Monthly Tonlamarsen Reduces Angiotensinogen, But Not Blood Pressure

New data from the KARDINAL trial at ACC.26 provides insight, but raises questions regarding tonlamarsen and hypertension.

Mar. 28, 2026 at 9:48pm

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A phase 2 randomized trial at the American College of Cardiology's Annual Scientific Session (ACC.26) found that the investigational antisense oligonucleotide tonlamarsen produced significant, dose-dependent reductions in plasma angiotensinogen among adults with uncontrolled hypertension, but failed to demonstrate additional blood pressure lowering with continued monthly dosing compared to a single dose followed by placebo.

Why it matters

The trial results raise more questions than answers, as the continued decrease in blood pressure after a single dose of tonlamarsen was unexpected, and the percentage of angiotensinogen reduction did not necessarily correspond to blood pressure lowering. This highlights the complex relationship between angiotensinogen levels and blood pressure control.

The details

The KARDINAL trial was a multicenter, prospective, double-blind, placebo-controlled phase 2 trial that enrolled adults with uncontrolled hypertension on multiple antihypertensive medications. Participants received either 4 additional monthly doses of tonlamarsen or a single dose followed by placebo. While tonlamarsen demonstrated significant, dose-dependent reductions in plasma angiotensinogen, the change in office systolic blood pressure was identical between the two arms at week 20.

  • The KARDINAL trial was conducted between February and August 2025.
  • Participants received a single subcutaneous 90 mg dose of tonlamarsen during an active run-in period, followed by either 4 additional monthly doses or placebo for 16 weeks.

The players

Luke Laffin, MD

A cardiologist at Cleveland Clinic and the study's lead author.

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What they’re saying

“Because the drug was dosed monthly, we predicted that angiotensinogen would be fully back to its baseline levels by 20 weeks, but we found tonlamarsen's effect was much longer acting than we would have predicted. The continued decrease in blood pressure after a single dose surprised us.”

— Luke Laffin, MD, Cardiologist, Cleveland Clinic

“We also did not anticipate the finding that the percentage of angiotensinogen reduction didn't necessarily correspond to blood pressure lowering 20 weeks out. This trial raises more questions than it gives answers at this point, but it gives us data that's unique.”

— Luke Laffin, MD, Cardiologist, Cleveland Clinic

What’s next

Future trials should include a true placebo group without a tonlamarsen run-in to better evaluate the true magnitude of blood pressure reduction.

The takeaway

The KARDINAL trial results highlight the complex relationship between angiotensinogen levels and blood pressure control, raising more questions than answers about the potential of tonlamarsen as a hypertension treatment.