Tonlamarsen Produces Persistent, Long-Term Angiotensin and BP Improvements

Tonlamarsen treatment resulted in persistent and long-term reductions in angiotensin and blood pressure (BP) after withdrawal, according to a secondary analysis of the KARDINAL trial.1

These data were presented at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, by Luke Laffin, MD, medical director of the Cleveland Clinic Coordinating Center for Clinical Research and lead investigator in the original KARDINAL trial.1

“This is important because these are data to support that cardiovascular risk can be predicted by how high your blood pressure goes at a single time, not just on an ongoing basis,” Laffin told HCPLive in an exclusive interview. “What this really does is set the stage for our next trial, which is ongoing and enrolling right now – KARDINAL-ASH, which is for acute severe hypertension.”

KARDINAL was a multicenter, prospective, randomized, active run-in, double-blind, placebo-controlled phase 2 trial conducted across 39 sites in the US. Eligible patients were ≥18 years old, were receiving stable doses of 2 to 5 antihypertensive medications, and had an office systolic BP between 135 and 170 mmHg. Patients with known secondary causes of hypertension or serum potassium >5.1 mmol/L, among other criteria, were excluded.2

The study’s coprimary endpoints included the percent change from baseline to week 20 in plasma angiotensin levels and the change in office systolic BP among patients receiving monthly tonlamarsen treatment, both compared with a single dose and subsequent placebo. Key secondary endpoints included the proportion of patients with systolic in-office BP <130 mmHg, change from baseline in mean self-assessed home systolic BP, and the change from baseline in mean office systolic BP, among others.2

Patients were first given a single 90-mg dose of tonlamarsen subcutaneously during an active run-in period before being randomly assigned in a 1:1 ratio to 4 doses of tonlamarsen or matching placebo for the next 16 weeks. A total of 519 patients were initially screened, and 279 were administered placebo lead-in. A total of 206 received active run-in with a single dose of tonlamarsen, and a final total of 198 patients were randomized to either placebo (n = 98) or tonlamarsen (n = 100). At enrollment, 118 patients (60%) were taking a 2-drug antihypertensive regimen, while others were taking ≥3 drugs.2

By week 20, the least squares mean percentage change in plasma angiotensin from baseline in patients treated with a single dose and then randomized to placebo was -23% (95% CI, -27.8% to -18.2%). Among patients treated with 20 weeks of tonlamarsen, angiotensin changed by -67.2% (95% CI, -71.9% to -62.4%). Change in office systolic BP in the single-dose arm was -6.7 mmHg (95% CI, -9.8 to -3.5 mmHg), while the change in the full treatment arm was -6.7 mmHg (97.5% CI, -51.9% to -36.4%; P <.0001).2

This secondary analysis extended both angiotensin and office BP measurements through 28 weeks, acting as a safety follow-up, as well as evaluating home BP time-in-target range (TTR) and incidence of markedly elevated home BP. Over this 28-week period, the placebo arm saw a reduction in angiotensin of 23.8%, while the treatment arm saw a 44% reduction. Office systolic BP also dropped by a mean of -7.1 mmHg in the placebo arm and -6.1 mmHg in the treatment arm.1

Additionally, the percentage of home systolic BP TTR <140 mmHg was 75% with tonlamarsen and 67% without during this extended follow-up period (difference, -8; 95% CI, -22.9 to 7). The percent of home systolic BP TTR from 110 to 130 mmHg was 39% with tonlamarsen and 34% with placebo (difference, -4.7; 95% CI, -18.7 to 9.2).1

Ultimately, Laffin and colleagues concluded that the analysis further underscores tonlamarsen’s efficacy and safety, highlighting the persistence of effect after an extended period post-treatment. Laffin also notes that these data pave the way for the next stage of trials, namely the KARDINAL-ASH trial, which is currently enrolling.1

“Home blood pressure is really where we have to be able to generate evidence,” Laffin said. “We know that patients do it, and we have new technologies to measure blood pressure. Office blood pressure is a fine surrogate for cardiovascular outcomes, but we get a much higher fidelity of data, and really more informative data, if we can see home blood pressure reductions.”

Editors’ Note: Laffin reports relevant disclosures with AstraZeneca, Arrowhead, Medtronic, Eli Lilly, Mineralys, Crispr Therapeutics, Novartis, Novo Nordisk, and others.

References

1. Laffin L. Extended Follow-Up of the KARDINAL Trial Assessing the Effect of Tonlamarsen in Uncontrolled Hypertension. Presented at the European Society of Cardiology (ESC) Congress 2026, Munich, Germany. August 28-31, 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. 2026 May, 87 (18) 2508–2520. https://doi.org/10.1016/j.jacc.2026.03.034