Investigational drug lowers angiotensinogen but shows unclear blood pressure benefits

The investigational drug tonlamarsen—which is designed to lower blood pressure by reducing the production of angiotensinogen, a protein that turns into the hormone that regulates blood pressure—caused a significant and sustained drop in angiotensinogen but its impact on blood pressure was less clear, according to a study presented at the American College of Cardiology's Annual Scientific Session (ACC.26).

High blood pressure, also known as hypertension, damages blood vessels and contributes to cardiovascular disease, dementia and other health problems, yet about half of U.S. adults have uncontrolled hypertension. Tonlamarsen is one of several therapies being developed to help patients who still have hypertension despite being on multiple blood pressure lowering medications.

Administered as a monthly injection, tonlamarsen suppresses angiotensinogen, a precursor involved in the production of angiotensin. The Phase 2 trial enrolled 206 patients at 39 U.S. sites who had baseline systolic blood pressure between 135 mmHg-170 mmHg, with an average of 147 mmHg, despite taking two to five blood pressure lowering medications. The average age of participants was 61 years, about half were Black or African American and 41% were female.

After receiving an initial placebo injection, all participants received one dose of tonlamarsen at the start of the trial (week 0). For the four monthly injections from weeks four to 20, half of the participants were randomized to receive tonlamarsen and half placebo.

At 20 weeks, angiotensinogen levels had dropped by 67.2% from baseline, on average, among those who continued taking tonlamarsen and by 23% among those who switched to placebo—one of the study's two primary endpoints. This was a significant between-group difference of 44.1% in favor of continuous tonlamarsen.

Systolic blood pressure readings taken in the clinic, the study's other primary endpoint, dropped by 6.7 mmHg, on average, across both study groups. This decrease occurred after the first dose of tonlamarsen was administered to all participants and was sustained in both study groups at week 20, with no significant between-group difference at this time point. There were also no significant differences in secondary blood pressure outcomes including change in blood pressure measured at home or the percentage of participants achieving target blood pressure levels.

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. 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 at Cleveland Clinic and study's lead author

Researchers attribute the mixed results to an unexpectedly long-lasting impact of the drug, which was administered to all study participants at the start of the trial. Four weeks after receiving an initial dose of tonlamarsen, half of the participants switched to a placebo for the remaining 16 weeks, while half continued to receive tonlamarsen. However, the specific drivers behind the mixed findings are not known, although researchers identified several possible explanations.

"One possibility, which we think is most likely, is that tonlamarsen lowers blood pressure by about 6-7 mmHg, and this is maintained even as angiotensinogen levels rise," Laffin said. "Another possibility is that residual angiotensin suppression among placebo participants resulted in greater blood pressure reduction than expected. It's also possible that decreasing angiotensin with tonlamarsen doesn't reduce blood pressure, although we think that's probably not likely based on the fact that blood pressure dropped during the drug run-in period."

Participants randomized to continue tonlamarsen experienced a higher rate of injection-site reactions, which was expected since these participants were receiving drug injections rather than a placebo.

In addition to the unanticipated prolonged suppression of angiotensinogen, Laffin said that the study was relatively small and did not assess cardiovascular outcomes. Researchers are planning a separate study to assess the use of a short course of tonlamarsen in patients with acute severe hypertension.

The study was funded by Kardigan, maker of tonlamarsen.

This study was simultaneously published online in JACC at the time of presentation.

Laffin will present the study, "Kardinal: A Phase 2 Study of Tonlamarsen for the Treatment of Uncontrolled Hypertension," on Saturday, March 28, at 3:45 p.m. CT / 20:45 UTC in the Main Tent, Great Hall.