Given as an injection every six months, zilebesiran suppresses the gene that produces a hormone called angiotensin that causes blood vessels to constrict. This contraction causes blood pressure to increase.
- A Phase 1 clinical trial is testing a new high blood pressure medication that is injected twice a year .
- Zilebesiran could replace or complement other high blood pressure treatments, researchers say
- Millions of Americans have high blood pressure, which is the leading risk factor for heart disease and stroke
Summary
Background
Angiotensinogen is the only precursor of angiotensin peptides and plays a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a long duration of action that inhibits hepatic angiotensinogen synthesis.
Methods
In this phase 1 study , patients with high blood pressure were randomly assigned in a 2:1 ratio to receive a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo. and were followed for 24 weeks (Part A).
Part B evaluated the effect of the 800 mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan.
Endpoints included safety, pharmacokinetic and pharmacodynamic characteristics, and change from baseline in systolic and diastolic blood pressure, measured by 24-hour ambulatory blood pressure monitoring.
Results
Of 107 patients enrolled, 5 had mild, transient injection site reactions. There were no reports of hypotension, hyperkalemia, or worsening renal function resulting in medical intervention.
In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that correlated with the dose administered (r = −0.56 at week 8; 95% confidence interval, −0.69 to − 0.39).
Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) at week 8; These changes were constant throughout the diurnal cycle and were maintained at 24 weeks.
The results of Parts B and E were consistent with an attenuated effect on blood pressure by a high-salt diet and an enhanced effect through coadministration with irbesartan, respectively.
Conclusions Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were maintained up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more. Mild injection site reactions were observed. |
(Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307. opens in new tab; EudraCT Number, 2019-000129-39. opens in new tab.)
