Results from open-label trial advance ambition to transform amyloidosis care and support local regulatory submission in Japan.

Positive high-level results from the Japan Phase III trial of acoramidis in adults with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) showed consistency to those in the global BridgeBio Pharma, Inc. (BridgeBio) ATTRibute-CM Phase III trial (NCT03860935), including survival, cardiac-related hospitalisations and other measures of improved functions (measured by six-minute walk test) and quality of life (measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score) at 30 months.¹ This trial in Japan was conducted to support local registration.

ATTR-CM is a rare, systemic, progressive and fatal condition that leads to heart failure and high rates of fatality within four years from diagnosis.²

Alexion, AstraZeneca Rare Disease, maintains an exclusive licence with BridgeBio’s affiliate, Eidos Therapeutics, Inc. to develop and commercialise acoramidis in Japan. The success criterion in the open-label Phase III trial in Japan was defined as greater estimated survival probability at 30 months than that observed among placebo patients in ATTRibute-CM. 

Professor Yukio Ando, MD, PhD, Department of Amyloidosis Research, Nagasaki International University, Nagasaki, Japan, said: “As people living with ATTR-CM are at risk of significant morbidity and mortality, including heart failure, halting disease progression is essential to improving outcomes. These results offer further evidence that TTR stabilisation with acoramidis may improve survival and reduce disease severity for patients by preventing further breakdown of these proteins.”

Marc Dunoyer, Chief Executive Officer, Alexion, AstraZeneca Rare Disease, said: “With one of the industry’s largest amyloidosis pipelines exploring multiple therapeutic modalities, we are working to redefine treatment and care as well as offer new hope for this underserved community. These positive results support our ambition to bring acoramidis to people living with ATTR-CM in Japan as soon as possible.”

Acoramidis is an investigational, next-generation, oral, highly potent small molecule stabiliser of transthyretin, designed to achieve maximal stabilisation and preserve native TTR.³

Acoramidis was well-tolerated, with no safety signals of potential clinical concern identified. The data will be presented at a forthcoming medical meeting and submitted to Japan’s health authority for regulatory review.

Notes

ATTR-CM
ATTR-CM is a progressive, rare, systemic disease caused by ageing or genetic mutations, resulting in misfolded TTR protein and accumulation as amyloid fibrils in the cardiac myocardium.^4,5 In patients with ATTR, both hereditary and wild type (non-hereditary), TTR protein builds up as fibrils in tissues, such as the peripheral nerves and heart, gastrointestinal system, eyes, kidneys, central nervous system, thyroid and bone marrow.^4,6 The presence of TTR fibrils interferes with the normal functions of these tissues.⁵ As the TTR protein fibrils accumulate, more tissue damage occurs and the disease worsens, resulting in poor quality of life and eventually death.⁵ Worldwide, there are an estimated 300,000 – 500,000 patients with ATTR-CM; however, many of those patients remain undiagnosed.^6,7

Phase III Open-Label Trial in Japan
A Phase III, open-label, multicentre, prospective trial (NCT04622046) evaluated the safety and efficacy of acoramidis in Japanese adults with ATTR-CM. This trial enrolled 25 patients in Japan, 22 of which completed the trial at 30 months. Participants were required to have a confirmed diagnosis of ATTR-CM with either wild-type TTR or a variant TTR genotype and clinical evidence of heart failure. Other requirements included class I-III symptoms due to ATTR-CM in the New York Heart Association Functional Classification.⁸

Enrolled patients received acoramidis hydrochloride twice daily at a dose of 800 milligrammes for an initial treatment period of 12 months followed by an additional 18 months (for a treatment period of 30 months). The primary endpoints were change from baseline to month 12 in six-minute walk distance, as well as rate of all-cause mortality and frequency of cardiovascular-related hospitalisation over 30 months.⁸

Statistical analyses were conducted once all participants completed 30 months of active treatment.

Patients who completed 30 months of active treatment were eligible to continue into a long-term extension period, which is ongoing.⁸

Acoramidis
Acoramidis is an investigational, next-generation, orally-administered, highly potent, small molecule stabiliser of transthyretin (TTR), designed to achieve maximal stabilisation and preserve native TTR.³

Alexion maintains an exclusive licence with BridgeBio’s affiliate, Eidos Therapeutics, Inc., to develop and commercialise acoramidis in Japan.

Alexion
Alexion, AstraZeneca Rare Disease, is the group within AstraZeneca focused on rare diseases, created following the 2021 acquisition of Alexion Pharmaceuticals, Inc. As a leader in rare diseases for more than 30 years, Alexion is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and commercialisation of life-changing medicines. Alexion focuses its research efforts on novel molecules and targets in the complement cascade and its development efforts on haematology, nephrology, neurology, metabolic disorders, cardiology and ophthalmology. Headquartered in Boston, Massachusetts, Alexion has offices around the globe and serves patients in more than 50 countries.

AstraZeneca in Amyloidosis
Amyloidosis is a group of complex rare diseases caused by abnormal proteins that misfold and clump together to form toxic amyloids that deposit in tissues or organs, including the heart, kidneys and peripheral nerves. The build-up of these toxic amyloids can result in significant organ damage and organ failure that can severely impact quality of life and ultimately be fatal. AstraZeneca and its Rare Disease Unit, Alexion, are developing and evaluating multiple modalities with the potential to halt and reduce organ damage across various types of amyloidosis. The Company is uniquely positioned to lead therapeutic and diagnostic advances for people living with amyloidosis with the largest and fastest-growing pipeline of investigational amyloidosis therapies to address the spectrum of patient needs.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on social media @AstraZeneca.

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References

1. Gilmore J, et al. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2024; 390:132-142.
2. Lauppe RE, et al. Nationwide prevalence and characteristics of transthyretin amyloid cardiomyopathy in Sweden. Open Heart. 2021;(2):e001755.
3. BridgeBio News Release: bridgebio announces consistently positive results from phase 3 attribute-cm study of acoramidis for patients with transthyretin amyloid cardiomyopathy (attr-cm). Available here. Accessed January 2024
4. Viney N, et al. Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data. ESC Heart Failure. 2021;8(1):652-661.
5. Rintell D, et al. Patient and family experience with transthyretin amyloid cardiomyopathy (ATTR-CM) and polyneuropathy (ATTR-PN) amyloidosis: results of two focus groups. Orphanet J Rare Dis. 2021;16(1):70.
6. Mohamed-Salem L, et al. Prevalence of wild type ATTR assessed as myocardial uptake in bone scan in the elderly population. Int J Cardiol. 2018;270:192-196.
7. Cuscaden C, et al. Estimation of prevalence of transthyretin (ATTR) cardiac amyloidosis in an Australian subpopulation using bone scans with echocardiography and clinical correlation. J Nucl Cardiol. 2021;28(6):2845-2856.
8. ClinicalTrials.gov. A Phase 3 Study of ALXN2060 in Japanese Participants With Symptomatic ATTR-CM. NCT Identifier: NCT04622046. Available here. Accessed January 2024.