Tonlamarsen Lowers Angiotensinogen in Patients With Uncontrolled Hypertension

The investigational drug tonlamarsen represents a new paradigm in the treatment of high blood pressure. The long-acting injectable drug is a nucleic acid-based therapeutic that suppresses production of angiotensinogen in the liver.

The breakdown of angiotensinogen is the first step in the renin-angiotensin-aldosterone system, a chemical cascade that regulates blood pressure. The more angiotensinogen upstream, the more vasoconstriction and higher blood pressure downstream.

“Uncontrolled hypertension remains a major issue worldwide,” says Luke Laffin, MD, co-Director of the Center for Blood Pressure Disorders at Cleveland Clinic. “Nonadherence to daily oral medication plays a role. Tonlamarsen, administered monthly as a subcutaneous injection, may offer an effective, longer acting alternative to oral medication.”

A recent phase 2 study has found that patients with uncontrolled hypertension receiving monthly injections of tonlamarsen recorded lower levels of plasma angiotensinogen than patients receiving only one injection of the drug over 20 weeks. However, the reduction in blood pressure was the same in both groups.

These were the key findings of a late-breaking clinical trial presented at the American College of Cardiology’s 2026 Scientific Session by Dr. Laffin, the study’s lead author. Study results were simultaneously published in the Journal of the American College of Cardiology.

Tonlamarsen vs. ACE inhibitors and ARBs

While this study was the first to assess tonlamarsen specifically, other investigational drugs targeting angiotensinogen production have been studied. Those drugs have shown reduced blood pressure in patients taking one or no antihypertensive medication. Tonlamarsen was studied in patients taking two or more antihypertensive medications.

Tonlamarsen and other angiotensinogen-inhibiting drugs work upstream in the renin-angiotensin-aldosterone system, Dr. Laffin explains. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) work on downstream components of that system.

“If you suppress angiotensinogen, theoretically you will have less downstream products and less increased blood pressure,” he says.

Over 20 weeks: One dose vs. five doses

In the multicenter trial of tonlamarsen, approximately 200 patients were randomized to receive either five monthly doses of tonlamarsen 90 mg (n = 100) or one monthly dose of tonlamarsen 90 mg followed by four monthly doses of placebo (n = 98). All patients received an injection of placebo one month before the first injection of tonlamarsen.

All patients were adults taking two to five antihypertensive medications. Eighty-two percent were taking an ACE inhibitor or ARB. Mean levels of plasma angiotensinogen and blood pressure were noted as follows:

Twenty weeks after the first tonlamarsen injection, the level of plasma angiotensinogen was reduced by a mean of 23% in patients who received one dose of tonlamarsen (95% CI, -27.8 to -18.2) and 67.2% in patients who received five doses (95% CI, -71.9 to -62.4).

Blood pressure was reduced by a mean of 6.7 mm Hg for patients who received one dose of tonlamarsen (95% CI, -9.8 to -3.5) and 6.7 mm Hg for patients who received five doses (95% CI, -9.8 to -3.6).

“Compared to a one-time injection, monthly injections of tonlamarsen were more effective at reducing angiotensinogen but not more effective at reducing blood pressure,” Dr. Laffin says. “That was an unanticipated finding.”

Possible explanations for the surprising results

There are three possible explanations for the surprising results, he says:

1. Monthly injections may lower blood pressure slightly more than a one-time injection, but that modest change was not detected in this study due to the small sample size.
2. Tonlamarsen provides similar blood pressure reduction regardless of dosing strategy because even a one-time dose “resets” the renin-angiotensin-aldosterone system.
3. Tonlamarsen actually has no effect on blood pressure. Findings of this study were merely regression to the mean.

“I think the third explanation is least likely,” Dr. Laffin says. “More likely, tonlamarsen does lower blood pressure, but patients may not need monthly doses because the effect is longer lasting and perhaps not directly correlated with angiotensinogen reduction. These findings will be valuable as we design future trials of angiotensinogen-targeted therapies.”

Adds Leslie Cho, MD, Section Head of Preventive Cardiology and Rehabilitation at Cleveland Clinic, “The surprising findings about the dose and the effect are very intriguing. Regardless, the future of chronic disease will be treatment like this — long-acting agents that patients can take on either a monthly or quarterly basis.”

Safety end points

The most common adverse event in the study was injection-site reaction, affecting 19 of the 100 patients receiving monthly tonlamarsen.

Use of the medication was not linked with hyperkalemia, hypotension, renal dysfunction or proteinuria in this study. Of note:

• No patients receiving monthly doses of tonlamarsen had hyperkalemia (serum potassium greater than 5.5 mmol/L), although two patients randomized to placebo did.
• Only one patient receiving monthly tonlamarsen had hypotension requiring emergent treatment.
• Three patients in each arm of the trial had renal dysfunction (decreased estimated glomerular filtration rate of more than 30% from baseline).
• Two patients in each arm of the trial had proteinuria (increased urine protein-creatinine ratio of more than 0.5 mg of protein per mg of creatinine from baseline).

Next steps in research

Future studies of tonlamarsen in patients with uncontrolled clinical hypertension are yet to be determined. The next study, beginning in April, will enroll patients with acute severe hypertension. These patients will be enrolled soon after their hospital discharge.

“We think tonlamarsen may be able to disrupt the overamplification of the renin-angiotensin-aldosterone system that is often present in patients with acute severe hypertension,” Dr. Laffin says. “This patient population does not have many treatment options to reduce their extremely high blood pressure and, therefore, extremely high cardiovascular risk. Currently we provide oral medications and advise patients to follow up with their primary care provider.”

The clinical trial reported here was funded by drug development company Kardigan.