Tonlamarsen Lowers Angiotensinogen, Minimal Effects on Blood Pressure, With Luke Laffin, MD

Monthly tonlamarsen successfully reduced plasma angiotensinogen compared with a single tonlamarsen dose in patients with uncontrolled hypertension, but led to no additional blood pressure reduction, according to data from the Kardinal study.1,2

These data were presented at the American College of Cardiology (ACC) Scientific Sessions 2026 in New Orleans, Louisiana, by Luke Laffin, MD, co-director of the Center for Blood Pressure Disorders, medical director of cardiac rehabilitation, and associate professor of medicine at Cleveland Clinic.

“It begs the question of whether you need that sustained angiotensinogen reduction to actually impact the pharmacodynamic marker of blood pressure long-term,” Laffin told HCPLive in an exclusive interview. “So how do we explain the changes in the angiotensinogen levels and the blood pressure levels in the study, which was not strictly placebo-controlled? We’ll have to establish that in future studies.”

Kardinal was a randomized, placebo-controlled trial investigating the safety and efficacy of 90 mg tonlamarsen delivered subcutaneously once a month for 5 months compared to a single dose of tonlamarsen and subsequent placebo. Patients were eligible for inclusion if they exhibited a systolic blood pressure >135 mmHg and were receiving 2-5 antihypertensive medications. Patients were excluded if they exhibited secondary causes of hypertension, an estimated glomerular filtration rate of <30 mL/min/1.73m2, or a serum potassium >5.1 mmol/L. The study included 2 primary endpoints – the between-group differences in change from baseline to week 20 in plasma angiotensinogen and in-office systolic blood pressure.2

The study consisted of a 4-week placebo lead-in, a 4-week active run-in with 1 dose of tonlamarsen, and subsequent randomization to 4 further doses of either tonlamarsen or matching placebo for 16 weeks. Following enrollment, 270 patients received placebo lead-in, 206 received 90mg of tonlamarsen during an active run-in period, and 198 were eventually randomized to receive either placebo or continuous tonlamarsen doses. Mean blood pressure among these randomized participants before and after lead-in was 147/90 mmHg and 147/89 mmHg, respectively.2

In the 20 weeks after the first dose of tonlamarsen, least squares (LS) mean percent change in plasma angiotensinogen levels were -23% (95% CI, -27.8 to 18.2) with a single dose and -67.2% (95% CI, -71.9 to -62.4) in patients receiving monthly doses, with a LS mean difference of -44.1% (97.5% CI, -51.9 to -36.4; P <.0001). LS mean changes in office systolic blood pressure were -6.7 mmHg (95% CI, -9.8 to -3.5) for patients receiving a single dose of tonlamarsen and subsequent placebo versus -6.7 mmHg (95% CI, -9.8 to -3.6) for those receiving monthly tonlamarsen, with a LS mean difference of -0.1 mmHg (95% CI, -4.5 to -4.4; P = .97).2

Ultimately, despite the successful angiotensinogen reductions, Laffin and colleagues also observed negligible differences in office systolic blood pressure between treatment arms. The team determined that further placebo-controlled trials are necessary to determine the efficacy of tonlamarsen, assessing either single or multi-dose tonlamarsen regimens.2

“The reason why new therapies for hypertension are so important is because, based on current guideline recommendations, less than 30% of Americans have their hypertension controlled,” Laffin said. “It’s great that we have a lot of generic options, but they’re not working for us right now. I think we need to think about different strategies, and I really believe that targeting angiotensinogen upstream is one such strategy that could be effective.”

Editors’ Note: Laffin reports disclosures with Medtronic, Novartis, Eli Lilly, Mineralys, Crispr Therapeutics, Idorsia, and others.

References

1. Laffin L, Sarraju A, Sclaich M, et al. Kardinal: A Phase 2 Study of Tonlamarsen for the Treatment of Uncontrolled Hypertension. Abstract presented at the American College of Cardiology Scientific Sessions 2026, New Orleans, LA. March 28-30, 2026.

2. Laffin L, Wang Q, Sarraju A, et al. Efficacy of Tonlamarsen in Patients with Uncontrolled Hypertension: The KARDINAL Phase 2 Randomized Clinical Trial. JACC. null2026, 0 (0). https://doi.org/10.1016/j.jacc.2026.03.034