Angiotensinogen plays a rate-limiting role in activation of the renin–angiotensin–aldosterone system (RAAS). A randomized, placebo-controlled trial, published in the Journal of the American College of Cardiology, assessed the efficacy and safety of tonlamarsen, an antisense oligonucleotide directed against hepatic angiotensinogen synthesis, in adults with uncontrolled hypertension receiving 2 to 5 antihypertensive medications.

The trial enrolled participants with office systolic blood pressure (BP) >135 mmHg and included a three-part treatment period consisting of a 4-week placebo lead-in, a 4-week active run-in with a single 90 mg dose of tonlamarsen, and subsequent randomization to 4 additional doses of tonlamarsen or matching placebo for 16 weeks. The co-primary endpoints were changes from baseline to Week 20 in plasma angiotensinogen and office systolic BP.

A total of 279 participants entered the placebo lead-in, 206 received the active run-in dose, and 198 were randomized. Mean BP before and after the placebo lead-in was 147/90 mmHg and 147/89 mmHg, respectively. Following the active run-in, mean BP was 140/87 mmHg.

At Week 20, LS mean percent changes in plasma angiotensinogen levels were -23.0% (95% CI, -27.8 to −18.2) with a single dose of tonlamarsen followed by placebo and -67.2% (95% CI, -71.9 to -62.4) with monthly tonlamarsen, with an LS mean difference of -44.1% (97.5% CI, -51.9 to -36.4; p<0.0001). LS mean changes in office systolic BP were -6.7 mmHg (95% CI, −9.8 to −3.5) and -6.7 mmHg (95% CI, −9.8 to −3.6), respectively, with an LS mean difference of −0.1 mmHg (95% CI, -4.5 to 4.4; p=0.97).

Serious adverse events were infrequent and similar between groups. These findings indicate that monthly tonlamarsen reduced plasma angiotensinogen compared with a single dose but did not result in additional BP reduction.