Investigational zilebesiran tied to potent dose-dependent reduction of BP: Topline phase 2 data

USA: In adults with hypertension, an investigational RNA interference agent targeting angiotensin, was shown to be associated with a clinically significant reduction in 24-hour mean systolic BP in a phase 2 trial. 

Topline data from the KARDIA-1 study showed that Zilebesiran was associated with a placebo-subtracted systolic BP reduction of greater than 15 mm Hg at 3 months with both the 300 mg and 600 mg doses, meeting the study’s primary endpoint.

Alnylam Pharmaceuticals, Inc. Nasdaq: ALNY), the leading RNAi therapeutics company, today announced that the KARDIA-1 Phase 2 study of zilebesiran, an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT) in development for the treatment of hypertension, met the primary endpoint demonstrating a dose-dependent, clinically significant reduction in 24-hour mean systolic blood pressure (SBP) measured by ambulatory blood pressure monitoring (ABPM) at Month 3, achieving a placebo-subtracted reduction greater than 15 mmHg (p less than 0.0001) with both 300 mg and 600 mg doses. The study also met key secondary endpoints including significant change in 24-hour mean SBP as measured by ABPM at Month 6, as well as a significant change in office SBP at Month 3 and Month 6, for all zilebesiran arms, compared to placebo. The study results indicate zilebesiran was associated with dose-dependent, potent and durable knockdown of serum AGT levels through Month 6. Zilebesiran also demonstrated an encouraging safety and tolerability profile that the company believes supports continued development. These findings of robust and tonic blood pressure control will help determine the optimal dose and regimen of zilebesiran for future studies.

“Hypertension is a growing global health crisis responsible for around 10 million deaths worldwide each year. Despite the availability of several classes of oral anti-hypertensive treatments, up to 80% of individuals globally remain uncontrolled, leaving them at an increased risk of cardiovascular, cerebrovascular and renal disease, which is further exacerbated by blood pressure variability, lack of nighttime blood pressure control and poor adherence,” 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. “As a physician, I believe these KARDIA-1 results, which demonstrate clinically significant reductions in systolic blood pressure of greater than 15 mmHg, along with the ability to achieve durable tonic blood pressure control, provide hope that we may one day have access to a novel therapy with the potential to address the significant unmet needs of patients with uncontrolled hypertension who are at high risk of future cardiovascular events.”

Zilebesiran demonstrated an encouraging safety and tolerability profile. There was one death due to cardiopulmonary arrest in a zilebesiran-treated patient that was considered unrelated to study drug. Serious adverse events were reported in 3.6% of zilebesiran-treated patients and 6.7% of placebo-treated patients. None were considered related to study drug. Adverse events occurring in 5% or more of zilebesiran-treated patients in any dose arm included COVID-19, injection site reaction (ISR), hyperkalemia, hypertension, upper respiratory tract infection, arthralgia and headache.

The KARDIA-1 Phase 2 trial is a randomized, double-blind (DB), placebo-controlled, multi-center global dose-ranging study designed to evaluate the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. The study enrolled 394 adults representing a diverse patient population with untreated hypertension or who were on stable therapy with one or more anti-hypertensive medications. Any patients taking prior anti-hypertensive medications completed at least a two- to four-week wash-out before randomization. Patients were randomized to one of five treatment arms during a 12-month DB period and DB extension period: 150 mg zilebesiran subcutaneously once every six months; 300 mg zilebesiran subcutaneously once every six months; 300 mg zilebesiran subcutaneously once every three months; 600 mg zilebesiran subcutaneously once every six months; or placebo. Patients who received placebo were randomized to one of the four initial zilebesiran dose regimens beginning at Month 6.

The primary endpoint is the change from baseline in SBP at Month 3, assessed by 24-hour ABPM. 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.

“We are thrilled that the KARDIA-1 Phase 2 results show zilebesiran’s ability to achieve sustained blood pressure reductions of greater than 15 mmHg, as well as long-term efficacy out to six months with infrequent dosing. We believe these results further validate the differentiated profile we observed in Phase 1. Moreover, they reinforce the potential for zilebesiran to be a transformative therapy to reduce cardiovascular risk in patients with hypertension and to offer new possibilities in a field of medicine that has seen limited innovation in nearly 20 years,” said Simon Fox, Ph.D., Vice President, Zilebesiran Program Lead at Alnylam. “We look forward to sharing the full KARDIA-1 results at an upcoming scientific conference and to reporting topline results from our KARDIA-2 Phase 2 study of zilebesiran in combination with one of three standard classes of anti-hypertensive medications in patients with mild-to-moderate hypertension in early 2024. It is a very exciting time for Alnylam, as these results build on the momentum from the recent strategic agreement to co-develop and co-commercialize zilebesiran with our collaboration partner, Roche, to potentially transform the landscape for patients with cardiovascular diseases.”

The KARDIA-2 Phase 2 study of zilebesiran used in combination with one of three standard classes of anti-hypertensive medications completed enrollment in June 2023. Topline results are expected in early 2024.

About Zilebesiran

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.

About Hypertension

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.i 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.

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 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.