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New 18-month results from exploratory cardiac endpoints in HELIOS-A phase III study of vutrisiran for treatment of ATTR amyloidosis

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Published:24th May 2022

Alnylam Pharmaceuticals, Inc., announced new positive results from an 18-month analysis of exploratory cardiac endpoints in the HELIOS-A Phase III study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis.

The 18-month findings show that in a pre-defined cardiac subpopulation, treatment with vutrisiran was associated with improvements in exploratory cardiac endpoints relative to external placebo, including levels of NT-proBNP, a measure of cardiac stress, and a trend towards improvement in echocardiographic parameters. Consistent beneficial effects on cardiac measures were observed in the modified intent-to-treat (mITT) group. Additionally, in a planned cohort of patients from the mITT population, vutrisiran treatment reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline in a majority of assessable patients, including those with Perugini grade greater than 2 at baseline, suggesting that patients with the highest degrees of cardiac amyloid burden may recognize benefit from a TTR silencer.

The exploratory findings were presented in a late breaking oral session during the annual congress of the Heart Failure Association of the European Society of Cardiology (Heart Failure 2022; May 21-24, 2022).

Alnylam previously announced that vutrisiran met its primary endpoint and all secondary endpoints at nine months in HELIOS-A, as well as all 18-month secondary endpoints in patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy, which were presented at the Société Francophone du Nerf Périphérique (SFNP) annual meeting earlier this year.

At 18 months, patients with pre-existing evidence of cardiac amyloid involvement (baseline LV wall thickness 1.3 cm and no aortic valve disease or hypertension in medical history; n=40/122 vutrisiran; n=36/77 external placebo group) treated with vutrisiran demonstrated improvement in NT-proBNP levels, with an adjusted geometric fold change of 0.95 compared to 1.93 in the external placebo group (p=0.0004). In the cardiac subpopulation, vutrisiran treatment was also associated with a trend towards improvement (nominal p values) in echocardiographic parameters at Month 18 relative to external placebo, including cardiac output (p=0.0426), LV end-diastolic volume (p=0.0607), global longitudinal strain (p=0.0781) and mean LV wall thickness (p=0.5397).

In a planned cohort of patients from the mITT population ,vutrisiran also reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline. 96 percent of assessable patients maintained a stable grade or improved by one grade or greater in the Perugini grading scale at Month 18 relative to baseline. Among vutrisiran-treated patients with Perugini grade 1 at baseline, 50 percent showed a one grade or greater improvement at Month 18. Of patients with baseline Perugini grade 2 who represent those with evidence of the greatest degree of cardiac amyloid burden evaluated in the analysis, the proportion with improvement in normalized left ventricle total uptake and heart-to-contralateral lung ratio was 100 percent (25/25) and 77 percent (20/26), respectively.

The majority of adverse events reported in the vutrisiran arm of HELIOS-A were mild or moderate in severity. As previously reported, there were three study discontinuations in the vutrisiran arm (2.5 percent) by Month 18 due to adverse events, one due to a non-fatal event of heart failure and two due to deaths, none of which were considered related to the study drug. Vutrisiran demonstrated an acceptable cardiac safety profile through 18 months of treatment.

Condition: Transthyretin Amyloid Polyneuropathy
Type: drug

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