Efficacy of Tonlamarsen in Patients With Uncontrolled Hypertension

BACKGROUND: Angiotensinogen production represents the rate-limiting step in activation of the renin-angiotensin-aldosterone system. Tonlamarsen is an investigational antisense oligonucleotide directed against hepatic angiotensinogen synthesis; its efficacy and safety among patients with hypertension are unknown. OBJECTIVES: The aim of this study was to assess the safety and efficacy of 90 mg tonlamarsen administered subcutaneously once monthly for 5 months compared with a single dose of tonlamarsen and subsequent placebo. METHODS: This randomized, placebo-controlled trial enrolled adults with office systolic blood pressure (BP) >135 mm Hg receiving 2 to 5 antihypertensive medications. Participants entered a 3-part treatment period with monthly administration of the study drug, consisting of a 4-week placebo lead-in, followed by 4-week active run-in with a single dose of tonlamarsen and subsequent randomization to 4 additional doses of tonlamarsen or matching placebo for 16 weeks. The coprimary endpoints were the between-group differences in the change from baseline to week 20 in plasma angiotensinogen and in office systolic BP. RESULTS: A total of 279 participants received placebo lead-in, 206 received 90 mg tonlamarsen during the active run-in, and 198 were randomized. The mean BP among randomized participants before and after the placebo lead-in was 147/90 and 147/89 mm Hg, respectively. Following active run-in with tonlamarsen, the mean BP was 140/87 mm Hg. Twenty weeks following the first dose of tonlamarsen, least squares (LS) mean percentage changes in plasma angiotensinogen levels were -23.0% (95% CI: -27.8% to -18.2%) with a single dose of tonlamarsen and subsequent placebo and -67.2% (95% CI: -71.9% to -62.4%) with monthly tonlamarsen administration, with a LS mean difference of -44.1% (97.5% CI: -51.9% to -36.4%; P < 0.0001). The LS mean changes in office systolic BP were -6.7 mm Hg (95% CI: -9.8 to -3.5 mm Hg) for participants following a single dose of tonlamarsen and subsequent placebo and -6.7 mm Hg (95% CI: -9.8 to -3.6 mm Hg) for participants treated with monthly tonlamarsen, with a LS mean difference of -0.1 mm Hg (95% CI: -4.5 to -4.4 mm Hg; P = 0.97). Serious adverse events were infrequent and similar between treatment groups. CONCLUSIONS: Among individuals with uncontrolled hypertension, monthly tonlamarsen administration was more effective at lowering plasma angiotensinogen compared with a single tonlamarsen dose, but there was no additional BP reduction. (A Study to Investigate Tonlamarsen for the Treatment of Adults With Uncontrolled Hypertension [KARDINAL]; NCT06864104).