Key Points
- Hypertension remains a leading modifiable cardiovascular risk factor, and novel therapies targeting the renin-angiotensin-aldosterone system (RAAS) have emerged.
- In this phase 2 trial, monthly tonlamarsen (which targets and reduces angiotensinogen [AGT] production) produced robust reductions in plasma AGT (about 67%) compared with about 23% after a single dose.
- The five monthly dose group demonstrated marked AGT suppression compared to single-dose; both arms demonstrated clinically significant SBP reduction (-6.7 mmHg), though there was no significant between-group difference in systolic blood pressure (SBP) reduction at 20 weeks. However, findings necessitate further study in higher-risk populations.
Hypertension (HTN) remains a leading modifiable cardiovascular risk factor, with many patients exhibiting persistent elevations despite multidrug therapy. Targeting the renin-angiotensin-aldosterone system (RAAS) upstream via hepatic angiotensinogen (AGT) suppression has emerged as a novel therapeutic strategy. Tonlamarsen, an antisense oligonucleotide, reduces AGT synthesis and may offer sustained RAAS modulation independent of daily adherence.
KARDINAL was a phase 2, randomized, double-blind, placebo-controlled trial evaluating tonlamarsen in patients with uncontrolled hypertension (SBP ≥ 135 mm Hg) despite 2-5 antihypertensive medications. The main results were presented as Late Breaking Clinical Trials at ACC 2026 with simultaneous publication in JACC.
This trial enrolled adults with office systolic blood pressure (BP) greater than 135 mmHg receiving 2 to 5 antihypertensive medications. Participants entered a 3-part treatment period with monthly administration of 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 co-primary end points were the differences between groups in the change from baseline to Week 20 in plasma angiotensinogen and in office systolic BP.
Among approximately 200 randomized patients (mean age 61 years; 33% diabetes), tonlamarsen significantly reduced AGT levels, with about 67% reduction in the multi-dose group versus about 23% with a single dose (p<0.0001). However, both treatment strategies resulted in similar reductions in office SBP (-6.7 mm Hg), with no significant difference between groups. Subgroup analyses suggested greater BP reductions in patients with higher baseline SBP, though these findings were exploratory.
Serious adverse events occurred in 2-5% of patients, and overall tolerability was acceptable.
KARDINAL demonstrates that while AGT suppression is biologically effective, it may not translate into incremental BP lowering in patients already treated with RAAS inhibitors. Potential explanations include residual AGT suppression in comparator groups, non-rate-limiting effects of AGT in RAAS activity, and background medication effects.
These findings raise important mechanistic questions regarding upstream RAAS targeting and suggest that near-complete AGT suppression or different patient populations (e.g. acute severe HTN) may be required to achieve clinical benefit. In summary, the KARDINAL trial highlights the promise and limitations of RNA-targeted therapies in HTN, achieving substantial biomarker modulation without clear clinical BP superiority, underscoring the need for further targeted trials.