Alnylam Presents New 18-Month Results from Exploratory Cardiac Endpoints in HELIOS-A Phase 3 Study of Investigational Vutrisiran

– New Exploratory Findings from 18-Month Analysis of HELIOS-A Suggest that Treatment with Investigational Vutrisiran May Benefit Patients with Hereditary ATTR (hATTR) Amyloidosis and Cardiac Involvement –

– Improvements in NT-proBNP and Echocardiographic Parameters Seen in Cardiac Subpopulation –

– Reductions in Technetium Uptake Observed in Patients with High Grade Uptake at Baseline –

Alnylam Pharmaceuticals, Inc. , the leading RNAi therapeutics company, announced new positive results from an 18-month analysis of exploratory cardiac endpoints in the HELIOS-A Phase 3 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 ≥2 at baseline, suggesting that patients with the highest degrees of cardiac amyloid burden may recognize benefit from a TTR silencer.

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“While the full clinical significance of these findings requires further evaluation, the 18-month exploratory results from HELIOS-A continue to support the potential for vutrisiran to reduce amyloid burden in the heart and suggest that patients with a high degree of cardiac amyloid burden may benefit from this investigational RNAi therapeutic”

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.

“While the full clinical significance of these findings requires further evaluation, the 18-month exploratory results from HELIOS-A continue to support the potential for vutrisiran to reduce amyloid burden in the heart and suggest that patients with a high degree of cardiac amyloid burden may benefit from this investigational RNAi therapeutic,” said Rena N. Denoncourt, Vice President, TTR Franchise Lead. “We look forward to seeing data from the APOLLO-B and HELIOS-B studies, which are investigating the efficacy and safety of patisiran and vutrisiran, respectively, to treat the cardiomyopathy of wild-type and hereditary ATTR amyloidosis. We are committed to bringing highly impactful therapeutic options to patients worldwide living with this progressive, multi-system and life-threatening disease.”

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.

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“hATTR amyloidosis is a rapidly progressive disease that can affect multiple organs and tissues, including the heart, nerves and gastrointestinal tract, with potentially fatal outcomes,” said Julian D. Gillmore, M.D., Ph.D., University College London. “The exploratory cardiac findings from the HELIOS-A Phase 3 study are encouraging as they add to the growing body of data that suggest vutrisiran has the potential to help improve multiple aspects of the disease, including cardiac manifestations that can be life-threatening for these patients.”

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.

Vutrisiran is under review by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency (ANVISA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). Vutrisiran has been granted Orphan Drug Designation in the U.S. and the European Union (EU) for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast Track designation in the U.S. for the treatment of the polyneuropathy of hATTR amyloidosis in adults. In April, Alnylam announced a 3-month extension of the review period for the new drug application for vutrisiran in the U.S. with a new action date under the Prescription Drug User Fee Act (PDUFA) of July 14, 2022. The Company received Orphan Drug Designation in Japan for transthyretin type familial amyloidosis with polyneuropathy. A biannual 50mg dosing regimen is under evaluation within the ongoing randomized treatment extension (RTE) period in the HELIOS-A trial. Vutrisiran is also being evaluated in the HELIOS-B Phase 3 study for the treatment of patients with ATTR amyloidosis with cardiomyopathy, including both hATTR and wild-type ATTR (wtATTR) amyloidosis.

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