Topline phase 2 data show potent, dose-dependent BP reduction with zilebesiran
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Key takeaways:
- Zilebesiran was associated with a significant reduction in 24-hour mean systolic BP at 3 months compared with placebo.
- Data from the KARDIA-1 study also showed a durable reduction in systolic BP at 6 months.
An investigational RNA interference agent targeting angiotensin demonstrated a dose-dependent, clinically significant reduction in 24-hour mean systolic BP in adults with hypertension in a phase 2 trial, according to a press release.
Topline data from the KARDIA-1 study show that zilebesiran (Alnylam), an investigational RNAi therapeutic targeting liver-expressed angiotensinogen in development for the treatment of hypertension, was associated with a placebo-subtracted systolic BP reduction of greater than 15 mm Hg at 3 months (P < .0001) with both the 300 mg and 600 mg doses, meeting the study’s primary endpoint.
The study also met key secondary endpoints, including significant change in 24-hour mean systolic BP as measured by ambulatory BP monitoring at 6 months, as well as significant change in office systolic BP at 3 and 6 months for all zilebesiran arms compared with placebo.
The study results indicate zilebesiran was associated with dose-dependent, potent and durable knockdown of serum angiotensin levels through 6 months, according to the release.
“Despite the availability of several classes of oral antihypertensive treatments, up to 80% of individuals globally remain uncontrolled, leaving them at an increased risk of CV, cerebrovascular and renal disease, which is further exacerbated by BP variability, lack of nighttime BP control and poor adherence,” Healio | Cardiology Today Editorial Board Member George L. Bakris, MD, FAHA, FASN, professor of medicine and director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago Medicine, said in the release. “As a physician, I believe these KARDIA-1 results, which demonstrate clinically significant reductions in systolic BP of greater than 15 mm Hg, along with the ability to achieve durable tonic BP 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 CV events.”
As Healio previously reported, a phase 1 study showed zilebesiran lowered systolic BP by 7 mm Hg to 9 mm Hg compared with placebo in patients already on triple therapy.
In the release, Alnylam stated that 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. There were fewer serious adverse events reported in the zilebesiran vs. placebo groups (3.6% vs. 6.7%), with none 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, hyperkalemia, hypertension, upper respiratory tract infection, arthralgia and headache.
Researchers designed the KARDIA-1 trial as a dose-ranging study to evaluate the efficacy and safety of zilebesiran as monotherapy in adults with mild-to-moderate hypertension. The study included 394 adults with untreated hypertension or who were on stable therapy with one or more antihypertensive medications. Any patients taking prior antihypertensive medications completed at least a 2- to 4-week washout period before randomization. Researchers randomly assigned participants to one of five treatment arms: 150 mg zilebesiran once every 6 months; 300 mg zilebesiran once every 6 months; 300 mg zilebesiran once every 3 months; 600 mg zilebesiran once every 6 months; or placebo. Patients who received placebo were randomly assigned to one of the four initial zilebesiran dose regimens beginning at month 6.
The primary endpoint is the change from baseline in systolic BP at month 3, assessed by 24-hour ABPM. Key secondary and exploratory endpoints in this study include additional measures of BP reduction at 6 months, time-adjusted change in BP and change in daytime average and nighttime average BP.
“We are thrilled that the KARDIA-1 phase 2 results show zilebesiran’s ability to achieve sustained blood pressure reductions of greater than 15 mm Hg, as well as long-term efficacy out to 6 months with infrequent dosing,” Simon Fox, PhD, vice president, Zilebesiran Program Lead at Alnylam, said in the release. “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 CV risk in patients with hypertension and to offer new possibilities in a field of medicine that has seen limited innovation in nearly 20 years.”
The full results of KARDIA-1 will be presented at an upcoming conference, according to the release.
The KARDIA-2 Phase 2 study of zilebesiran used in combination with one of three standard classes of antihypertensive medications completed enrollment in June 2023, according to the release. Topline results are expected in early 2024.
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