Clinical Context

Angiotensinogen production is the rate-limiting step in activation of the renin-angiotensin-aldosterone system (RAAS), a central pathway in hypertension. Tonlamarsen is an investigational antisense oligonucleotide designed to reduce hepatic angiotensinogen synthesis.

The KARDINAL trial evaluated whether monthly subcutaneous tonlamarsen could safely lower plasma angiotensinogen and improve BP control in adults with uncontrolled hypertension receiving multiple antihypertensive medications.

Study Design

KARDINAL was a multicenter, prospective, randomized, active run-in, double-blind, placebo-controlled phase 2 trial conducted at 39 sites in the United States.

Adults with office systolic BP >135 mm Hg who were receiving 2 to 5 antihypertensive medications were enrolled. The treatment period included a 4-week placebo lead-in, followed by a 4-week active run-in with one 90-mg subcutaneous dose of tonlamarsen. Eligible participants were then randomized to 4 additional monthly doses of tonlamarsen or matching placebo through week 20.

A total of 279 participants received placebo lead-in, 206 received active run-in with tonlamarsen, and 198 were randomized. The mean age was 61 years, 59% were men, 33% had diabetes, 49% were Black, and 82% were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at randomization.

Key Findings

Before placebo lead-in, mean office BP among randomized participants was 147/90 mm Hg. After placebo lead-in, mean BP remained similar at 147/89 mm Hg. Four weeks after the first tonlamarsen dose, mean BP decreased to 140/87 mm Hg.

At week 20, monthly tonlamarsen produced substantially greater plasma angiotensinogen reduction than a single dose followed by placebo. Least squares mean angiotensinogen change was −67.2% with monthly tonlamarsen and −23.0% with single-dose tonlamarsen followed by placebo. The between-group difference was −44.1% (97.5% confidence interval [CI]: −51.9% to −36.4%; P < 0.0001).

Despite this greater angiotensinogen suppression, office systolic BP lowering was identical between groups. Least squares mean office systolic BP change was −6.7 mm Hg in both the monthly tonlamarsen group and the single-dose followed by placebo group. The between-group difference was −0.1 mm Hg (95% CI: −4.5 to 4.4 mm Hg; P = 0.97).

Secondary BP outcomes showed no clear additional benefit with ongoing tonlamarsen. Office systolic BP <130 mm Hg was achieved by 26% with monthly tonlamarsen and 23% with single-dose tonlamarsen followed by placebo. Home systolic BP changed by −0.3 mm Hg with monthly tonlamarsen and increased by 2.8 mm Hg in the comparator group, with a between-group difference of −3.1 mm Hg (95% CI: −6.6 to 0.4 mm Hg).

Safety Profile

Serious adverse events were infrequent. They occurred in 5.0% of participants receiving ongoing tonlamarsen and 2.1% of those receiving a single dose followed by placebo.

Hyperkalemia, defined as serum potassium >5.5 mmol/L, occurred in 2 participants in the single-dose followed by placebo group and in no participants receiving ongoing tonlamarsen. Injection-site reactions were more frequent with ongoing tonlamarsen.

One death occurred in the ongoing tonlamarsen group and was considered unrelated to study drug by the site investigator.

Study Limitations

The active run-in design limited interpretation because a single 90-mg dose of tonlamarsen caused unexpectedly prolonged angiotensinogen suppression. At week 20, plasma angiotensinogen remained 23% below baseline in the group that received only one tonlamarsen dose followed by placebo.

The trial was conducted only in the United States, which may limit generalizability. The sample size and follow-up duration were also insufficient to assess cardiovascular outcomes.

Clinical Perspective

Monthly tonlamarsen achieved greater and sustained angiotensinogen suppression, confirming pharmacologic target engagement. However, this did not translate into additional office systolic BP reduction compared with a single dose followed by placebo.

The findings suggest that future trials should compare tonlamarsen directly against placebo without an active run-in phase to clarify the magnitude and durability of BP lowering with single-dose and multidose regimens.

Key Takeaway

In KARDINAL, monthly tonlamarsen lowered plasma angiotensinogen more than a single dose followed by placebo, but did not provide additional office systolic BP reduction at week 20.

Author

Manjusha Shetty is Senior Editor at MedApt, a physician-focused platform covering clinical updates, congress insights, and expert perspectives