CAMBRIDGE, Mass. – Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of the polyneuropathy associated with hereditary transthyretin-mediated (hATTR) amyloidosis, met all secondary endpoints measured at 18 months, including statistically significant improvements in neuropathy as measured by the modified Neuropathy Impairment Score (mNIS+7), quality of life (QOL), gait speed, nutritional status and overall disability, relative to external placebo data from the APOLLO Phase 3 study of patisiran. The final secondary endpoint, reduction in serum TTR levels with vutrisiran, demonstrated non-inferiority relative to the within-study patisiran arm, as expected. In addition, patients treated with vutrisiran showed improvements in exploratory endpoints, including the biomarker NT-proBNP and certain echocardiographic parameters, relative to placebo, and an improvement in technetium uptake relative to baseline in a majority of patients in a planned cohort, providing potential evidence for reduced cardiac amyloid burden. Vutrisiran continued to demonstrate an encouraging safety and tolerability profile. Alnylam previously announced that HELIOS-A met its primary and secondary endpoints at nine months and study results were presented at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting.
“These results build on the positive vutrisiran data shared earlier this year and suggest that the reduction of neurologic impairment and improvement in quality of life in patients with hATTR amyloidosis with polyneuropathy observed as early as nine months are maintained at 18 months. We are also encouraged by the hypothesis-supporting, exploratory endpoints and cardiac amyloid imaging results,” said Rena N. Denoncourt, Vice President, TTR Franchise Lead. “Vutrisiran is currently under review by multiple regulatory authorities around the world, bringing this low-dose, once-quarterly, subcutaneously administered investigational therapy with a highly-attractive profile one step closer to being a potentially available therapeutic option for patients living with this progressive, life-threatening, multi-system disease. We look forward to presenting full 18-month results of the HELIOS-A study at a medical conference in early 2022, and progressing our efforts to build an industry-leading franchise of medicines for the treatment of the polyneuropathy of hATTR amyloidosis and potentially additional indications for the future.”
At 18 months, patients treated with vutrisiran showed quantitative improvement across a number of exploratory endpoints. Compared to placebo, patients in the vutrisiran arm demonstrated improvement in the cardiac biomarker endpoint, NT-proBNP, a measure of cardiac stress. In addition, patients treated with vutrisiran also demonstrated improvement in certain echocardiographic parameters, relative to placebo. Finally, in a planned cohort of 48 patients, treatment with vutrisiran was associated with an improvement in technetium uptake in the heart in a majority of patients, providing potential evidence for reduced cardiac amyloid burden.
Vutrisiran demonstrated an encouraging safety profile. There were three study discontinuations (2.5 percent) due to adverse events in the vutrisiran arm during the 18 Month treatment period; the single new discontinuation since Month 9 was an event of cardiac failure considered unrelated to study drug by the investigator. During the 18 Month treatment period, there were two deaths (neither of which was considered related to study drug) and two serious adverse events (SAEs) deemed related to vutrisiran by the study investigator; these deaths and related SAEs all occurred by Month 9 and were previously reported. Treatment emergent adverse events (AEs) occurring in 10 percent or more patients included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia and dizziness; with the exception of pain in extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with external placebo. Injection site reactions (ISRs) were reported in 5 patients (4.1 percent) and were all mild and transient. There were no hepatic safety concerns.
Vutrisiran is under review by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Brazilian Health Regulatory Agency (ANVISA). 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 the U.S., vutrisiran has received an action date under the Prescription Drug User Fee Act (PDUFA) of April 14, 2022. The Company received Orphan Drug Designation in Japan for transthyretin type familial amyloidosis with polyneuropathy.
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.
Vutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hATTR 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 U.S. Food and Drug Administration, European Medicines Agency, or any other health authority.
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 external 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 was the change from baseline in mNIS+7 at nine months. Secondary endpoints at nine months were the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT. Additional secondary endpoints at 18 months evaluated in the HELIOS-A study included 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 endpoint data at 18-months, included NT-proBNP, echocardiographic measures and cardiac amyloid burden as measured by technetium scintigraphy imaging. Following the 18-month treatment period, all patients are eligible to receive vutrisiran for an additional 18 months as part of the randomized treatment extension where they will receive either 25mg vutrisiran once quarterly or 50mg vutrisiran once every six months.
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 Pharmaceuticals
Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran) being developed and commercialized by Alnylam’s partner Novartis. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.
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Christine Regan Lindenboom