AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Blood Pressure Lowering Following a Single Dose of Tonlamarsen Compared with a Single Dose of Placebo: A Post-Hoc Analysis of the KARDINAL Randomized Trial
By Sarraju A, Wang Q, Wolski KE et al.
Introduction: Tonlamarsen is an investigational antisense oligonucleotide therapy that targets the synthesis of hepatic angiotensinogen ( AGT ) messenger RNA. The KARDINAL phase 2 randomized trial evaluated the safety and efficacy of tonlamarsen administered once a month subcutaneously for 5 months versus a single dose of tonlamarsen followed by placebo for 4 months in patients with hypertension on 2-5 antihypertensive drugs. Research Question: What is the change in office blood pressure (BP) associated with administration of a single dose of tonlamarsen compared with placebo? Methods The KARDINAL trial randomized adults with office systolic BP (SBP) between 135 and 170 mm Hg while on stable doses of 2-5 antihypertensives. The trial included 3 treatment periods: first, a 4-week placebo lead-in period (part A), followed by a 4-week active run-in period in which all participants were administered a single dose of tonlamarsen subcutaneously (part B), during both of which participants were blinded to treatment. Participants were subsequently randomized to either monthly tonlamarsen or placebo for 16 weeks (part C). Interpretation of the trial’s co-primary end point of office SBP lowering 20 weeks following initial tonlamarsen administration was complicated by unexpected persistent AGT and BP lowering among participants who received a single dose of tonlamarsen during active run-in and were subsequently randomized to placebo. Here we focused on parts A and B. To estimate the BP-lowering effect of tonlamarsen in the absence of a true placebo arm, this intra-patient analysis evaluated the efficacy of tonlamarsen by assessing differences in change in SBP and diastolic BP (DBP) 4 weeks after a single dose of tonlamarsen (part B) compared with changes 4 weeks following placebo lead-in (part A). Results: A total of 204 participants who underwent 4-week placebo lead-in period, received a single dose of tonlamarsen and experienced 4-week active run-in period were included in the intra-patient analysis. At baseline, more than 80% of participants were taking an ARB or ACE inhibitor for BP reduction (Table). At 4 weeks following a single dose of tonlamarsen, the placebo-subtracted mean change in office SBP was -5.6 mmHg (95% CI, -8.6, -2.6, p<0.001) and the mean office DBP change was -1.5 mmHg (95% CI, -3.4, 0.4, p=0.13). BP lowering among pre-specified subgroups are shown in the figure. The median SBP at baseline was 144.5 mm Hg. Compared with participants with baseline SBP less than the median, participants with baseline SBP greater than the median demonstrated larger placebo-subtracted SBP changes (-14.5 mmHg, [95% CI -18.6 to -10.5]). Conclusion: Among adults with uncontrolled BP taking 2-5 antihypertensive drugs, with most taking an ARB or ACE inhibitor, KARDINAL trial participants demonstrated greater office SBP lowering 4 weeks following a single dose of tonlamarsen, compared with 4 weeks following placebo.