HELIOS-A: 18-month exploratory cardiac results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis.

Hereditary transthyretin amyloidosis is a fatal, multisystem disease that presents with progressive polyneuropathy and/or cardiomyopathy. HELIOS-A assessed the efficacy of vutrisiran, an investigational RNAi, in patients with hATTR amyloidosis with polyneuropathy. To evaluate the effect of 18 months of vutrisiran treatment on exploratory cardiac endpoints in the HELIOS-A Phase 3 study. Patients were randomised (3:1) to vutrisiran (25 mg SC, q3 m) or patisiran (0.3 mg/kg IV, q3w), a reference comparator. The APOLLO placebo group (n = 77) was an external control. Primary endpoint was change from baseline in the modified Neuropathy Impairment Score +7 at M9, vs. external placebo. Exploratory cardiac endpoints included change from baseline in NT-proBNP levels, echocardiography parameters, and 99mTc scintigraphy parameters at M18. A prespecified cardiac subpopulation was included (baseline left ventricular wall thickness ≥1.3 cm and no medical history of aortic valve disease or hypertension). HELIOS-A enrolled 164 patients and the primary endpoint was met. In the cardiac subpopulation (n = 40/122 vutrisiran; n = 36/77 placebo), 18 months of vutrisiran treatment significantly improved NT-ProBNP levels vs. external placebo and demonstrated a trend towards improvement in echocardiographic parameters vs. external placebo (including a significant difference in cardiac output [least squares mean difference: 0.41; P = 0.043]). 99mTc scintigraphy assessment was captured for 64 vutrisiran-treated patients at baseline, 35 (54.7%) of whom had Perugini grade ≥ 2. Among patients with scintigraphy parameters repeated at M18 (evaluable patients), heart-to-contralateral lung ratio and normalised LV total uptake on scintigraphy improved in 64.6% (31/48) and 68.1% (32/47), respectively, at M18. Of the evaluable patients, 28.1% (16/57) had an improvement in Perugini grade, 68.4% (39/57) had no change and 3.5% (2/57) worsened in grade. Of evaluable patients with baseline Perugini grade ≥ 2, the proportion with improvement in heart-to-contralateral lung ratio and normalised LV total uptake was 76.9% (20/26) and 100% (25/25) respectively. No cardiac safety concerns were identified with vutrisiran treatment. In this exploratory analysis, vutrisiran was associated with a positive impact on NT-ProBNP levels and echocardiographic parameters vs. external placebo in the cardiac subpopulation. It also reduced cardiac uptake of 99mTc potentially suggesting reduction in cardiac amyloid. [ABSTRACT FROM AUTHOR]