Positive phase 2 study of zilebesiran for patients with hypertension

Published on 12 April 2024

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive results from the KARDIA-2 Phase 2 study evaluating the efficacy and safety of a single subcutaneous dose of zilebesiran when added to one of three standard of care antihypertensives including a thiazide-like diuretic (indapamide), calcium channel blocker (amlodipine) or angiotensin receptor blocker (olmesartan). Zilebesiran is an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension with the potential for biannual dosing. The results were presented today as a late-breaking clinical trial at the 2024 American College of Cardiology (ACC) Annual Scientific Session. The Company previously announced positive topline results from the KARDIA-2 study in March 2024.

The KARDIA-2 study achieved its primary endpoint demonstrating clinically and statistically significant additive, placebo-adjusted reductions of up to 12.1 mmHg in 24-hour mean systolic blood pressure (SBP) measured by ambulatory blood pressure monitoring (ABPM) when zilebesiran was added to a thiazide-like diuretic, calcium channel blocker or angiotensin receptor blocker, measured independently at Month 3. The study achieved the key secondary endpoint evaluated at Month 3, demonstrating clinically significant additive reductions in office SBP across all three independent cohorts. At Month 6, zilebesiran demonstrated clinically significant and sustained placebo-adjusted, time-adjusted reductions in office SBP when added to indapamide, amlodipine and olmesartan, despite the addition of rescue antihypertensives at Month 3. In addition, zilebesiran resulted in clinically significant placebo-adjusted, time-adjusted reductions in 24-hour mean SBP, assessed by ABPM, when added to indapamide and amlodipine, sustained to Month 6. A non-statistically significant result was observed when zilebesiran was added to the maximum dose of olmesartan when evaluated by time-adjusted change from baseline in 24-hour mean SBP, assessed by ABPM at Month 6.

“Although many effective oral treatments are available, a large proportion of patients with hypertension are not managed to guideline-recommended targets. Inconsistent adherence to complex, daily, oral medication regimens as well as therapeutic inertia on the part of clinicians may be important contributors to this treatment gap,” said Akshay Desai, M.D., Director of the Cardiomyopathy and Heart Failure Program, Brigham and Women’s Hospital. “Even in those who are treated, residual blood pressure variability may ultimately enhance risk for cardiovascular events. Zilebesiran may help to address many of these limitations of current treatment options. Although further evidence is needed to ensure long term efficacy and safety in a broader population, these data are encouraging and the potential to reduce blood pressure consistently with two injections a year might be transformative for clinical practice.”

KARDIA-2 Study Results

The KARDIA-2 study results are as follows:

The final key secondary endpoint evaluated the proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg and/or reduction ≥20 mmHg without rescue antihypertensive medication at Month 6. As outlined in the study protocol, after three months of treatment, all patients were permitted to receive rescue antihypertensives as needed based on rescue response criteria. Across all cohorts, a higher percentage of placebo-treated patients required treatment with rescue antihypertensives compared to zilebesiran-treated patients. Additionally, the odds of meeting the SBP response criteria were significantly higher with zilebesiran in the indapamide and amlodipine cohorts, compared to placebo.

Zilebesiran demonstrated an encouraging safety and tolerability profile when added to standard of care antihypertensives.

Most laboratory abnormalities of interest were mild, occurred in the first three months of treatment and resolved upon repeat measure within one to two weeks without intervention. There were no deaths reported, and no AEs led to study discontinuation during the six-month double-blind period.

“The KARDIA program has built a robust body of evidence, with more than six hundred patients having received zilebesiran in Phase 2 trials, demonstrating clinically significant blood pressure reductions with encouraging safety as both a monotherapy and as an add-on therapy, with the potential for both quarterly and biannual dosing,” said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam. “At Alnylam, we are aiming to disrupt cardiovascular disease, and in collaboration with our partner Roche, we are committed to moving zilebesiran forward in the hope of changing the hypertension treatment paradigm for patients. We are taking that next step with our recently initiated third Phase 2 study, KARDIA-3, designed to evaluate zilebesiran as an add-on therapy in high cardiovascular risk patients with uncontrolled hypertension despite receiving two or more antihypertensives.”

The KARDIA-2 Phase 2 study is a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of zilebesiran, when added to standard of care antihypertensive medications, in adults with mild-to-moderate hypertension. This global, multicenter study enrolled 672 adults with hypertension. Patients who met all inclusion criteria and none of the exclusion criteria during a screening period were first randomized into three different cohorts to receive open-label therapy with indapamide, amlodipine or olmesartan as their protocol-specified background antihypertensive medication during a run-in period of at least four weeks. Following the run-in period, eligible patients with elevated SBP were randomized 1:1 to receive a single dose of 600 mg zilebesiran or placebo in addition to their protocol-specified background antihypertensive medication for six months.

To review the KARDIA-2 study results and the KARDIA-1 subgroup results presented at ACC, please visit Capella.

Read the press release here.

 

ⁱ Hypertension. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/hypertension. Published September 2019. Accessed November 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.

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