• 15 Nov 2023
• Admin
• News Article

Alnylam presents positive results from KARDIA-1 phase 2 study of zilebesiran to treat hypertension in patients at high cardiovascular risk

Alnylam Pharmaceuticals, Inc., the leading RNAi therapeutics company, announced positive results from the KARDIA-1 phase 2 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of patients with hypertension and high cardiovascular risk. The study results were presented during the American Heart Association (AHA) Scientific Sessions being held in Philadelphia, Pennsylvania from November 11-13, 2023. The company previously announced positive topline results from the KARDIA-1 study in September 2023.

The KARDIA-1 study achieved its primary endpoint, with single doses of zilebesiran demonstrating clinically significant reductions in 24-hour mean systolic blood pressure (SBP) measured by ambulatory blood pressure monitoring (ABPM) at Month 3 across all doses, with the 150 mg, 300 mg, and 600 mg doses achieving placebo-adjusted reductions of 14.1 mmHg, 16.7 mmHg, and 15.7 mmHg, respectively (all p-values less than 0.0001). The study also met key secondary endpoints across all doses, including demonstration of durable efficacy out to 6 months. At the 150 mg Q6M, 300 mg Q6M, 300 mg Q3M, and 600 mg Q6M doses, zilebesiran showed placebo-adjusted reductions in 24-hour mean SBP measured by ABPM of 11.1 mmHg, 14.5 mmHg, 14.1 mmHg, and 14.2 mmHg, respectively, at Month 6 (all p-values less than 0.0001). Zilebesiran demonstrated an encouraging safety and tolerability profile that the company believes supports continued development.

“These KARDIA-1 results are impressive, showing that in a diverse group of patients with mild-to-moderate hypertension, zilebesiran can safely achieve clinically significant reductions in systolic blood pressure and tonic blood pressure control administered subcutaneously with either quarterly or bi-annual dosing,” said Professor George L. Bakris, M.D., Board-Certified Hypertension Specialist and Director of the American Heart Association Comprehensive Hypertension Center, University of Chicago Medicine. “I continue to be encouraged and optimistic that zilebesiran has the potential to become not only a novel treatment for hypertension but also a transformative therapy to lower cardiovascular and renal risk in patients with hypertension, an area where new and innovative therapies are desperately needed.”

The KARDIA-1 phase 2 study is a randomized, double-blind, placebo-controlled, multi-center global dose-ranging study designed to evaluate the efficacy and safety of subcutaneously administered zilebesiran as monotherapy in adults with mild-to-moderate hypertension.

The study enrolled 394 adults representing a diverse patient population, of which more than 40% were female and nearly 25% were Black, with untreated hypertension or who were on stable therapy with one or more anti-hypertensive medications. Any patients taking prior antihypertensive medications completed at least a two- to four-week wash-out before randomization. Patients were randomized to one of five treatment arms: 150 mg zilebesiran once every six months (Q6M); 300 mg zilebesiran Q6M; 300 mg zilebesiran once every three months (Q3M); 600 mg zilebesiran Q6M; or placebo.

The primary endpoint was the change from baseline in 24-hour mean SBP at Month 3, assessed by ABPM. Key secondary endpoints in this study include additional measures of blood pressure reduction at Month 3 and Month 6, and the proportion of patients achieving treatment response criteria at Month 6, defined as 24-hour mean ambulatory SBP <130 mmHg and/or reduction =20 mmHg without additional antihypertensive medications.

At six months, the study met its primary endpoint and all key secondary endpoints. The placebo-adjusted study results presented are as follows:

Zilebesiran demonstrated an encouraging safety profile through Month 6. Serious adverse events were reported in 6.7% of patients in the placebo group and 3.6% of patients in the zilebesiran groups. There was one death due to cardiopulmonary arrest in a zilebesiran-treated patient that was considered unrelated to study drug. Drug-related adverse events (AEs) reported in more than 5% of patients in any zilebesiran arm were injection site reaction (ISR) occurring in 6.3% of patients and hyperkalemia in 5.3% of patients. No drug-related AEs were classified as serious or severe. ISR and hyperkalemia AEs were mostly mild and transient. No hyperkalemia events were associated with acute kidney injury or led to study drug discontinuation. Four patients had drug-related AEs leading to an investigator decision to discontinue zilebesiran. These AEs included orthostatic hypotension (n=2), blood pressure elevation (n=1), and ISR (n=1). Hypotension AEs were mild or moderate, non-serious, and transient. A single event in the zilebesiran 300 mg Q3M group was treated with normal saline. Clinically relevant AEs of acute renal failure, hepatic AEs, hypotension, and hyperkalemia of any relatedness were reported in 1.3%, 3.0%, 4.3%, and 6.3% of patients receiving zilebesiran, and 0%, 1.3%, 1.3%, and 2.7% of patients receiving placebo.

“The totality of the data presented at the American Heart Association Scientific Sessions gives us confidence in zilebesiran’s potentially differentiated profile and its ability to transform the treatment landscape for patients with uncontrolled hypertension who are at high risk of future cardiovascular events,” said Simon Fox, Ph.D., vice president, Zilebesiran Program Lead at Alnylam. “We look forward to sharing topline results from the KARDIA-2 Phase 2 study, designed to evaluate the efficacy and safety of zilebesiran when used in combination with one other antihypertensive medication in patients with mild-to-moderate hypertension, in early 2024.”

Zilebesiran 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 (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 infrequent subcutaneous dosing with increased selectivity and the potential to achieve tonic blood pressure control demonstrating consistent and durable blood pressure reduction throughout a 24-hour period, sustained up to six months after a single dose of zilebesiran. The safety and efficacy of zilebesiran have not been established or evaluated by the FDA, EMA or any other health authority. Zilebesiran is being co-developed and co-commercialized by Alnylam and Roche.

Uncontrolled hypertension is the chronic elevation of blood pressure (BP), defined by the 2017 ACC/AHA guidelines as =130 mmHg systolic blood pressure (SBP) and =80 mmHg diastolic blood pressure (DBP). More than one billion people worldwide live with hypertension. Approximately one in three adults are living with hypertension worldwide, with up to 80% of individuals remaining uncontrolled despite the availability of several classes of oral anti-hypertensive treatments. 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 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 and in patients with high cardiovascular risk.

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 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.

Alnylam Pharmaceuticals 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.