Tonlamarsen Shows Promise in Resistant Hypertension Despite Mixed Phase 2 Results
核心洞察
The KARDINAL Phase 2 trial demonstrated that tonlamarsen, an antisense oligonucleotide targeting angiotensinogen (搜索), achieved a 67% reduction in plasma angiotensinogen levels with monthly dosing compared to 23% with a single dose.
Both single-dose and monthly tonlamarsen groups showed clinically meaningful blood pressure reductions of 6.7 mmHg, though monthly dosing did not provide additional blood pressure benefits despite greater angiotensinogen (搜索) suppression.
Patients with the highest hypertensive burden (systolic BP >150 mmHg) experienced the greatest blood pressure reductions of 8.9 mmHg, supporting evaluation in acute severe hypertension (搜索) populations.
Kardigan (搜索) announced positive results from the KARDINAL Phase 2 clinical trial evaluating tonlamarsen, an investigational antisense oligonucleotide targeting angiotensinogen (搜索), in patients with uncontrolled hypertension (搜索). The data, presented at the American College of Cardiology's Annual Scientific Session and simultaneously published in The Journal of the American College of Cardiology, showed statistically significant reductions in plasma angiotensinogen levels and clinically meaningful blood pressure improvements.
Trial Design and Patient Population
KARDINAL was a randomized, double-blind, placebo-controlled Phase 2 trial enrolling 198 patients with uncontrolled hypertension (搜索) despite treatment with two to five antihypertensive medications. Participants had systolic blood pressure between 135-170 mmHg, with more than 80% receiving ACE inhibitor (搜索) or angiotensin receptor blocker therapy. The mean age was 61 years, 59% were women, 33% had diabetes, and 49% were Black.
The study design included a four-week placebo run-in period, followed by a four-week active run-in where all participants received a single 90 mg tonlamarsen injection. Patients were then randomized to receive either four additional monthly doses of tonlamarsen or placebo for 16 weeks.
Primary Endpoint Results
The trial achieved one of its two co-primary endpoints. Monthly dosing of tonlamarsen produced a dose-dependent, statistically significant reduction in angiotensinogen (搜索) levels, with patients receiving five monthly doses achieving a 67% mean reduction from baseline to Week 20 compared to a 23% mean reduction in the single-dose group (p<0.0001).
However, the second co-primary endpoint was not met. Reduction in office systolic blood pressure from baseline to Week 20 did not differ significantly between treatment groups due to an unexpected, prolonged reduction in blood pressure in the single-dose arm (p=0.97).
Clinical Blood Pressure Benefits
Despite the lack of difference between groups, both treatment arms demonstrated clinically meaningful blood pressure reductions. Each group showed a 6.7 mmHg reduction in office systolic blood pressure from baseline to Week 20 (single-dose: 95% CI, -9.8 to -3.5 mmHg; five-dose: 95% CI, -9.8 to -3.6 mmHg).
In a post hoc analysis, participants with the highest hypertensive burden (office systolic BP >150 mmHg at baseline) in the five-dose group experienced the greatest reductions of 8.9 mmHg at Week 20. This finding supports the clinical rationale for evaluating tonlamarsen in patients with acute severe hypertension (搜索).
An additional post hoc analysis revealed that participants receiving five doses experienced a decline in at-home systolic blood pressure surges above 150 mmHg, with an absolute 28% reduction in such surges at Week 20 compared to the single-dose arm (50% vs 78%).
Safety Profile
Tonlamarsen was generally well-tolerated with a safety profile comparable to prior studies. Worsening renal function was uncommon, and there were no meaningful signs of treatment-related hypotension or hyperkalemia. Serious adverse events occurred in 2.1% of the single-dose group and 5.0% of the monthly-dose group, with the latter experiencing more injection-site reactions.
Expert Commentary
"The KARDINAL clinical trial supported tonlamarsen's hypothesized mechanism of action by demonstrating sufficient modulation of angiotensinogen (搜索), resulting in clinically meaningful blood pressure lowering, and potential for a favorable safety profile, particularly in patients with higher hypertensive burden," said Jay Edelberg, M.D., Ph.D., co-founder and chief medical officer at Kardigan (搜索).
Luke Laffin, M.D., principal investigator and co-director of the Center for Blood Pressure Disorders at Cleveland Clinic, noted: "While continued dosing with tonlamarsen reduced angiotensinogen (搜索) more than a one-time treatment, both treatment strategies reduced blood pressure to a similar extent. It's important to continue to study tonlamarsen in patients who really need it, including those with acute severe hypertension (搜索), since so many struggle to take daily medications."
Mechanism and Therapeutic Rationale
Tonlamarsen is a liver-directed antisense oligonucleotide designed to target hepatic angiotensinogen (搜索), the sole precursor of the Renin-Angiotensin-Aldosterone System (RAAS (搜索)). By directly down-modulating angiotensinogen at its source in the liver, tonlamarsen aims to modulate the RAAS pathway upstream as an alternative approach to blood pressure management.
The drug represents a nucleic acid-based therapeutic that decreases hepatic angiotensinogen (搜索) synthesis, offering a new approach to RAAS (搜索) modulation with drugs that are durable and not dependent on daily adherence.
Next Steps and Clinical Development
These findings strengthen Kardigan (搜索)'s therapeutic hypothesis for tonlamarsen in patients with acute severe hypertension (搜索) and will inform the KARDINAL-ASH Phase 2b clinical trial planned for later this year. The company intends to evaluate tonlamarsen in this high-risk population with urgent unmet medical need.
Acute severe hypertension (搜索) affects approximately six million patients presenting in emergency rooms annually in the United States, with about two million cases leading to hospitalization. Currently, no treatments are indicated for post-hospitalization blood pressure management in patients with acute severe hypertension.