Therapy Areas: Cardiovascular
Alnylam Initiates KARDIA-2 Phase 2 Study of Investigational Zilebesiran (ALN-AGT) in Patients with Inadequately Controlled Hypertension
8 November 2021 - - US-Based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has initiated KARDIA-2, a global Phase 2 study to evaluate the efficacy and safety of zilebesiran (formerly known as ALN-AGT), an investigational subcutaneous RNAi therapeutic targeting liver-expressed angiotensinogen in development for the treatment of hypertension, the company said.

KARDIA-2 will evaluate the efficacy and safety of zilebesiran administered biannually as a concomitant therapy in patients whose blood pressure is not adequately controlled by standard of care antihypertensive medications.

The primary endpoint of KARDIA-2 is the change from baseline in 24-hour mean systolic blood pressure after three months of treatment, as measured by ambulatory blood pressure monitoring.

Additional endpoints will include change from baseline in blood pressure at six months and time-averaged reduction of blood pressure as a measure of tonic control. Safety will be assessed throughout the study.

KARDIA-2 has been activated at clinical sites in the US and will be conducted at approximately 80 clinical study centers worldwide.

KARDIA-2 is the second Phase 2 study evaluating zilebesiran in hypertension, with KARDIA-1, announced earlier this year, assessing zilebesiran as monotherapy across different doses administered quarterly and biannually.

These Phase 2 studies are based on encouraging Phase 1 data, including results presented earlier this year at the 2021 Joint Meeting of the European Society of Hypertension and the International Society of Hypertension.

Additional clinical results from the Phase 1 study of zilebesiran will be presented at the American Heart Association Scientific Sessions 2021, being held November 13-15, 2021.

The KARDIA-2 Phase 2 trial is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of zilebesiran used as a concomitant therapy in adults with hypertension despite treatment with standard of care antihypertensive medications.

This global, multicenter trial will enroll approximately 800 adults with hypertension. Patients who meet all inclusion/exclusion criteria during a screening period will be randomized to receive open-label therapy with olmesartan, amlodipine or indapamide as their protocol-specified background antihypertensive medication during a run-in period of at least four weeks.

Following the run-in period, eligible patients will be randomized 1: 1 to receive 600 mg zilebesiran or placebo concomitantly with their protocol-specified background antihypertensive medication during a 6-month DB period.

After three months, additional conventional oral antihypertensives may be added to the protocol-specified background antihypertensive medication for elevated blood pressure.

Once the DB period has concluded, protocol-specified background antihypertensive medications will be discontinued, and patients may be eligible to participate in a separate zilebesiran open-label extension study.

The study's primary efficacy endpoint is the change from baseline in 24-hour mean systolic blood pressure, as measured by ambulatory blood pressure monitoring, after three months of treatment.

Additional endpoints include the change in 24-hour mean SBP after six months of treatment assessed by ABPM, change in office SBP at months three and six, and change in 24-hour mean diastolic blood pressure measured by ABPM -- as well as office DBP -- at months three and six. Safety will be assessed throughout the study.

Formerly known as ALN-AGT, zilebesiran (pronounced "zile-BEE-siran") is an investigational, subcutaneously administered RNAi therapeutic targeting angiotensinogen in development for the treatment of hypertension in high unmet need populations.

AGT is the most upstream precursor in the Renin-Angiotensin-Aldosterone System, a cascade which has a demonstrated role in blood pressure regulation and its inhibition has well-established antihypertensive effects.

Zilebesiran inhibits the synthesis of AGT in the liver, potentially leading to durable reductions in AGT protein and ultimately, in the vasoconstrictor angiotensin II.

Zilebesiran utilizes Alnylam's Enhanced Stabilization Chemistry Plus 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.

Hypertension is a complex multifactorial disease clinically defined by most major guidelines as a systolic blood pressure of above 140 mm Hg and/or a diastolic blood pressure 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 bn people worldwide live with hypertension.i In the US alone, approximately 47 % of adults live with hypertension, with more than half of patients on medication remaining above the blood pressure target level.

Despite the availability of antihypertensive 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.

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.