Over 1.3 billion people worldwide have hypertension, and nearly half fail to reach the target blood pressure despite multiple daily drugs. ACE inhibitors and ARBs block the Renin–Angiotensin–Aldosterone System (RAAS) downstream, but long-term control is limited by compensatory activation, hyperkalemia, renal effects, and poor adherence.
A newer strategy targets the system at its source by silencing hepatic angiotensinogen, the sole precursor of all angiotensin peptides. By reducing angiotensin I and II upstream, this approach may provide more stable and sustained BP control with fewer escape mechanisms.
Zilebesiran, developed by Alnylam Pharmaceuticals, is a GalNAc-conjugated siRNA targeting AGT mRNA in hepatocytes. In trials, a single subcutaneous dose every 3–6 months achieved >90% AGT reduction and systolic BP lowering up to 20 mmHg, with consistent 24-hour control in the KARDIA phase 2 program and only mild, transient hyperkalemia. A major partnership with Roche supports its projected 2030 launch.
Meanwhile, Ionis Pharmaceuticals developed antisense therapies: evazarsen required weekly dosing with modest BP reduction, while Tonlamarsen offers stronger suppression with monthly or bi-monthly dosing, though zilebesiran leads in durability.
Long-term cardiovascular outcomes, safety, cost, and reversibility remain to be proven. If phase 3 confirms these findings, hypertension care could shift from daily pills to infrequent gene-silencing injections, a true paradigm shift in RAAS modulation.
Hypertension Treatment With One Shot Every Six Months | BioPharma.News
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