Efficacy of Tonlamarsen in Patients With Uncontrolled Hypertension: The KARDINAL Phase 2 Randomized Clinical Trial

Clinical Snapshot

Key Findings

• P Value: P = 0.97 for blood pressure difference

• Effect Size: No clinically significant difference in blood pressure between treatment arms

• Primary Outcome: Monthly tonlamarsen reduced plasma angiotensinogen by 67.2% vs 23.0% with single dose (difference -44.1%, P<0.0001), but no difference in systolic BP reduction (-6.7 mmHg both groups)

• Nnt Or Sensitivity: Not applicable - no clinical benefit demonstrated

• Confidence Interval: BP difference: -0.1 mmHg (95% CI: -4.5 to 4.4 mmHg)

Clinical Application

Monthly subcutaneous injections would be challenging to implement in routine practice Would require TGA approval as novel antisense oligonucleotide; unlikely to receive PBS listing without demonstrated clinical benefit over existing therapies Adults with uncontrolled hypertension on multiple antihypertensive medications

Abstract

BACKGROUND: Angiotensinogen production represents the rate-limiting step in activation of the renin-angiotensin-aldosterone system. Tonlamarsen is an investigational antisense oligonucleotide directed against hepatic angiotensinogen synthesis; its efficacy and safety among patients with hypertension are unknown. OBJECTIVES: The aim of this study was to assess the safety and efficacy of 90 mg tonlamarsen administered subcutaneously once monthly for 5 months compared with a single dose of tonlamarsen and subsequent placebo. METHODS: This randomized, placebo-controlled trial enrolled adults with office systolic blood pressure (BP) >135 mm Hg receiving 2 to 5 antihypertensive medications. Participants entered a 3-part treatment period with monthly administration of the study drug, consisting of a 4-week placebo lead-in, followed by 4-week active run-in with a single dose of tonlamarsen and subsequent randomization to 4 additional doses of tonlamarsen or matching placebo for 16 weeks. The coprimary endpoints were the between-group differences in the change from baseline to week 20 in plasma angiotensinogen and in office systolic BP. RESULTS: A total of 279 participants received placebo lead-in, 206 received 90 mg tonlamarsen during the active run-in, and 198 were randomized. The mean BP among randomized participants before and after the placebo lead-in was 147/90 and 147/89 mm Hg, respectively. Following active run-in with tonlamarsen, the mean BP was 140/87 mm Hg. Twenty weeks following the first dose of tonlamarsen, least squares (LS) mean percentage changes in plasma angiotensinogen levels were -23.0% (95% CI: -27.8% to -18.2%) with a single dose of tonlamarsen and subsequent placebo and -67.2% (95% CI: -71.9% to -62.4%) with monthly tonlamarsen administration, with a LS mean difference of -44.1% (97.5% CI: -51.9% to -36.4%; P < 0.0001). The LS mean changes in office systolic BP were -6.7 mm Hg (95% CI: -9.8 to -3.5 mm Hg) for participants following a single dose of tonlamarsen and subsequent placebo and -6.7 mm Hg (95% CI: -9.8 to -3.6 mm Hg) for participants treated with monthly tonlamarsen, with a LS mean difference of -0.1 mm Hg (95% CI: -4.5 to -4.4 mm Hg; P = 0.97). Serious adverse events were infrequent and similar between treatment groups. CONCLUSIONS: Among individuals with uncontrolled hypertension, monthly tonlamarsen administration was more effective at lowering plasma angiotensinogen compared with a single tonlamarsen dose, but there was no additional BP reduction. (A Study to Investigate Tonlamarsen for the Treatment of Adults With Uncontrolled Hypertension [KARDINAL]; NCT06864104).

References

1. 1.Laffin, L. J., Wang, Q., Sarraju, A., Touyz, R. M., Schlaich, M. P., Cohen, D. L., Mahfoud, F., Mitchell, L. M., Mitchell, J., Wolski, K., Dennis, P., Akere, A., Li, W., Chen, G., Cohen, Y. Z., Kim, J., Cooper, C. G., Ramesan, P., Edelberg, J. M., & Nissen, S. E. (2026). Efficacy of Tonlamarsen in Patients With Uncontrolled Hypertension: The KARDINAL Phase 2 Randomized Clinical Trial. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2026.03.034