New data from the KARDINAL trial at ACC.26 provides insight, but raises questions regarding tonlamarsen and hypertension.
A phase 2 randomized trial at the
Simultaneously published in the Journal of the American College of Cardiology, results demonstrate the investigational antisense oligonucleotide produced significant, dose-dependent reductions in plasma angiotensinogen among adults with uncontrolled hypertension on multiple antihypertensive medications, but failed to demonstrate additional blood pressure lowering with continued monthly dosing compared with a single dose followed by placebo.
“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,” said Luke Laffin, MD, a cardiologist at Cleveland Clinic and the study’s lead author. “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.”
KARDINAL was a multicenter, prospective, double-blind, placebo-controlled phase 2 trial conducted at 39 US sites between February and August 2025. The trial enrolled adults aged 18 years or older with office systolic blood pressure between 135 and 170 mmHg who were receiving stable doses of 2 to 5 antihypertensive agents. Key exclusion criteria included secondary hypertension, estimated glomerular filtration rate below 30 mL/min/1.73 m², and serum potassium greater than 5.1 mmol/L.
Following a 4-week placebo lead-in, all eligible participants received a single subcutaneous 90 mg dose of tonlamarsen during an active run-in period. Participants were then randomized 1:1 to either 4 additional monthly doses of tonlamarsen or matching placebo for 16 weeks.
Of 519 patients screened, 206 received the active run-in dose and 198 were ultimately randomized: 100 to ongoing monthly tonlamarsen and 98 to single-dose tonlamarsen followed by placebo.
The overall study cohort had a mean age of 61 years, 49% were Black, 41% were female, and 82% were receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) at baseline. The mean baseline office systolic blood pressure of the cohort was approximately 147 mmHg.
The coprimary endpoints were the between-group differences in percent change from baseline in plasma angiotensinogen and change in office systolic blood pressure at week 20.
At week 20, participants receiving monthly tonlamarsen demonstrated a least-squares (LS) mean reduction in plasma angiotensinogen of 67.2% (95% CI, -71.9 to -62.4) compared with 23.0% (95% CI, -27.8 to -18.2) among those receiving a single dose followed by placebo, a statistically significant between-group difference of -44.1% (97.5% CI, -51.9 to -36.4; P <.0001).
However, the change in office systolic blood pressure was identical between arms at week 20. Specifically, a reduction of -6.7 mmHg was observed in both groups, yielding a between-group difference of -0.1 mmHg (95% CI, -4.5 to 4.4; P = .97). No significant between-group differences were observed in home systolic blood pressure, office diastolic blood pressure, or proportion of participants achieving a systolic blood pressure below 130 mmHg.
The investigators noted the 23% residual suppression of angiotensinogen observed at week 20 in participants who received only 1 dose was unexpected given tonlamarsen's elimination half-life of 2 to 4 weeks. The persistence of angiotensinogen suppression in the placebo arm may have introduced a carryover effect confounded the blood pressure comparison between arms.
“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 added. “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.”
Serious adverse events were infrequent and occurred in 2.1% of single-dose participants and 5.0% of those receiving ongoing tonlamarsen. A single death occurred in the monthly dosing arm and was assessed as unrelated to study drug by the site investigator. Injection site reactions were more common with multiple doses (19% vs 3%).
Trial investigators called attention to multiple limitations, including its active run-in design, which precluded a clean placebo comparator for assessing the true magnitude of blood pressure reduction. Additional limitations highlighted by investigators included its restriction to US sites, which may limit generalizability, and its modest sample size and short duration, which were insufficient to evaluate cardiovascular outcomes. Investigators suggested future trials should include a true placebo group without a tonlamarsen run-in.
