More players in the treatment of transthyretin amyloidosis? The HELIOS-B study

Transthyretin amyloidosis (ATTR) is a systemic, progressive, and fatal disease caused by misfolding of the transthyretin protein resulting in fibril infiltration into multiple organs and tissues, including the heart and peripheral nervous system.^1–3external link, opens in a new tab

Transthyretin cardiomyopathy (ATTR-CM) can be caused by mutations in the transthyretin gene, either familial (hATTR) or wild-type (wt-ATTR), the latter being more common in older patients without evidence of pathogenic mutations.^3–7external link, opens in a new tab Patients with ATTR-CM have debilitating symptoms and high morbidity and mortality, with a median survival of 2–6 years from diagnosis.⁷external link, opens in a new tab^,8external link, opens in a new tab

To date, the only therapy that a cardiologist can prescribe for ATTR-CM is tafamidis. This transthyretin stabilizer inhibits the dissociation into monomers and thus the formation of new amyloid fibrils. As demonstrated in the ATTR-ACT study, tafamidis therapy slows the decline in functional capacity and quality of life and improves the prognosis after a period of 18 months in the case of mortality from any cause.⁹external link, opens in a new tab

Among the various molecules analysed for the aetiological treatment of ATTR-CM, there is vutrisiran.

Vutrisiran is a subcutaneously administered gene silencer that inhibits the hepatic synthesis of both hATTR and wt-ATTR transthyretin messenger RNA, resulting in rapid breakdown of the pathogenic protein before amyloid-causing monomers can form.^10–12external link, opens in a new tab Vutrisiran is currently approved for the treatment of hATTR amyloidosis with polyneuropathy based on results from the phase three ‘HELIOS-A’ study, which demonstrated significant improvement in multiple disease-relevant endpoints in the vutrisiran arm vs. the placebo arm.¹¹external link, opens in a new tab^,12external link, opens in a new tab Results from an exploratory analysis of cardiac endpoints in the HELIOS-A study indicated a potential benefit of vutrisiran also in cardiac manifestations of the disease [N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, echocardiographic findings, and scintigraphic with technetium-99 m]; these results support the hypothesis that a reduction in the level of the amyloidogenic transthyretin protein may have a therapeutic benefit in patients with ATTR-CM.¹³external link, opens in a new tab

Starting from these assumptions, the ‘HELIOS-B’ study was designed. In this trial, the efficacy and safety of vutrisiran in patients affected by familial or wild-type ATTR-CM were analysed compared with placebo. The inclusion criteria included age between 18 and 85 years, diagnosis of ATTR-CA, and signs of cardiac involvement (interventricular septal thickness > 12 mm), a history of heart failure, NT-proBNP between 300 and 8500 ng/L, and ability to walk at least 150 m in the walk test.

In the study, patients were assigned in a 1:1 ratio to receive either vutrisiran (25 mg) or placebo subcutaneously every 12 weeks for up to 36 months. Randomization was stratified by tafamidis use at baseline, aetiologic type of transthyretin amyloidosis (hATTR vs. wt-ATTR), New York Heart Association (NYHA) functional class, and age (NYHA class I or II and age < 75 years vs. all others). Patients who were not receiving tafamidis at baseline could start receiving it after enrolment if deemed necessary by the study investigator. All patients were asked to take the recommended daily dose of vitamin A because of the potential disruption of vitamin A transport. At the end of the double-blind period (follow-up ranging from 33 to 36 months), patients were eligible to enrol in the open-label extension period of up to 24 months.

The study enrolled 655 patients with ATTR-CA. Baseline demographic and clinical characteristics of patients were similar between the two groups, except among patients in the monotherapy population where NT-proBNP and troponin I levels were higher in the vutrisiran group than in the placebo group. In the overall population, the mean age was 77 years and the majority of patients were men (93%), with wt-ATTR (88%) and NYHA functional class II (78%). Among the 76 patients with hATTR amyloidosis, there were 13 different pathogenic variants of transthyretin; 49 patients (64%) had the V122I variant. Demographic and clinical characteristics of patients in the monotherapy population at baseline did not differ from those of the overall population.

The primary endpoint was a composite of death from any cause and recurrent cardiovascular events (defined as hospital admissions for cardiovascular causes or urgent care visits for heart failure) in the overall population and the monotherapy population.

Secondary endpoints investigated all-cause mortality up to 42 months, change from baseline to 30 months in functional capacity [assessed by 6 m walk distance (6MWD)], and quality of life [assessed by the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS)]. The monotherapy population was defined as patients not receiving tafamidis at baseline.