and correlated with improved survival and reduced cardiovascular-related hospitalizations;
- each 5-mg/dL increase in serum TTR was associated with a reduction in mortality risk, demonstrating a dose–dependent survival benefit from TTR stabilization; and
- early and sustained serum TTR increases mediated the survival benefit of acoramidis, highlighting serum TTR as a critical therapeutic target and prognostic marker in ATTR-CM treatment.
Moving toward a new standard of care
Current therapies for ATTR amyloidosis are approved for use in patients with diagnosed disease and primarily aim to slow progression rather than prevent onset. The ACT-EARLY study represents a paradigm shift, focusing on the prevention of disease in asymptomatic carriers.2
Experts advocate for regular monitoring of asymptomatic carriers to detect early signs of disease and initiate treatment promptly. Such proactive management may offer the best opportunity to prevent irreversible organ damage and improve long-term outcomes.7
The initiation of the ACT-EARLY study is a promising development in the field of ATTRv, potentially paving the way for preventive strategies that could alter the course of this debilitating disease.
Study investigator, Dr Ahmad Masri (Cardiomyopathy Section Head and Director of the Cardiac Amyloidosis Program at Oregon Health and Science University) said:
“I am hopeful that we can fill the significant gap in care for asymptomatic carriers of a genetic variant by providing potential preventative intervention early with resulting greater clinical benefit than addressing the disease at a later stage.”
President of Amyloidosis Support Groups, Muriel Finkel said:
“I am hopeful that with ACT-EARLY, loved ones of those with variant ATTR will be able to get genetic testing done, and if they meet the qualification criteria, can get started on a clinical trial that might identify whether prophylactic treatment will slow down or prevent ATTR at its genetic source.”
References
- ClinicalTrials.gov. Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant. ClinicalTrials.gov identifier: NCT06563895. Available at: https://clinicaltrials.gov/study/NCT06563895 (accessed 22 May 2025).
- Amyloidosis Foundation. First Participant Dosed with Acoramidis in ACT-EARLY, the First Ever ATTR Primary Prevention Study. Available at: https://amyloidosis.org/news/560/first-participant-dosed-with-acoramidis-in-act-early-the-first-ever-attr-primary (accessed 22 May 2025).
- Bhatt K, Delgado DH, Khella S, et al. Hereditary transthyretin amyloidosis in patients referred to a genetic testing program. J Am Heart Assoc. 2024;13:e033770. doi:10.1161/JAHA.123.033770
- Coelho T, Conceição I, Waddington-Cruz M, et al. A natural history analysis of asymptomatic TTR gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS). Amyloid. 2022;29:228–236.
- ClinicalTrials.gov. Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM). ClinicalTrials.gov identifier: NCT03860935. Available at: https://clinicaltrials.gov/study/NCT06563895 (accessed 22 May 2025).
- Maurer M, Judge D, Gillmore J, et al. Early Increase in Serum Transthyretin by Acoramidis Independently Predicts Improved Survival in TTR Amyloid Cardiomyopathy. J Am Coll Cardiol. 2025;85:1911–23.
- Ueda M, Sekijima Y, Koike H, et al. Monitoring of asymptomatic family members at risk of hereditary transthyretin amyloidosis for early intervention with disease-modifying therapies. J Neurol Sci. 2020;15:116813.
Further content in congenital conditions and cardiovascular disease.
Editor: Victoria Jones, Senior Content Editor.
Disclosures: This article was created by the touchCARDIOLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.
Cite: First Asymptomatic Gene Carrier Dosed in Pioneering Trial for Rare ATTRv Amyloidosis: the ACT-EARLY Study. touchCARDIOLOGY. May 2025.
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