A monthly dose of the novel drug tonlamarsen significantly reduced plasma angiotensinogen (AGT) levels in patients with uncontrolled hypertension compared with a single dose of the drug followed by a placebo, but its impact on blood pressure was less clear, according to results from the KARDINAL trial presented at ACC.26 in New Orleans and simultaneously published in JACC.

The randomized, placebo-controlled trial enrolled 485 patients from 39 states in the U.S. who had SBP ≥135 mm Hg and were taking two to five antihypertensive medications. The mean age of patients was 61 years, 59% were men, 49% were Black, 33% had diabetes. The co-primary endpoints were the differences between patient groups in the change from baseline to week 20 in plasma AGT and office SBP.

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.

This was a significant between-group difference of 44.1% in favor of continuous tonlamarsen. Systolic blood pressure readings taken in the clinic, 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.

“We did not anticipate the finding that the percentage of angiotensinogen reduction didn’t necessarily correspond to blood pressure lowering 20 weeks out,” said Luke Laffin, MD, FACC, the study’s lead author. “This trial raises more questions than it gives answers at this point, but it gives us data that’s unique.”

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.”

A review of the safety endpoints showed that serious adverse events occurred in 2% of the patients in the tonlamarsen/placebo group and 5% of the tonlamarsen group.

Clinical Topics: Prevention, Novel Agents, Hypertension

Keywords: ACC Annual Scientific Session, ACC26, Angiotensinogen, Antihypertensive Agents, Blood Pressure, New Orleans, Oligonucleotides, Antisense, Injections, Subcutaneous, Hypertension