Tonlamarsen Shows Biochemical Activity Without Additional Clinical BP Control in a Phase 2 Trial
USA: Multiple doses of tonlamarsen reduced angiotensinogen levels more than a single dose, but did not lead to additional blood pressure reduction, showing mixed clinical benefits in this phase 2 trial.
A phase 2 randomized clinical trial published in the Journal of the American College of Cardiology (JACC) by Luke J. Laffin from the Cleveland Clinic Coordinating Center for Clinical Research and colleagues evaluated the efficacy and safety of tonlamarsen, an investigational therapy targeting angiotensinogen synthesis, in patients with uncontrolled hypertension. The findings provide important insights into the drug’s biological effects, while raising questions about its clinical impact on blood pressure control.
Tonlamarsen is an antisense oligonucleotide designed to reduce hepatic production of angiotensinogen, a key precursor in the renin–angiotensin–aldosterone system, which plays a central role in regulating blood pressure. By targeting this rate-limiting step, the therapy aims to offer a novel approach for patients whose hypertension remains uncontrolled despite standard treatment.
For this purpose, the researchers conducted a randomized, placebo-controlled trial involving adults with office systolic blood pressure above 135 mmHg who were already on two to five antihypertensive medications. The study followed a structured three-phase design, including an initial placebo lead-in period, followed by a single active dose of tonlamarsen, and subsequent randomization to receive either monthly tonlamarsen injections or placebo for an additional 16 weeks.
A total of 279 participants entered the placebo lead-in phase, 206 received the initial dose of tonlamarsen, and 198 were ultimately randomized.
The trial revealed the following findings:
- The mean baseline blood pressure was approximately 147/90 mmHg and remained largely unchanged after the placebo phase.
- After the initial dose of tonlamarsen, blood pressure showed a modest reduction to around 140/87 mmHg.
- At 20 weeks, tonlamarsen therapy led to a marked reduction in plasma angiotensinogen levels.
- Monthly dosing resulted in a significantly greater decline in angiotensinogen levels (over 67%) compared to a single dose followed by placebo (around 23%).
- Despite the greater reduction in angiotensinogen, both groups showed a similar decrease in office systolic blood pressure, averaging about 6.7 mmHg.
- No additional blood pressure–lowering benefit was observed with repeated monthly dosing compared to a single dose.
- Serious adverse events were infrequent.
- The incidence of serious adverse events was similar between the tonlamarsen and placebo groups.
- Tonlamarsen was generally well tolerated throughout the study period.
Overall, while tonlamarsen effectively reduced angiotensinogen levels, this did not translate into greater blood pressure lowering with repeated dosing. The findings highlight a disconnect between biomarker modulation and clinical outcomes, underscoring the need for further research to determine whether longer treatment duration, different dosing strategies, or combination approaches may enhance its therapeutic potential in hypertension management.
Reference: https://www.jacc.org/doi/10.1016/j.jacc.2026.03.034
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