Weekly Journal Scan: HELIOS-B sheds light on new therapeutic options for transthyretin amyloidosis with cardiomyopathy

This comment refers to ‘Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy’, published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2409134. HELIOS-B was an international, phase-3, multicentre, double-blind, randomized, placebo-controlled trial aimed at assessing whether vutrisiran—a subcutaneously administered RNA interference agent inhibiting the production of hepatic transthyretin (TTR)—may reduce all-cause death and recurrent cardiovascular events in patients with transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM), both as monotherapy and on top of tafamidis.1 The primary endpoint was a composite of death from any cause and recurrent cardiovascular events, defined as hospitalizations for cardiovascular causes or urgent visits for heart failure (HF). Secondary endpoints included death from any cause, the change from baseline in the distance covered on the 6 min walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire—Overall Summary (KCCQ-OS) score (ranging from 0 to 100, with higher scores indicating better quality of life). Inclusion criteria were: an age of 18–85 years; a confirmed diagnosis of ATTR-CM (either variant or wild-type), defined as the presence of TTR amyloid in tissue biopsies or the fulfilment of scintigraphy-based diagnostic criteria in the absence of monoclonal gammopathy, and evidence of cardiac involvement on echocardiography (septal wall thickness > 12 mm); a history of HF with at least one previous hospitalization or HF symptoms; an NT-proBNP level > 300 pg/mL and <8500 pg/mL [or >600 pg/mL and <8500 pg/mL for patients with atrial fibrillation (AF)] and the ability to cover a distance of at least 150 m on the 6 min walk test. At baseline, patients either received tafamidis for ATTR-CM or not, with no active plan to start it during the first 12 months after randomization. Key exclusion criteria were a New York Heart Association (NYHA) class IV, or NYHA class III with a National Amyloidosis Centre ATTR stage 3 [defined as NT-proBNP > 3000 pg/mL and estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2); a polyneuropathy disability score of IIIa, IIIb, or IV; cardiomyopathies not associated with ATTR amyloidosis; and eGFR < 30 mL/min/1.73 m2. A total of 655 patients enrolled at 87 sites in 26 countries were randomized in a 1:1 ratio to receive vutrisiran (25 mg, n = 326) or placebo (n = 329) every 12 weeks for up to 36 months. The mean age was 77, with 7% women, 85% White, 88% wild-type amyloidosis, and 78% in NYHA class II HF. At the end of the double-blind period, patients were eligible to be enrolled in the ongoing open-label extension period for up to 24 months. In both groups, 60% of patients did not take tafamidis at baseline (monotherapy population), and ∼21% initiated tafamidis after randomization when deemed necessary. During the trial, 22% of the patients in the monotherapy population and 33% in the overall population started therapy with a sodium-glucose cotransporter (SGLT)2-inhibitor. In both populations, treatment with vutrisiran lowered the risk of death from any cause and recurrent cardiovascular events vs. placebo [hazard ratio (HR) in the overall population, .72; 95% confidence interval (CI), .56–.93; P = .01; HR in the monotherapy population, .67; 95% CI, .49–.93; P = .02]. Among secondary outcomes, all-cause mortality, assessed at 42 months, was reduced by 35% in the overall population and 34% in those taking vutrisiran alone (P = .01 and P = .045, respectively). Vutrisiran treatment resulted in a lower decline in the distance covered on the 6 min walk test (difference 26.5 m, P < .001). Results were consistent in prespecified subgroups, including age, ATTR disease type (wild-type vs. variant), NYHA class, and baseline NT-proBNP level. The rates of adverse events and serious adverse events—including HF, AF, gout, and any event that led to drug discontinuation—were similar in the vutrisiran and placebo study arms. ATTR-CM is an infiltrative cardiomyopathy caused by the accumulation of misfolded and aggregated TTR, and associated with aging in its more prevalent non-hereditary form (wild-type ATTR), or with mutations in the TTR gene (variant ATTR), which can occur in younger patients. Traditionally considered a rare, progressive, and inevitably fatal condition, ATTR-CM prevalence is steadily increasing due to the expanding use of multimodality imaging approaches, including global longitudinal strain in echocardiography and cardiac magnetic resonance for suspected cases, which have led to better characterization of ATTR-CM phenotypes and earlier diagnosis.2 This, in turn, has paved the way to earlier introduction of treatments able to slow down or halt disease progression, including conventional HF medications, known to be poorly tolerated and futile in patients with advanced disease.3 Tafamidis, a TTR stabilizer, is currently the only approved therapy for ATTR-CM with a class IB recommendation in HF guidelines for patients in NYHA functional classes I and II, regardless of coexisting polyneuropathy.4 With different mechanisms, antisense oligonucleotide and small-interfering RNA (siRNA) therapies act by inducing the degradation of TTR mRNA in hepatocytes, resulting in the knockdown of serum TTR concentration. Patisiran was the first siRNA therapy to demonstrate high efficacy in reducing the progression of amyloidosis-associated neuropathy, with efficacy and safety data also for patients with wild-type and variant ATTR-CM.5 Vutrisiran is a second-generation siRNA currently approved for the treatment of polyneuropathy associated with hereditary TTR-mediated amyloidosis. The HELIOS-B trial demonstrated the efficacy of vutrisiran in reducing all-cause mortality and recurrent cardiovascular events in the overall population studied and in those treated with vutrisiran as monotherapy. The long-term follow-up represents a major strength of the study, with a prespecified analysis including six months of open-label extension data. Both in the monotherapy group and in the overall population, the Kaplan–Maier curves of the primary endpoint diverged after six months, and continued to separate thereafter. From a practical standpoint, the addition of a once-every-three-month subcutaneous drug to the therapeutic armamentarium of ATTR-CM might be particularly helpful for elderly patients who are already taking numerous daily medications. Furthermore, the reassuring safety data represent an additional advantage. When considering concomitant treatments during the study, the one-third drop-in of SGLT2-inhibitors during the double-blind phase of the study suggests additive benefits of vutrisiran in combination with other effective agents. However, data regarding the distribution in the two groups of other conventional HF therapies with potential beneficial effects, such as low-dose beta-blockers or mineral-corticosteroid receptor antagonists, are lacking. When interpreting the trial results, other limitations should be taken into account. As acknowledged by the authors, although 40% of the patients were on tafamidis treatment at baseline, the trial was not powered to show statistical significance in this subgroup. Direct comparisons will be needed to assess the relative efficacy of vutrisiran vs. tafamidis or other TTR stabilizers.6 Based on the recent experience with tafamidis, which has been defined as the most expensive cardiac medication in history, a cost-effectiveness analysis might help understand the impact of vutrisiran on healthcare resources.7,8 Finally, the enrolled population consisted almost entirely of males (92%) and wild-type ATTR-CM individuals (89%), which reflects a real-world scenario, although with poor racial generalizability (85% White). Despite recent advances in diagnosis and treatment, ATTR-CM remains a progressive and fatal disease with very limited treatment options. HELIOS-B results support vutrisiran as a potential new standard of care for patients with ATTR-CM, including those on tafamidis treatment, and might suggest its use as a first-line treatment option. Further studies exploring the effects of other siRNAs are probably needed to strengthen this result, with larger trials expected to clarify the best timing and treatment combinations for ATTR-CM towards a patient-tailored approach.9 D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. M.V. reports personal fees for speaker bureau and/or consulting in Advisory Boards from Astra Zeneca, Bayer, GSK, Menarini Int, Novartis Pharma, Novo Nordisk, Pfizer, Sanofi Pasteur, and Servier. M.V. is supported by a research grant from Italian Ministry of Health (‘Ricerca corrente’).