Zilebesiran lowers blood pressure in phase 1 trial
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Key takeaways:
- Zilebesiran lowered serum angiotensinogen levels and 24-hour ambulatory blood pressure for 24 weeks in a phase 1 trial.
- Additional clinical trials for the novel RNA interference agent are in progress.
Zilebesiran, a novel RNA interference agent, lowered serum angiotensinogen levels and 24-hour ambulatory blood pressure for 24 weeks, according to the results of a phase 1 trial.
“Hypertension is the leading cause of premature death, cardiovascular disease and chronic kidney disease worldwide, and the global prevalence is steadily increasing in parallel with population aging and secular trends in the prevalence of risk factors including obesity, physical inactivity, and unhealthy diet. Despite the availability of effective antihypertensive treatments, nearly half of patients with hypertension fail to achieve guideline-recommended blood pressure targets, leaving them at residual risk for myocardial infarction, stroke, kidney disease progression and mortality. For clinicians, the challenge in optimizing treatment of hypertension is frequently compounded by poor adherence to prescribed medical therapy and substantial variability in blood pressure between office visits and over the 24-hour cycle,” Akshay S. Desai, MD, MPH, director of the Cardiomyopathy and Heart Failure Program in the Advanced Heart Disease Section of the Cardiovascular Division at Brigham and Women’s Hospital, said in a press release.
Image: Adobe Stock
Zilebesiran’s pathway
Zilebesiran inhibits hepatic synthesis of angiotensinogen, which is a key precursor of angiotensin peptides and plays a role in the pathogenesis of hypertension, Desai and colleagues wrote in The New England Journal of Medicine.
For the phase 1 trial, the researchers randomly assigned 107 patients with hypertension (mean age, 54 years; 62% men) to receive a single ascending subcutaneous dose of zilebesiran (10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg or 800 mg) or placebo.
There were no cases of hypotension, hyperkalemia or worsening renal function requiring intervention, though five patients had mild injection-site reactions, Desai and colleagues wrote.
Patients receiving zilebesiran had reductions in serum angiotensinogen levels corresponding to their respective dose (r at week 8 = –0.56; 95% CI, –0.69 to –0.39), according to the researchers.
At 8 weeks, those who received a single dose of zilebesiran 200 mg or more had decreased systolic BP by –10 mm Hg and decreased diastolic BP by –5 mm Hg, and the reductions were sustained out to 24 weeks, the researchers wrote.
In a supplementary analysis, a low-salt diet plus zilebesiran 800 mg conferred a greater BP reduction than a low-salt diet alone, but a return to a high-salt diet attenuated the effects of both. In another analysis, patients whose systolic BP remained at least 120 mm Hg after 6 weeks of zilebesiran 800 mg were given irbesartan, and at 8 weeks, systolic BP declined –6.3 mm Hg and diastolic BP declined –3 mm Hg.
‘A potential role’
The data suggest a “potential role for zilebesiran to treat hypertension in a novel way via a novel, subcutaneously administered gene silencing approach to hypertension,” Desai said in the release. “This novel approach may provide durable, tonic blood pressure control with infrequent, office-based dosing and a favorable safety profile. Additional clinical trials will provide further insights into the potential of this approach to improve clinical outcomes in the growing population of patients with hypertension.”
Two phase 2 studies, KARDIA-1 and KARDIA-2, are underway, the researchers wrote.
Reference:
- Alnylam Pharmaceuticals. investors.alnylam.com/press-release?id=27601. Published July 19, 2023. Accessed July 20, 2023.
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