A monthly dose of the novel drug tonlamarsen significantly reduced plasma angiotensinogen (AGT) levels compared to a single dose of the drug followed by a placebo, but no reduction in systolic blood pressure (SBP) was observed in patients with uncontrolled hypertension, according to the phase 2 KARDINAL trial presented during a Late-Breaking Clinical Trial session at ACC.26 in New Orleans and simultaneously published in JACC.

The trial was designed to evaluate the efficacy of tonlamarsen, an investigational antisense oligonucleotide-targeting hepatic AGT synthesis in patients with uncontrolled hypertension who were taking two to five antihypertensive medications. The co-primary endpoints were the differences between patient groups in the change from baseline to week 20 in plasma AGT and office SBP.

The randomized, placebo-controlled trial enrolled 485 patients with SBP ≥135 mm Hg at 39 sites in the U.S. from February through August 2025, with 279 given a placebo lead-in in Part A and 206 given a single 90 mg subcutaneous injection of tonlamarsen in Part B. The most common reason for patient ineligibility for Part B was having an office SBP <135 mm Hg.

Four weeks after the injection, 100 patients were randomized to receive 90 mg of tonlamarsen every four weeks for 16 weeks (tonlamarsen group) and 98 were randomized to receive a placebo (tonlamarsen). The mean age of patients was 61 years, 59% were men, 49% were Black, 33% had diabetes and 11% had an eGFR <60 mL/min/1.732.

Among patients in the tonlamarsen group, plasma AGT levels were reduced by 67% from baseline, vs. 23% in patients in the tonlamarsen/placebo group. Both groups had a reduction of 6.7 mm Hg in office SBP at 20 weeks. In addition, patients receiving tonlamarsen for 20 weeks did not achieve an office SBP of <130 mm Hg more frequently than those who received the placebo.

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.

“Although there was a significant difference in percent AGT lowering between treatment groups, 20 weeks following a single dose of tonlamarsen there was still a mean reduction of 23% from baseline in serum AGT levels,” write Luke J. Laffin, MD, FACC; Steven E. Nissen, MD, MACC, et al. “The prolonged and unanticipated AGT reduction among participants who received a single dose of tonlamarsen necessitates additional placebo-controlled trials assessing single or multi-dose tonlamarsen regimens.”

Clinical Topics: Prevention, Novel Agents, Hypertension

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