Alnylam Initiates KARDIA-1 Phase 2 Study of Zilebesiran (ALN-AGT) in Patients with Mild-to-Moderate Hypertension

– KARDIA-1 will Evaluate Efficacy and Safety of Quarterly and Biannual Regimens of Zilebesiran as Monotherapy –

CAMBRIDGE, MA, USA I June 30, 2021 I Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced initiation of KARDIA-1, a global Phase 2 study evaluating the efficacy and safety of zilebesiran (pronounced “zile-BEE-siran” and formerly known as ALN-AGT), an investigational subcutaneous RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension. KARDIA-1 will evaluate zilebesiran as monotherapy across different doses administered quarterly and biannually. The Company will host an “RNAi Roundtable” webinar today at 10:00 a.m. ET to discuss the zilebesiran program.

The primary endpoint of KARDIA-1 is the change from baseline in systolic blood pressure as measured by 24-hour ambulatory blood pressure monitoring after three months of treatment. Additional endpoints will include change from baseline in blood pressure at six months, time-averaged reduction of blood pressure as a measure of tonic control, and safety. The study initiation is based on encouraging Phase 1 data, including results presented earlier this year at the 2021 Joint Meeting of the European Society of Hypertension (ESH) and the International Society of Hypertension (ISH). KARDIA-1 has been activated at clinical sites in the U.S. and will also be conducted at sites in Europe.

“According to the World Health Organization, hypertension is the largest modifiable risk factor for cardiovascular morbidity and mortality. Despite the availability of numerous anti-hypertensive medications, tonic control of blood pressure remains elusive and represents a major unmet need, elevating the risk of fatal and nonfatal cardiovascular events, primarily stroke and heart attack. In addition, lack of patient adherence to therapy with daily oral medications further contributes to the challenges of inadequate blood pressure control,” said Weinong Guo, M.D., Ph.D., Senior Vice President of Clinical Development at Alnylam. “The initiation of KARDIA-1, along with the planned start of the KARDIA-2 Phase 2 study later this year, signifies Alnylam’s commitment to advance zilebesiran as a potential treatment to help address the worldwide burden of uncontrolled hypertension.”

Additional details about the RNAi Roundtable can be found on the Capella section of the Company’s website here.

About KARDIA-1 Phase 2 Study

The KARDIA-1 Phase 2 trial is a randomized, double-blind (DB), placebo-controlled, dose-ranging study to evaluate the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. This global, multicenter trial will enroll approximately 375 adults with untreated hypertension or who are on stable therapy with one or more anti-hypertensive medications. Any patients taking prior anti-hypertensive medications will complete at least a four-week wash-out before randomization. Study participants will be randomized to one of five treatment arms during a 12-month DB period and DB extension period: 1) 150 mg zilebesiran subcutaneously once every six months; 2) 300 mg zilebesiran subcutaneously once every six months; 3) 300 mg zilebesiran subcutaneously once every three months; 4) 600 mg zilebesiran subcutaneously once every six months; or 5) placebo. Patients who receive placebo will be randomized to one of the four initial zilebesiran dose regimens beginning at month six. The study’s primary efficacy endpoint is the change from baseline in systolic blood pressure, assessed by 24-hour ambulatory blood pressure monitoring, after three months of treatment. In addition to the evaluation of the safety of zilebesiran, key secondary and exploratory endpoints in this study include additional measures of blood pressure reduction at six months, time-adjusted change in blood pressure, and change in daytime average and night-time average blood pressure. For more information on KARDIA-1 (NCT04936035), please visit clinicaltrials.gov, email This email address is being protected from spambots. You need JavaScript enabled to view it. or call 877-256-9526 in North America and +31 20 369 7861 in Europe.

About Zilebesiran

Formerly known as ALN-AGT, zilebesiran (pronounced “zile-BEE-siran”) is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT) in 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 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.

About Hypertension

Hypertension is a complex multifactorial disease clinically defined by most major guidelines as a systolic blood pressure (SBP) of above 140 mm Hg and/or a diastolic blood pressure (DBP) greater than 90 mm Hg, though AHA/ACC guidelines have a lower threshold of a SBP above 130 mm Hg and/or a DBP greater than 80 mm Hg. More than one billion people worldwide live with hypertension.i 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 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 and daily peak and trough effects, resulting in inconsistent blood pressure control and an increased risk for stroke, heart attack and premature death.ii 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.

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 potently 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.

i Hypertension. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/hypertension. Published September 2019. Accessed June 2021.
ii 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), 1278–1293. https://doi.org/10.1016/j.jacc.2018.07.008

SOURCE: Alnylam Pharmaceuticals

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