As a new type of therapeutics, small interfering RNA (siRNA) drugs are revolutionizing the field of cardiometabolic diseases. These drugs provide patients with more personalized and effective treatment options by precisely targeting and silencing the expression of specific genes. At the recently held "27th Chinese Medical Doctor Association Interventional Cardiology Conference and 13th China Chest Pain Center Conference (CCIF&CCPCC2024)", Professor Gao Xiufang from the Department of Cardiology of Huashan Hospital affiliated to Fudan University gave us an in-depth analysis of the application prospects of siRNA drugs in the treatment of cardiometabolic diseases.
What is siRNA
siRNA (small molecule interfering ribonucleic acid) is a biomolecule capable of inducing RNA interference (RNAi) in mammals, resulting in mRNA degradation or inactivation by fully complementary pairing with messenger RNA (mRNA) of the gene of interest. Unlike siRNAs, microRNAs typically pair with only some of the mRNAs of interest and can therefore affect multiple mRNAs. siRNAs can precisely degrade specific mRNAs due to their high specificity, while microRNAs rapidly inhibit the translation of multiple mRNAs and prevent protein synthesis.
In drug development, both microRNA and siRNA have shown potential for the treatment of cardiometabolic diseases. MicroRNA drugs have the advantage of rapidly silencing the target mRNA, while siRNA drugs need to be precisely designed to specifically target. With the advancement of research and technology, these small molecule drugs are expected to provide patients with more precise and effective treatment options.
siRNAs are used in the field of cardiovascular metabolism
Inclisiran is a specific siRNA targeting PCSK9 that reduces PCSK9 production and thereby LDL-C levels by inhibiting mRNA translation of PCSK9 in hepatocytes. Inkslane is a chemically modified, double-stranded siRNA containing 44 modified nucleotides that are essential for reducing immunogenicity responses, enhancing molecular stability, and improving liver-specific uptake. In particular, the structure of 3-N-acetylgalactosamine allows Inksland to bind to the liver-expressed sialic acid glycoprotein receptor (ASGPR) with high affinity, enabling efficient and targeted hepatocyte uptake, allowing therapeutic effects to be achieved at lower doses, while reducing the risk of potential adverse effects and reducing the frequency of dosing.
Infenslan's clinical series of studies have explored the efficacy and safety of Inksland for different research objectives. The ORION-1 Phase I clinical trial, released in 2017, evaluated the safety and PCSK9 inhibition of Infslan, and showed that a single dose could reduce LDL-C for up to 240 days. Based on the results of this study, the post-marketing dosing regimen of Inksland is one dose on the first day and one dose three months later, followed by semi-annual dosing.
ORION-9, ORION-10, and ORION-11 are all Phase III clinical studies that investigated the efficacy and safety of Inksland in patients with heterozygous familial hypercholesterolemia, patients with atherosclerotic cardiovascular disease (ASCVD), and patients with ASCVD or similar risk factors, respectively. The interventions in these studies were consistent, so the data could be analysed together. The results of the study showed that Inkslane can significantly reduce the incidence of major adverse cardiovascular events (MACE) by 25%, suggesting that Inkslane can not only effectively reduce LDL-C, but also improve clinical outcomes.
siRNAs in the treatment of hypertension
Zilebesiran is an angiotensin-specific (AGT) siRNA drug currently in clinical development. AGT is the only precursor of angiotensin peptides and plays an important role in the pathogenesis of hypertension. The molecular structure of Zilebesiran includes the covalent attachment of the siRNA to the N-acetylgalactosamine (GalNac) ligand, which specifically binds to receptors on the surface of hepatocytes for precise drug delivery. Through this mechanism, Zilebesiran significantly reduces the production of AGT in hepatocytes and achieves long-term inhibition through the recycling of the RNA interference silencing complex (RISC).
Preliminary clinical studies have shown that Zilebesiran consistently inhibits AGT levels for 24 weeks after administration. Studies investigating its use in combination with angiotensin II receptor antagonists (ARBs) have shown that the inhibitory effect on AGT levels remains consistent even after treatment with irbesartan 300 mg increased. In addition, in the phase I clinical study, Zilebesiran demonstrated a sustained antihypertensive effect and a good safety profile, albeit by a small magnitude, suggesting the potential clinical application prospects of Zilebesiran.
In addition, the KARDIA-2 Phase II clinical trial met its primary endpoint. The addition of Zilebesiran to the standard regimen significantly reduced the patient's 24-hour mean systolic blood pressure (SBP) at 3 months. The trial data further suggest that only two doses per year can be used to maintain a sustained reduction in blood pressure, a finding that has important implications for hypertension treatment.
Use of siRNAs in the treatment of diabetes mellitus and metabolic syndrome
ALN-KHK is an experimental RNA interference (RNAi) therapy targeting pentankokinase (KHK) for the treatment of type 2 diabetes and metabolic syndrome. KHK plays a key role in fructose metabolism, and its mediated metabolic processes have important effects on hepatic fat synthesis and insulin resistance. Currently, ALN-KHK has submitted applications for Phase I and Phase II clinical trials.
SiRNAs in the treatment of diabetes
The glucagon receptor (GCGR) gene is a potential target for the treatment of type 2 diabetes mellitus (T2DM). In the treatment of T2DM, modulating glucagon activity may help stabilize blood glucose levels in patients, whether characterized by insulin resistance or inadequate insulin secretion. Glucagon can significantly promote gluconeogenesis and glycogenolysis, help alleviate the symptoms of T2DM by inhibiting its glycemic effect, and may indirectly promote the secretion of insulin, thereby achieving the effect of improving symptoms.
GCGR is a member of the G protein-coupled receptor family, which is widely found in the liver, kidney, pancreas and other organs, especially in the liver, which is extremely important for blood glucose regulation. Recent studies have shown that small-molecule GCGR antagonists are effective in lowering blood glucose and maintaining stability in animal models of diabetes. At the same time, antisense nucleotide inhibitors targeting GCGR have also been shown to be effective in improving hyperglycemia in animal models.
siRNAs in the treatment of obesity
STP705's progress to Phase I clinical trials is due in part to its innovative peptide nanoparticle (PNP) technology. PNPs are composed of synthetic histidine and lysine, which can enter the cell through endocytosis. In the acidic environment of cellular inclusions, PNPs react with histidine, resulting in the dissolution of nanoparticles and the release of siRNAs into the cytoplasm. Although this technique was initially questioned as only suitable for local injections, PNP technology is particularly suitable for applications where the goal is to reduce abdominal fat. STP705 can be injected directly into the lower abdomen, thus avoiding problems related to the liver and kidney barriers. In addition, STP705 has shown efficacy and safety in clinical trials for skin cancer and hypertrophic scars, further enhancing its viability as a potential agent.
SiRNAs in the treatment of inherited metabolic abnormalities
Transthyretin (TTR) is a plasma protein synthesized by the liver that carries the retinol-binding protein-vitamin A complex and thyroid hormones. Under normal physiological conditions, TTR exists as a tetramer, but when it dissociates into monomers and misfolds, forming amyloid and depositing in the myocardial interstitium, it causes myocardial lesions that may eventually lead to progressive heart failure, or ATTR-CA.
ALN-TTRSC04 is an RNAi therapy targeting the TTR gene designed to treat ATTR-CA by decreasing the synthesis of TTR proteins. A phase 1 clinical study in healthy volunteers showed that a single dose of 300 mg of ALN-TTRSC04 had a rapid and significant gene silencing effect. The results of the study showed that on average the participants had an average reduction of more than 90% in TTR gene expression on day 15 after dosing. By day 29, the average reduction in TTR protein levels peaked at 97% and maintained an average reduction of 93% on day 180.
Of all doses currently evaluated, a single dose of ALN-TTRSC04 was well tolerated, and no drug-related adverse events were observed. The data collected in the Phase 1 study is still ongoing, and the data collected will inform the determination of the dose and dosing regimen for the Phase 3 clinical study of ATTR amyloidosis with cardiomyopathy. Phase 3 trials are expected to be initiated at or around the end of 2024.
brief summary
➤ With the rise of siRNA therapeutic strategies, the market has witnessed the successful launch of multiple siRNA drugs, despite technical challenges in areas such as drug delivery systems and immunogenicity. These drugs have demonstrated stable efficacy and long-term duration of action, greatly improving patient adherence. For chronic pathologies such as cardiometabolic diseases, the application potential of siRNA drugs is particularly significant.
➤ In the field of cardiometabolic disease treatment, the siRNA drug Inksland has demonstrated its effectiveness in sustaining LDL-C levels and has been shown to be beneficial in improving major MACE. In addition, Zilebesiran, an siRNA drug for hypertension, has also completed the phase II clinical study.
➤ In the therapeutic areas of metabolic diseases such as metabolic syndrome, type 2 diabetes and obesity, the research and development of related siRNA drugs is steadily advancing. Advances in these studies bode well for siRNA therapeutic strategies that may revolutionize the management of chronic diseases in the future.
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