Zilebesiran is being evaluated as a monotherapy in the KARDIA-1 study and as a combination therapy in KARDIA-2, which will report topline data in early 2024.
Alnylam Pharmaceuticals has announced that its KARDIA-1 phase 2 trial (NCT04936035) of zilebesiran RNA interference (RNAi) therapy has met its primary endpoint of significantly reducing 4-hour mean systolic blood pressure (SBP) at month 3 in participants with hypertension and high cardiovascular risk.
“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,” George L. Bakris, MD, Board-Certified Hypertension Specialist and Director of the American Heart Association Comprehensive Hypertension Center, and professor, University of Chicago Medicine, said in a statement. “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 is an investigational RNAi therapeutic targeting liver-expressed angiotensinogen (AGT). KARDIA-1 is a randomized, double-blind, multicenter, placebo-controlled international trial evaluating zilebesiranmonotherapy to treat hypertension in 394 adults with high cardiovascular risk, untreated hypertension or who were on stable therapy with 1 or more anti-hypertensive medications.
Patients taking prior anti-hypertensive medications completed at least a 2-4-week wash-out before randomization. The participants were randomized to 1of 5 treatment arms during a 12-month double-blind (DB) period and DB extension period to receive either 150 mg zilebesiran subcutaneously once every 6 months; 300 mg zilebesiran subcutaneously once every 6 months; 300 mg zilebesiran subcutaneously once every 3 months; 600 mg zilebesiran subcutaneously once every 6 months; or placebo. Patients in the placebo arm were randomized to an experimental dose arm starting at month 6.
Investigators found that zilebesiran resulted in a dose-dependent, clinically significant reduction in 24-hour mean SBP measured by ambulatory blood pressure monitoring (ABPM) at Month 3, achieving a placebo-subtracted reduction greater than 15 mmHg (P <.0001) in both the 300 mg and 600 mg dose arms. KARDIA-1 also met secondary endpoints including significant change in 24-hour mean SBP as measured by ABPM at Month 6 and significant change in office SBP at Month 3 and Month 6 compared to placebo in all dose arms. Zilebesiran was associated with dose-dependent, potent and durable knockdown of serum angiotensinogen levels through Month 6. Other endpoints include additional measures of blood pressure reduction at 6 months, time-adjusted change in blood pressure, and change in daytime average and night-time average blood pressure.
Zilebesiran has shown a manageable safety and tolerability profile, with 1 death due to cardiopulmonary arrest in a treated patient considered unrelated to the therapy. Serious adverse events were reported in 3.6% of zilebesiran-treated patients and 6.7% of placebo-treated patients, none of which were considered related to study drug. Adverse events including COVID-19, injection site reaction, hyperkalemia, hypertension, upper respiratory tract infection, arthralgia and headache occurred in over 5% of treated patients.
Zilebesiran is also being evaluated in the KARDIA-2 phase 2 trial (NCT05103332) for the same indicationin combination with 1 of 3 standard classes of anti-hypertensive medications. The study completed enrollment in June 2023 and topline results are expected in early 2024.
“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 6 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,” Simon Fox, PhD, Vice President, Zilebesiran Program Lead, Alnylam, added. “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... 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.”