Alnylam Presents New 18-Month Results from Exploratory Cardiac Endpoints in HELIOS-A Phase 3 Study of Investigational Vutrisiran
Alnylam Pharmaceuticals (Nasdaq: ALNY) reported positive 18-month findings from the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic for hereditary ATTR amyloidosis. The analysis indicated significant improvements in NT-proBNP levels, a key cardiac stress marker, in patients treated with vutrisiran compared to an external placebo. Cardiac echocardiographic parameters also showed favorable trends. Vutrisiran treatment reduced cardiac technetium uptake, suggesting benefits for patients with high amyloid burden. The drug has Orphan Drug Designation and is undergoing review by regulatory authorities, with a PDUFA date of July 14, 2022.
- Significant improvement in NT-proBNP levels (0.95 in vutrisiran group vs. 1.93 in placebo, p=0.0004).
- Echocardiographic parameters showed promising trends for vutrisiran-treated patients.
- Reduction in cardiac technetium uptake in 96% of assessable patients.
- 100% improvement in left ventricle total uptake among patients with high-grade cardiac amyloid burden.
- Acceptable cardiac safety profile with mild to moderate adverse events.
- Three discontinuations in the vutrisiran arm (2.5%) due to adverse events, with two deaths reported, though not linked to the drug.
– 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 –
The exploratory findings were presented in a late breaking oral session during the annual congress of the
“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
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.
“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
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
About Vutrisiran
Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, potentially blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly, and potentially biannual, administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the
About hATTR Amyloidosis
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by variants (i.e., mutations) in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Variants in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.
About HELIOS-A Phase 3 Study
HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The efficacy results of vutrisiran in HELIOS-A are compared to the placebo group from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. The primary endpoint is the change from baseline in mNIS+7 at 9 months. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at 9 months. Additional secondary endpoints at 18 months were evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point include NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month treatment period, all patients were eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.
About RNAi
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
About
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam’s expectations, plans, aspirations and goals, including, without limitation, those related to the investigational therapeutic vutrisiran and its potential as a low-dose, once quarterly, subcutaneously administered treatment option with an encouraging safety profile for patients diagnosed with the polyneuropathy of hATTR amyloidosis, the 18-month exploratory results from HELIOS-A which support the potential for vutrisiran to reduce amyloid burden in the heart, the potential of patisiran and vutrisiran to treat the cardiomyopathy of wild-type and hereditary ATTR amyloidosis, the ongoing regulatory review of vutrisiran around the world, including the extended PDUFA date in the
This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.
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