https://doi.org/10.1007/s00392-024-02526-y
1Universitätsklinikum Würzburg Medizinische Klinik I, Kardiologie Würzburg, Deutschland; 2Alnylam Pharmaceuticals Research & Development Cambridge, MA, USA; 3Columbia University Division of Cardiology New York, NY, USA; 4University College London Cardiology London, Großbritannien; 5Boston University Medical Campus Boston, USA; 6Stanford Medicine Heart Failure Program CV Medicine Stanford CA, USA; 7Mayo Clinic Cardiovascular Medicine Rochester MN, USA; 8Penn Medicine Philadelphia Heart & Vascular Pavilion Philadelphia, PA, USA; 9Brigham and Women´s Hospital Heart and Vascular Center Boston, MA, USA; 10Spanish National Center for Cardiovascular Research Inherited Cardiomyopathies Madrid, Spanien; 11University Medical Center Groningen UMCG Cardiology Research Institute Groningen, Niederlande; 12Alnylam Pharmaceuticals Research & Development Cambridge MA, USA
Transthyretin amyloidosis (ATTR) is a progressive, fatal disease caused by the deposition of misfolded transthyretin (TTR) amyloid fibrils in multiple organs and tissues, with the most prevalent manifestations being cardiomyopathy (CM) and polyneuropathy (PN). Patients with ATTR with CM (ATTR-CM) experience progressive symptoms of heart failure (HF), are frequently hospitalised and have a decreased survival rate, with few treatment options. Vutrisiran, an RNA interference therapeutic that rapidly and profoundly knocks down serum TTR, is approved for the treatment of hereditary ATTR with PN (hATTR-PN). Exploratory analyses of a predefined cardiac subpopulation in the HELIOS-A study (NCT03759379) demonstrated the potential for vutrisiran to improve the manifestations of CM in patients with hATTR-PN. The safety and efficacy of vutrisiran in patients with either wild-type ATTR (wtATTR) or hATTR-CM are being investigated in the HELIOS-B study (NCT04153149).
HELIOS-B is a phase 3, randomised, double-blind (DB), placebo-controlled, multicentre study of vutrisiran in patients with wtATTR or hATTR-CM. Patients were 18–85 years old with medical history of HF, evidence of cardiac amyloidosis by echocardiography, and ATTR amyloid deposition confirmed by tissue biopsy or non-biopsy diagnostic criteria, including cardiac technetium scintigraphy. At baseline (BL), patients were either not on tafamidis or were currently receiving tafamidis per the approved indication and dose for their country. Patients were randomised (1:1) to vutrisiran 25 mg subcutaneously or placebo, once every 3 months for up to 36 months, followed by open-label treatment with vutrisiran for up to 2 years. The two primary endpoints were a composite of all-cause mortality and recurrent cardiovascular (CV) events (CV hospitalisations and urgent HF visits) assessed in the overall population and in the vutrisiran monotherapy group (defined as patients not being on tafamidis at BL). Secondary endpoints (assessed in overall population and vutrisiran monotherapy), were all-cause mortality and the change from BL to 30 months in functional capacity (6-minute walk test), health status and quality of life (Kansas City Cardiomyopathy Questionnaire-Overall Summary), and New York Heart Association Class. The pharmacodynamic effect of vutrisiran on serum TTR levels was assessed through 30 months, and the frequency and severity of adverse events were assessed throughout the study.
Enrolment in HELIOS-B was completed in August 2021 with 655 patients, 654 dosed (25% US, 62% Europe, 13% Rest of World); median (range) age, 77 (45–85) years; male, 92.5%; on tafamidis at BL, 40%. Complete DB data will be available in July 2024. Primary and secondary endpoint data will be presented, in addition to safety data.
Vutrisiran has the potential to improve the CM associated with ATTR. The primary results of the HELIOS-B study will provide important information on the impact of vutrisiran on CV outcomes and survival, functional capacity, and health status and quality of life in patients with ATTR-CM.