The Rise of Oligonucleotide Therapeutics: A New Investment Frontier Amid Surging Capital Interest!

Recently, the official website of the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) announced that Suzhou Ribo Life Science Co., Ltd. has submittedRBD1016 Injection Granted Clinical Implied Permission, Indicated for chronic hepatitis B virus (HBV) infection; in addition,Rigerna's self-developed siRNA drug RBD7007, which targets C5, received EU clinical trial approval in September and will initiate its first-in-human clinical trial in Sweden.

RBD1016 is a GalNAc-conjugated siRNA drug targeting hepatitis B, covering the majority of A-E genotype hepatitis B patients in China, Europe, and the United States.; Non-clinical studies show that it can efficiently and sustainably reduce HBsAg in serum and liver tissue, with a single dose suppressing HBsAg for up to nearly 6 months; it is currently the world's only single-agent drug to achieve seroconversion in preclinical animal models, suggesting that RBD1016 has Best-In-Class potential.

RBD7007 is an siRNA drug independently developed by Ribo Bio based on its RIBO-GalSTARTM liver-targeting technology platform, targeting C5., inhibiting the expression of C5 protein and blocking the activation of the complement pathway to achieve its therapeutic effect on complement-mediated diseases. Preclinical trial data show that RBD7007 has a lasting and potent inhibitory effect on the activation of the complement pathway while maintaining good safety, with the expectation of bringing significant therapeutic benefits to patients with IgA nephropathy and other complement-mediated diseases.

Recently, Fujian Shengdi Pharmaceutical Co., Ltd. ("Shengdi Pharmaceutical"), a subsidiary of Jiangsu Hengrui Pharmaceutical Co., Ltd. ("Hengrui Pharmaceutical"), independently developed a small interfering RNA (siRNA) Class I innovative drug.HRS-9563 Injection Officially Approved for Clinical Trials, Intended for Hypertension TreatmentHRS-9563 injection effectively inhibits the expression of key proteins that cause blood pressure elevation by precisely targeting specific gene sequences, offering hope to overcome the aforementioned shortcomings of current therapeutic drugs.

In the first half of this year, Hengrui Medicine's new drug in the small interfering RNA (siRNA) therapy classHRS-5635 Enters Phase 2 Clinical Trial for the Treatment of Chronic Hepatitis BHRS-5635 is a novel covalently conjugated triantennary N-acetylgalactosamine (GalNAc) double-stranded small interfering RNA (siRNA). The molecule is selectively delivered into hepatocytes through the binding of GalNAc to the asialoglycoprotein receptor (ASGPR) on the surface of liver cells. Non-clinical efficacy studies have shown that HRS-5635 exhibits excellent antiviral activity against all HBV genotypes and demonstrates potent and sustained antiviral effects in vivo. Non-clinical safety evaluations indicate that HRS-5635 has no off-target activity and is highly safe.

In August 2024, Yookon Pharmaceutical announced that its subsidiary, Hangzhou Tianlong Pharmaceutical Co., Ltd. (hereinafter referred to as "Hangzhou Tianlong")Argo Biopharma's YKYY015 Injection Receives FDA Approval for Clinical Trials in the United StatesYKYY015 is a small interfering ribonucleic acid (siRNA) candidate drug independently developed by Hangzhou Tianlong, targeting the PCSK9 gene. It is intended for the treatment of primary (familial and non-familial) hypercholesterolemia or mixed hyperlipidemia characterized by elevated LDL-C.

YKYY015 Injection has a completely new sequence and adopts self-developedNovel siRNA Sequence Modification Template, the core patent for the compound of this drug has been granted an invention patent by the National Intellectual Property Administration, and a PCT international application has been completed simultaneously; additionally, YKYY015 injection is conjugated with a self-developed, proprietaryFully Independent Intellectual Property GalNAc Delivery System, the system has been granted an invention patent by the China National Intellectual Property Administration and has simultaneously completed a PCT international application, enabling highly efficient liver-targeted delivery.

In August 2024, Rigerna announced its self-developed Class I innovative drug, a small interfering RNA (siRNA), for the treatment of complement-related diseases.The Investigational New Drug (IND) application for "RG002C0106 Injection" has been approved by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration.Previously, RG002C0106 was approved by the Australian Human Research Ethics Committee (HREC) to conduct a Phase I clinical trial.

RG002C0106 Injection is an siRNA drug developed by Rigerna based on its proprietary core technology platforms such as RIHOST®, RICMO®, and LICOD®, utilizing its self-developed second-generation N'-acetylgalactosamine (GalNAc) conjugation technology, targeting the complement factor C3, and is alsoRigerna's First Pipeline Entering Clinical Trial StageOn October 23, the first subject dosing of RG002C0106 injection was successfully completed in the research ward of Beijing Friendship Hospital in Phase I clinical trial.

In July 2024, Daring Bio announced its independently developed potential best-in-class siRNA pipeline product.RN0361 Receives Approval for Phase I Clinical Trial Application in Australia, the product targets (severe) hypertriglyceridemia (sHTG), mixed dyslipidemia, and familial chylomicronemia syndrome; additionally, in July of the same year, Daring Biotech announced the successful completion of a $35 million Series A+ financing round.

RN0361 is a product originating from Daring Biotech.GAIA Liver-Targeting Platform's Double-Stranded Small Interfering RNA (siRNA) Drug Targeting the APOC3 Gene. Dari GAIA Liver Targeting Platform has proprietary intellectual property with superior GalNAc conjugation in its class, a finely optimized fully chemically modified backbone structure, and chemical modifications that enhance activity and specificity to achieve deeper and more sustained gene silencing effects in liver targeting. RN0361 reduces the expression of APOC3 protein by efficiently, significantly, durably, and safely silencing the mRNA level of apolipoprotein C3 (APOC3), showing promise as the best-in-class siRNA drug molecule for this target.

In July 2024, Suzhou SinoArgo Biopharmaceutical Co., Ltd. (hereinafter referred to as "SinoArgo Bio") and Innovent Biologics Group jointly developed a small nucleic acid (siRNA) drug for the treatment of hypertension.SGB-3908 Injection Receives Clinical Trial Implied Permission; In June of the same year, Stainbio's Class 1 new drugSGB-9768 Injection Receives Clinical Trial Implied PermissionThe indications are for complement-mediated kidney diseases, including adult IgA nephropathy, C3 glomerulopathy, and immune complex-mediated membranoproliferative glomerulonephritis. Currently, the first subjects for both drugs have completed dosing. In addition, another siRNA therapy targeting hepatic PCSK9, SGB-3403, has also entered the clinical stage.

SGB-9768: An siRNA drug targeting complement C3 protein, delivered to liver cells using the next-generation LEAD™ GalNAc technology, inhibits C3 synthesis through the RNAi mechanism, thereby suppressing complement activation. It holds promise for treating complement-mediated kidney diseases.SGB-9768 has initiated Phase 1 clinical trials in New Zealand in early 2024., multiple groups of subjects have been dosed so far, showing good safety and tolerability.

SGB-3908: An siRNA drug targeting angiotensinogen (AGT), intended for the treatment of hypertension. Preclinical studies have shown that SGB-3908 significantly reduces AGT protein and related biomarkers (ANG I, ANG II) in the serum of hypertensive cynomolgus monkeys, with a marked and sustained blood pressure-lowering effect, and no safety issues such as hypotension were observed.In December 2023, Sino Biopharma and Innovent Biologics reached a collaboration to jointly advance the development of SGB-3908. Innovent Biologics obtained the option for future development, manufacturing, and commercialization of the drug in different regions.

In June 2024, Aimabio Biotechnology (Nanjing) Co., Ltd.ER2001 Injection Receives CDE Clinical Trial Implied PermissionER2001 Injection is a Class 1 therapeutic biological product developed based on Rigerna's proprietary IVSA™ technology platform. It is the first pipeline product for treating Huntington's disease. ER2001 Injection is administered intravenously, undergoes processing in the liver, and achieves self-assembly in vivo to enable central nervous system-targeted delivery of siRNA, thereby producing a therapeutic effect. Previously, ER2001 Injection received approval from the U.S. Food and Drug Administration (FDA).

Currently, there are only globally marketed drugs for alleviating symptoms of Huntington's disease, while other potential drugs that may control disease progression are still in clinical or preclinical stages. In previously conducted IIT studies, ER2001 demonstrated good safety and preliminary clinical efficacy.

In May 2024, RiboNova Therapeutics (Nantong) Research Institute Co., Ltd. ("RiboNova Therapeutics" for short) announced the independently developed small nucleic acid drug.RAG-17 Injection Receives CDE Approval for Investigational New Drug (IND) Application, intended for the treatment of amyotrophic lateral sclerosis (ALS) in adults caused by superoxide dismutase 1 (SOD1) mutations; In April, RiboNova announced its self-developed therapy for non-muscle invasive bladder cancer.saRNA Drug RAG-01 Receives FDA IND ApprovalRAG-01 is the world's first saRNA drug of its kind to receive FDA approval, as well as China's first saRNA drug.

RAG-17 is a double-stranded small interfering RNA (siRNA) targeting the SOD1 gene, used for treating amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig's disease) caused by pathogenic mutations in the superoxide dismutase 1 (SOD1) gene. It works by reducing SOD1 protein expression to treat ALS patients with SOD1 mutations. On September 10, 2024, RiboNova announced positive clinical results of RAG-17 in an investigator-initiated clinical study (IIT). Safety assessments included detailed laboratory tests, vital sign monitoring, and electrocardiograms following intrathecal administration.RAG-17 demonstrated good tolerability and safety throughout the study period, with all adverse events being mild.

RAG-01 is a first-in-class saRNA drug designed to activate the tumor suppressor gene p21 in patients with non-muscle-invasive bladder cancer (NMIBC), thereby inhibiting the recurrence and progression of bladder cancer. Previously, RAG-01 had already initiated a Phase I clinical trial in Australia, with three subjects enrolled and dosed.RAG-01 uses the LiCO™ delivery system independently developed by中美瑞康公司.The system uses a unique lipid chemistry approach, supporting multiple drug delivery routes such as subcutaneous, intravenous, intravesical, and intravitreal injections. The versatility and efficacy of LiCO™ have been validated in multiple preclinical projects, enabling efficient and long-lasting delivery to tissues such as the heart, muscle, fat, and eyes, completely revolutionizing the delivery method for oligonucleotides.

In May 2024, Argo's subsidiary, Hangzhou Boli Pharmaceutical Technology Co., Ltd., filed a Class 1 new drug.BW-20507 Injection Receives CDE Clinical Trial Implied Permission, Intended for Development to Treat Chronic Hepatitis BBW-20507 is a small interfering RNA (siRNA) drug independently developed by the company that targets the hepatitis B virus (HBV). On September 13, 2023, the therapy initiated a Phase 1/2 clinical trial in Australia to evaluate its safety, tolerability, pharmacokinetics, and dose escalation in healthy subjects and chronic hepatitis B virus-infected individuals. On June 27, 2024, the first patient was dosed in the Phase 1 clinical trial of BW-20507 for chronic hepatitis B in China at the research ward of Beijing Friendship Hospital, Capital Medical University.

Founded over three years ago, Argo Biopharma, which focuses on the research and development of siRNA, has 30 R&D products in cardiovascular diseases, rare diseases, hepatitis B, autoimmune diseases, and neurological disorders. The company is conducting international synchronized clinical trials in multiple regions, including China, the United States, and Australia.Five pipelines are already in clinical stages.Among them, two drugs targeting the cardiovascular field, after more than two years of research and development, have caught the attention of pharmaceutical giant Novartis with their impressive data. Novartis intends to acquire them in a deal with a potential total value of up to $4.165 billion. In October last year, Argo completed a 300 million yuan Series A+ round of financing. Prior to that, it had completed an angel round of financing worth tens of millions of yuan.

In April 2024, the innovative small nucleic acid drug independently developed by Highnoon BiotechWGI-0301 Receives Clinical Trial ApprovalPreviously, the drug had received the FDA's Phase II clinical trial approval by default in February 2024. Notably, WGI-0301 has also been granted Orphan Drug Designation by the FDA, highlighting its unique value and potential in treating rare diseases internationally.

WGI-0301 is a novel AKT-1 inhibitor successfully developed based on QTsomeTM, a proprietary nucleic acid delivery technology independently developed by High Chance Biotech. This technology efficiently encapsulates the antisense oligonucleotide Archexin within lipid nanoparticles, achieving effective inhibition of AKT-1. As a crucial target for cancer treatment, AKT-1 is closely associated with the proliferation and survival processes of various solid tumors, including advanced liver cancer.WGI-0301 effectively reduces its protein expression by specifically binding to AKT-1, demonstrating a unique anti-tumor mechanism.

In March 2024, Jingyin Pharmaceuticals (Shanghai) Co., Ltd. (referred to as "Jingyin Pharmaceuticals") submittedSRSD107 Injection Receives CDE Clinical Trial Implied Permission, Intended for Development to Prevent or Treat Arteriovenous ThrombosisIn July 2024, Jingyin Pharmaceuticals announced the successful completion of subject enrollment and dosing for the Phase I clinical trial of SRSD107 injection. This Phase I clinical study was conducted simultaneously in Australia and mainland China. Preliminary research data showed that SRSD107 has good safety and tolerability, as well as expected pharmacokinetic characteristics.

SRSD107 Injection is a double-stranded product independently developed by Jingyin Pharmaceuticals.Small interfering RNA (siRNA) drugsBy specifically targeting the liver with coagulation factor XI (FXI) mRNA, protein expression of FXI is inhibited, blocking the activation of the intrinsic coagulation pathway, thereby achieving anticoagulant/antithrombotic effects.

In March 2024, Chengdu Xianyan Biotechnology Co., Ltd. (hereinafter referred to as "Xianyan Biotechnology") submittedA24110He Injection (Lipisense®) Clinical Trial Application (IND) Approved by CDEA24110He Injection, developed by Lipigon Pharmaceuticals, is an ASO drug targeting ANGPTL4, intended for the treatment of severe hypertriglyceridemia.Rigerna owns the rights to this product in Greater China and will jointly advance clinical development with Lipigon.ANGPTL4 is a protein highly expressed in adipose tissue and has become a novel drug target for lipid-lowering therapy following recent research breakthroughs. The A24110He injection aims to achieve long-term triglyceride reduction while improving insulin resistance, intended for treating dyslipidemia, particularly in patients with severe hypertriglyceridemia.

On August 29, 2024, Xianyan Biologics submitted the targeted angiotensinogen (AGT)LDR2402 Injection, a Novel Small Nucleic Acid Drug, Receives CDE Acceptance for Clinical Trial Application (IND)LDR2402 Injection is a novel small nucleic acid drug developed based on RNA interference (RNAi) technology for the treatment of hypertension. The siRNA targeting AGT, after being conjugated with N-acetylgalactosamine (GalNAc), specifically binds to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocyte membranes, enters the hepatocytes, and recognizes and degrades AGT mRNA, thereby reducing blood pressure by inhibiting AGT synthesis. LDR2402 demonstrated the potential for stable and sustained efficacy lasting over six months after a single dose in preclinical animal experiments, showing excellent safety.

Nanjing Jisheng Aoma Biopharmaceutical Co., Ltd. (hereinafter referred to as "Jisheng Aoma") IAMA-001 Nasal Spray is a small nucleic acid immune modulator, intended for development in the treatment of seasonal allergic rhinitis.The product was approved for IND in China in March 2024.Currently, the immunomodulatory small nucleic acid product IAMA-001 nasal spray has completed Phase I clinical trials, demonstrating excellent safety and tolerability, and is about to enter Phase II clinical trials.