- LDR2402 is an investigational small interfering RNA therapy designed to suppress hepatic angiotensinogen (AGT) production, offering a potential long-acting treatment strategy for hypertension.
- In phase 1 and phase 2a randomized trials involving 100 participants, LDR2402 produced rapid, dose-dependent, and sustained reductions in circulating AGT levels, with reductions up to 97% at 24 weeks.
- In the phase 1 trial, a single 150-mg injection reduced 24-hour systolic blood pressure by 18.2 mm Hg at 12 weeks, compared with 7.1 mm Hg with placebo.
- In phase 2a, LDR2402 reduced 24-hour systolic blood pressure by 11.0 to 16.8 mm Hg at 24 weeks across different dosing regimens. No treatment-related serious adverse events or deaths were reported.
Despite the availability of effective antihypertensive medications, achieving sustained blood pressure control remains a major challenge, partly because of poor medication adherence and the need for lifelong daily treatment. The renin–angiotensin–aldosterone system (RAAS) plays a central role in blood pressure regulation and remains an important therapeutic target. Angiotensinogen (AGT), produced predominantly by the liver, is the sole precursor of angiotensin peptides and represents the most upstream substrate of the RAAS. Targeting hepatic AGT synthesis through RNA interference offers a novel approach to achieving prolonged blood pressure reduction with infrequent dosing.
At the American Heart Association (AHA) Scientific Sessions 2026 on November 8, Dr. Wei Zhang, MD, PhD, (Shanghai Institute of Hypertension/Ruijin Hospital, Shanghai, China), presented results from phase 1 and phase 2a randomized trials evaluating LDR2402, an investigational small interfering RNA (siRNA) therapeutic designed to selectively suppress hepatic AGT production. The studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of LDR2402, including its ability to achieve sustained reductions in circulating AGT and blood pressure.
The phase 1 trial was a first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose study involving 50 healthy participants or patients with mild hypertension aged 18 to 65 years. Participants were assigned to receive a single subcutaneous injection of LDR2402 at doses ranging from 25 to 600 mg (n=40) or placebo (n=10). Safety, tolerability, and pharmacodynamic responses were assessed through 24 weeks, with extended follow-up of actively treated participants through 52 weeks.
Investigators also conducted a randomized, double-blind, placebo- and active-controlled phase 2a trial involving 50 participants with mild to moderate hypertension across six centers in China. Participants were assigned to four LDR2402 regimens (75 mg every six months, 150 mg every three or six months, or 300 mg every six months), valsartan 80 mg daily, or placebo. Patients initially receiving placebo crossed over to LDR2402 at week 12. The primary endpoints were changes in serum AGT levels and safety, while changes in 24-hour ambulatory systolic blood pressure were assessed as a secondary endpoint.
In phase 1, LDR2402 produced rapid, dose-dependent suppression of serum AGT, with reductions ranging from approximately 79% to 96% at 12 weeks across escalating doses. These effects were sustained through 24 weeks, with AGT reductions ranging from 66% to 97%. At the 150-mg dose, serum AGT declined by approximately 90% at 12 weeks and 82% at 24 weeks. Similar sustained AGT suppression was observed in phase 2a, with reductions ranging from 58% to 87% at 24 weeks.
Moreover, AGT suppression was accompanied by sustained blood pressure reductions. In phase 1, a single 150-mg dose of LDR2402 reduced 24-hour systolic blood pressure by 18.2 mm Hg at 12 weeks, compared with 7.1 mm Hg with placebo. At 24 weeks, the corresponding reductions were 13.9 and 9.5 mm Hg, respectively. Blood pressure reductions persisted through 36 weeks in actively treated participants, although placebo comparisons were unavailable beyond 24 weeks.
In phase 2a, reductions in 24-hour systolic blood pressure ranged from 11.0 to 16.8 mm Hg across the four LDR2402 regimens at 24 weeks, compared with a 9.8-mm Hg reduction with valsartan. Clinic systolic blood pressure reductions were similarly sustained, ranging from approximately 20 to 28 mm Hg across the LDR2402 treatment groups. However, these comparisons were exploratory, and the small sample size limits conclusions regarding comparative efficacy.
LDR2402 was generally well tolerated across both studies. In phase 1, treatment-related adverse events occurred in 20% of participants receiving LDR2402, primarily mild injection-site reactions and rash. In phase 2a, treatment-related adverse events occurred in 9.1% of LDR2402-treated participants, with one treatment discontinuation due to an adverse event. No serious adverse events or deaths occurred among participants receiving LDR2402, and no hyperkalemia events were reported.
These findings provide preliminary evidence that hepatic AGT suppression with LDR2402 can achieve sustained blood pressure reductions following a single injection or dosing at three- to six-month intervals. However, the small study populations, the short and controlled follow-up, and exploratory blood pressure comparisons warrant caution. “Our results demonstrate promising pharmacodynamic activity and preliminary blood pressure lowering effects, but larger trials will be needed to determine the optimal dose, dosing interval and the long-term safety,” said Dr. Zhang. Those trials will also need to establish comparative efficacy and whether sustained blood pressure reductions translate into improved cardiovascular outcomes.