\n\u201cHypertension is the leading cause of premature death, cardiovascular disease, and chronic kidney disease worldwide, and the global prevalence is steadily increasing in parallel with population aging and secular trends in the prevalence of risk factors including obesity, physical inactivity, and unhealthy diet. Despite the availability of effective antihypertensive treatments, nearly half of patients with hypertension fail to achieve guideline-recommended blood pressure targets, leaving them at residual risk for myocardial infarction, stroke, kidney disease progression, and mortality. For clinicians, the challenge in optimizing treatment of hypertension is frequently compounded by poor adherence to prescribed medical therapy and substantial variability in blood pressure between office visits and over the 24-hour cycle,\u201d said Akshay Desai, M.D., the lead author of the manuscript and Director of the Cardiomyopathy and Heart Failure Program in the Advanced Heart Disease Section of the Cardiovascular Division at Brigham and Women\u2019s Hospital. \u201cIn this context, the data we have published in NEJM <\/i>are exciting, suggesting the potential role for zilebesiran to treat hypertension in a novel way via a novel, subcutaneously administered gene silencing approach to hypertension. This novel approach may provide durable, tonic blood pressure control with infrequent, office-based dosing and a favorable safety profile. Additional clinical trials will provide further insights into the potential of this approach to improve clinical outcomes in the growing population of patients with hypertension.\u201d<\/p>\n
\n\u201cThe data published in NEJM<\/i> suggest the potential for zilebesiran to be an effective and highly-differentiated treatment that may help people with hypertension achieve sustained blood pressure control,\u201d said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam. \u201cTo that end, we are currently evaluating the safety and efficacy of zilebesiran in our KARDIA Phase 2 clinical program either as a monotherapy (KARDIA-1) or in combination with a standard-of-care antihypertensive medication (KARDIA-2), and we look forward to reporting results from these programs in mid- and late 2023, respectively.\u201d<\/p>\n
Summary of Published Results<\/b><\/p>\n
\nThe study was conducted in 107* patients (zilebesiran, N=80; placebo, N=32) with mild-to-moderate hypertension. In Part A, patients were randomized 2:1 to receive single ascending subcutaneous doses of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo. Part B of the study assessed the effects of zilebesiran (800 mg) on blood pressure under low- and high-salt diet conditions and Part E assessed the effects of zilebesiran (800 mg) coadministration with irbesartan (an angiotensin II receptor blocker). The study primary endpoint was the frequency of adverse events (AEs). AEs were reported for 58 patients receiving zilebesiran (72 percent) and 28 receiving placebo (88 percent). The most frequent treatment-related adverse events were mild, transient injection-site reactions reported in five (6 percent) patients who received zilebesiran. No events of hypotension, hyperkalemia, or worsening renal function requiring intervention were observed. Secondary and exploratory endpoints included change from baseline in serum AGT, pharmacokinetics, and change from baseline in blood pressure. In Part A, versus placebo, zilebesiran was associated with dose-dependent reductions in serum AGT that were sustained for up to six months. Single doses of zilebesiran (\u2265200 mg) resulted in reductions in systolic (>10 mm Hg) and diastolic (>5 mm Hg) blood pressure by Week 8, which were consistent throughout the diurnal cycle and sustained to six months. At the 800 mg dose, zilebesiran treatment resulted in mean (\u00b1 standard error) systolic and diastolic reductions of 22.5 \u00b1 5.1 mm Hg and 10.8 \u00b1 2.7 mm Hg at Month 6, respectively. In Parts B and E of the study, blood pressure changes following zilebesiran treatment could be attenuated through high dietary salt intake and were augmented by irbesartan coadministration.<\/p>\n
\n*Five patients receiving placebo in Part A of the study re-enrolled into Part E of the study and thus transitioned from placebo to zilebesiran.<\/p>\n
About Zilebesiran<\/b><\/p>\n
\nZilebesiran is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in Phase 2 development for the treatment of hypertension in high unmet need populations. AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System (RAAS), a cascade which has a demonstrated role in blood pressure (BP) regulation and its inhibition has well-established anti-hypertensive effects. Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin (Ang) II. Zilebesiran utilizes Alnylam’s Enhanced Stabilization Chemistry Plus (ESC+) GalNAc-conjugate technology, which enables subcutaneous dosing with increased selectivity and a wide therapeutic index. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority.<\/p>\n
About Hypertension<\/b><\/p>\n
\nUncontrolled hypertension is the chronic elevation of blood pressure (BP), defined by the 2017 ACC\/AHA guidelines as \u2265130 mmHg systolic blood pressure (SBP) and \u226580 mmHg diastolic blood pressure (DBP). More than one billion people worldwide live with hypertension.i<\/sup> In the U.S. alone, approximately 47 percent of adults live with hypertension, with more than half of patients on medication remaining above the blood pressure (BP) target level. Despite the availability of anti-hypertensive medications, there remains a significant unmet medical need, especially given the poor rates of adherence to existing daily oral medications, resulting in inconsistent BP control and an increased risk for stroke, heart attack and premature death.ii<\/sup> In particular, there are a number of high unmet need settings where novel approaches to hypertension warrant additional development focus, including patients with poor medication adherence, difficult-to-treat and resistant hypertension, and in patients with high cardiovascular risk.<\/p>\n About RNAi<\/b><\/p>\n \nRNAi (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 \u201ca major scientific breakthrough that happens once every decade or so,\u201d 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\u2019s medicines by potently silencing messenger RNA (mRNA) \u2013 the genetic precursors \u2013 that encode for disease-causing or disease pathway 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.<\/p>\n About Alnylam Pharmaceuticals<\/b><\/p>\n \nAlnylam Pharmaceuticals (Nasdaq: ALNY) has led 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 and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam\u2019s commercial RNAi therapeutic products are ONPATTRO\u00ae<\/sup> (patisiran), AMVUTTRA\u00ae<\/sup> (vutrisiran), GIVLAARI\u00ae<\/sup> (givosiran), OXLUMO\u00ae<\/sup> (lumasiran), and Leqvio\u00ae<\/sup> (inclisiran), which is being developed and commercialized by Alnylam\u2019s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its \u201cAlnylam P5<\/sup>x25<\/i>\u201d 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<\/a> and engage with us on Twitter at @Alnylam<\/a>, on LinkedIn<\/a>, on Instagram<\/a>, or on Facebook at @AlnylamPharma<\/a>.<\/p>\n Alnylam Forward Looking Statements<\/b><\/p>\n \nThis press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam\u2019s expectations, beliefs, goals, plans or prospects including, without limitation, Alnylam\u2019s views with respect to the potential role for zilebesiran as a novel, subcutaneously administered gene silencing approach to hypertension, its views that zilebesiran has the potential to be an effective and highly-differentiated treatment; its expectations regarding its aspiration to become a leading biotech company and the planned achievement of its \u201cAlnylam P5<\/sup>x25<\/i>\u201d strategy, the potential for Alnylam to identify new potential drug development candidates and advance its research and development programs, Alnylam\u2019s ability to obtain approval for new commercial products or additional indications for its existing products, and Alnylam\u2019s projected commercial and financial performance, should be considered forward-looking statements. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or any future pandemic on Alnylam\u2019s business, results of operations and financial condition and the effectiveness or timeliness of Alnylam\u2019s efforts to mitigate the impact of the pandemic; Alnylam\u2019s ability to successfully execute on its \u201cAlnylam P5<\/sup>x25<\/i>\u201d strategy; Alnylam\u2019s ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam\u2019s product candidates, including patisiran and vutrisiran; actions or advice of regulatory agencies and Alnylam\u2019s ability to obtain and maintain regulatory approval for its product candidates, including patisiran and vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam\u2019s approved products globally; delays, interruptions or failures in the manufacture and supply of Alnylam\u2019s product candidates or its marketed products; delays or interruptions in the supply of resources needed to advance Alnylam\u2019s research and development programs, including as may arise from recent disruptions in the supply of non-human primates; obtaining, maintaining and protecting intellectual property; Alnylam\u2019s ability to successfully expand the indication for ONPATTRO or AMVUTTRA in the future; Alnylam\u2019s ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylam\u2019s ability to maintain strategic business collaborations; Alnylam\u2019s dependence on third parties for the development and commercialization of certain products, including Novartis, Sanofi, Regeneron and Vir; the outcome of litigation; the potential impact of a current government investigation and the risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the \u201cRisk Factors\u201d filed with Alnylam\u2019s 2022 Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as may be updated from time to time in Alnylam\u2019s subsequent Quarterly Reports on Form 10-Q and in its other SEC filings. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.<\/p>\n i<\/sup> Hypertension. World Health Organization. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/hypertension<\/a>. Published September 2019. Accessed November 2021.<\/p>\n ii<\/sup> Carey, R. M., Muntner, P., Bosworth, H. B., & Whelton, P. K. (2018). Prevention and Control of Hypertension: JACC Health Promotion Series. Journal of the American College of Cardiology, 72(11), 1278\u20131293. https:\/\/doi.org\/10.1016\/j.jacc.2018.07.008<\/a><\/p>\n View source version on businesswire.com: <\/span>https:\/\/www.businesswire.com\/news\/home\/20230719155322\/en\/<\/a><\/span><\/p>\n Alnylam Pharmaceuticals, Inc.<\/b><\/p>\n \nChristine Regan Lindenboom \nJosh Brodsky KEYWORDS:<\/b> North America United States Asia Pacific Europe Japan Massachusetts<\/p>\n INDUSTRY KEYWORDS:<\/b> Biotechnology Health Genetics Pharmaceutical Clinical Trials<\/p>\n<\/p>\n
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