At the 2026 American College of Cardiology (ACC) Scientific Session in New Orleans, the KARDINAL phase II trial assessed tonlamarsen, an investigational antisense medicine that lowers angiotensinogen, in adults with uncontrolled hypertension on multiple drugs. The study compared the effect of one dose versus repeated monthly dosing on blood pressure and a key blood marker.
High blood pressure that remains above target despite several medicines continues to drive heart attack, stroke, and kidney disease. Many current treatment options act on the renin–angiotensin–aldosterone system, which is one of the main hormone systems that regulates blood pressure. Tonlamarsen is designed to work higher up in this system by reducing production of angiotensinogen in the liver.
The trial enrolled adults with office systolic blood pressure above 135 mm Hg who were taking two to five antihypertensive medicines. All participants first received placebo, then a single 90 mg dose of tonlamarsen, and were finally randomized to either four additional monthly doses of tonlamarsen or matching placebo for 16 weeks. The main outcomes were changes by Week 20 in plasma angiotensinogen levels and office systolic blood pressure.
In total, 279 people received the placebo lead-in, 206 received tonlamarsen in the active run-in, and 198 were randomized. Mean blood pressure stayed at 147/90–89 mm Hg through the placebo phase and fell to 140/87 mm Hg after the single dose of tonlamarsen. At Week 20, angiotensinogen levels were still 23% lower than baseline in the group that received only the single dose and then placebo, compared with a 67.2% reduction in the group that continued monthly tonlamarsen. Serious adverse events were uncommon and similar between the two arms.
However, this clear difference in the blood marker did not translate into extra blood pressure benefit. Both groups had the same least squares mean reduction in office systolic blood pressure of 6.7 mm Hg at Week 20, and there was no meaningful difference between continued monthly dosing and a single dose. For an approach aimed at a key upstream step in the blood pressure pathway, the lack of added blood pressure lowering with repeated dosing is a notable limitation of the current regimen.
Experts are expected to view KARDINAL as showing strong target engagement for tonlamarsen but not yet delivering the level of blood pressure effect needed to change clinical practice. Discussions among KOLs are likely to focus on why sustained angiotensinogen lowering did not lead to more blood pressure reduction and whether different doses, schedules, or patient selection could close this gap.
From a strategy perspective, these results keep tonlamarsen in an exploratory phase rather than positioning it as a near-term option for resistant hypertension. The long-lasting fall in angiotensinogen after a single dose could support future trials of less frequent dosing, but without clearer blood pressure gains, payers and physicians are unlikely to prioritize an injectable therapy over established, inexpensive oral RAAS blockers.
Looking ahead, new placebo-controlled studies that test alternative dosing strategies, longer follow-up, and more carefully selected patient groups will be needed to determine whether tonlamarsen can deliver a stronger and more durable blood pressure effect. If future data still show a disconnect between biomarker and blood pressure outcomes, the main impact of this program may be to guide how antisense approaches to the RAAS pathway are developed rather than to add a new treatment option for uncontrolled hypertension.
