SynerK Announces FDA IND Approval for SNK-2726, a Novel siRNA Therapeutic Targeting AGT for Hypertension

 2025On February 27, Synerk, a leading biopharmaceutical company focused on developing RNAi therapies, announced that its self-developed oligonucleotide (siRNA) candidate drug SNK-2726, which targets angiotensinogen (AGT), has received approval from the U.S. Food and Drug Administration (FDA) for an Investigational New Drug (IND) application. This allows the company to initiate Phase I clinical trials in subjects with mild hypertension.

The Renin-Angiotensin-Aldosterone System (RAAS) is a complex cascade of hormones and biochemical pathways that regulate blood pressure, fluid balance, and electrolyte homeostasis.When the kidneys release renin in response to decreased sodium concentration or blood pressure drop, the system is activated. Angiotensinogen (AGT) is cleaved by renin to produce angiotensin I (Ang I), which is then converted into angiotensin II (Ang II) through the angiotensin-converting enzyme (ACE). Ang II is a vasoconstrictor that stimulates the release of aldosterone from the adrenal glands. Aldosterone promotes sodium and water retention in the kidneys, leading to increased blood volume and blood pressure. In hypertension, the RAAS becomes overactive, resulting in elevated levels of Ang II and aldosterone.

Components of the RAAS can serve as therapeutic targets. Common angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) that inhibit the RAAS pathway are among the effective methods, but they have three limitations: 1) A higher risk of targeted toxicity such as hyperkalemia and renal dysfunction, with lower medication doses limiting optimal dosing and clinical benefits; 2) RAS escape occurs, meaning downstream inhibition of the RAAS pathway leads to upstream compensatory pathways, further restricting therapeutic effects. Long-term use of general renin-angiotensin system (RAS) drugs, such as ACEi or ARB, results in a compensatory increase in renin due to reduced blood pressure and loss of Ang II-mediated negative feedback. The increase in renin, along with the high physiological concentration of angiotensinogen, leads to the restoration of Ang II levels; 3) Patients need to take medication daily, leading to poor compliance.

AGT is the most upstream precursor in RAAS.AGT, a glycoprotein secreted by hepatocytes, is the rate-limiting factor for Ang II production. Studies have shown that AGT and Ang II are associated with hypertension. The more copies of the AGT gene, the higher the blood pressure. Therefore, inhibiting AGT is a promising approach to target the RAAS pathway for lowering blood pressure.Three Potential Advantages of Silencing Hepatic AGT Gene through RNA Therapy:

1) Better safety, inhibiting the production of AGT in the liver, allowing renal homeostasis and tubuloglomerular feedback to remain intact, alleviating the increase in potassium, and reducing renal dysfunction;

2) Minimize the escape mechanism of AngII transmission`, more completely inhibit Ang II, which is beneficial to the treatment of RHTN.`

3) Better compliance。

Small nucleic acid drugs provide a new therapeutic strategy for hypertension, which is expected to improve treatment outcomes and patients' quality of life. In view of this, small nucleic acid drug developers in China have掀起了一股针对高血压药物研发的热潮.

According to incomplete statistics，Currently, there are about 20 small nucleic acid drugs targeting AGT under research.，The most advanced Zilebesiran was introduced by Roche for $2.8 billion from Alnylam.. Published inJAMATheKARDIA-1The results of the Phase 2 trial showed that, in mild toAdult patients with moderate hypertension (defined as daytime average dynamic systolic blood pressure of 135 mmHg~160 mmHg after discontinuation of antihypertensive drug treatment)Zilebesiran administration every quarter or every six months can serve as an effective antihypertensive treatment, with a reduction in ambulatory systolic blood pressure ranging from 7.3 mmHg to 10.0 mmHg.Alnylam expects,The sales peak potential of Zilebesiran may far exceed 4 billion US dollars.

Bowang Pharmaceutical's BW-00163In Phase 1 clinical trials, it is a chemically synthesized double-stranded siRNA molecule that efficiently degrades AGT gene mRNA through siRNA, reducing the production of angiotensin at the source and exerting a long-acting blood pressure-lowering effect. September 2023Month, the therapy was approved for clinical use in China to treat hypertension. According to publicly available patents, preclinical efficacy studies in monkeys showed excellent results, with a significant reduction of 28 mmHg in SBP (from a baseline of 147 mmHg to 119 mmHg) on the 35th day after administration.

SGB-3908 by Shengyin Bio/Innovent BiologicsApproved for clinical use in China in July 2024 for the treatment of primary hypertension. This drug is an siRNA drug targeting AGT, developed based on Saint Biologics' proprietary small nucleic acid drug development platform LEAD™. It inhibits the synthesis of AGT through RNAi, demonstrating superior activity and prolonged efficacy, with excellent safety and tolerability. Preclinical trial data showed that SGB-3908 significantly reduced AGT protein and related biomarkers (ANG I, ANG II) in the serum of hypertensive cynomolgus monkeys, achieving a marked blood pressure-lowering effect with long-lasting results, and no safety issues such as hypotension were observed.

HRS-9563 Injection from Shengdi Pharmaceutical, a subsidiary of Hengrui MedicineApproved for clinical use in China in October 2024, intended for the treatment of hypertension. HRS-9563 injection effectively inhibits the expression of key proteins that cause blood pressure elevation by precisely targeting specific gene sequences, with the potential to overcome the aforementioned shortcomings of current therapeutic drugs.

LDR2402 Injection by Chengdu XiandaoIn November 2024Approved for clinical use in ChinaThis drug utilizes RNA interference technology. After being linked with N-acetylgalactosamine (GalNAc), it precisely targets the liver cell membrane receptor to enter liver cells, degrading AGT mRNA and thereby lowering blood pressure. In preclinical animal experiments, a single dose maintained stable efficacy for over six months with excellent safety. In clinical treatment, extending the dosing interval (once every quarter or every six months) may improve patient compliance and could reduce blood pressure variability (BPV) by maintaining 24-hour blood pressure control, offering cardiovascular benefits to patients with hypertension. Therefore, LDR2402 has the potential to break traditional hypertension treatment paradigms and become a new generation of hypertension therapy. This means that in the future, patients might only need to receive an injection once every quarter or every six months, significantly improving medication adherence while reducing blood pressure fluctuations and providing cardiovascular benefits.

SYH2062 Injection by CSPCIn December 2024Approved for clinical use in China。This product is an siRNA drug delivered through conjugated N-acetylgalactosamine (GalNAc), which can target and inhibit angiotensinogen (AGT) and is suitable for treating hypertension. By optimizing sequence and chemical modification strategies, the product achieves longer-lasting gene silencing effects and is expected to become a stable blood pressure control drug administered once every six months. Preclinical studies show that the drug’s activity duration is significantly longer than similar siRNA products, with anticipated advantages such as prolonged efficacy, good safety, and high patient compliance, demonstrating significant clinical development value.

Antorna's ART101 InjectionIn January 2025Approved for clinical use in China。ART101 Injection, as a siRNA drug independently developed by Synerk, achieves its antihypertensive effect by targeting and inhibiting the expression of liver AGT mRNA, thereby reducing AGT protein production.