However, Lin Wei, manager of Qingqiao Sunshine Fund, who focuses on pharmaceutical investment, believes that nucleic acid drugs have become the core of the third wave of global biopharmaceutical research and development. Even at the stage where they are currently limited to liver

The new crown epidemic has made the mRNA vaccine widely known and has also made small nucleic acid drugs enter more people's vision.

is limited by the immature delivery technology. At present, the targets of small nucleic acid drugs are still mainly limited to liver tissue, and the indications are mostly rare disease and genetic diseases. However, Lin Wei, manager of Qingqiao Sunshine Fund, who focuses on pharmaceutical investment, believes that nucleic acid drugs have become the core of the third wave of global biopharmaceutical research and development. Even at the stage where they are currently limited to liver targets, their application prospects are immeasurable, especially in the fields of chronic diseases such as lipid and blood pressure reduction.

, known as the "first stock of RNA therapy", Dr. Lu Yang, chairman of Shengnuo Pharmaceuticals (02257.HK), told First Financial that new nucleic acid therapy led by siRNA drugs has huge potential. Once the liver targeting restrictions are broken, its wide application scenarios will bring considerable market space, especially in tumor treatment. There is huge demand and development space in the future. "Benchmarking the development process of monoclonal antibody drugs, the market size of nucleic acid drugs still has great potential."

small nucleic acid drugs have outstanding advantages, and delivery technology is the key.

nucleic acids are a biological macromolecule, including DNA and ribonucleic acids (RNA). Among them, those that can be used for disease prevention and treatment are collectively called nucleic acid drugs. Small nucleic acid drugs refer to single-stranded or double-stranded nucleic acid drug molecules with a short length and less than 30 bases or base pairs. They mainly act on mRNA in the cell through base complementary pairing, thereby regulating protein expression to achieve therapeutic effects.

is directly acting on the gene expression regulation level. Compared with protein-targeting therapy, small nucleic acid drugs have many advantages such as short R&D cycle, high success rate, low toxicity in the body, and long efficacy time. Especially in terms of long-term effectiveness, some small nucleic acid drugs that have been on the market have achieved effectiveness of 6-9 months, which is difficult to match between small molecule chemical drugs and antibody drugs.

covers a wide range of targets and a large scale. Its potential indications are another major advantage of small nucleic acid drugs. Due to the special structural requirements for protein targets, there are currently only hundreds of human proteins that can be targeted by small molecule chemical drugs and antibody drugs, while small nucleic acid drugs target RNA, and thousands of known targets, which means that small nucleic acid drugs have a wider potential for therapeutic indications.

Currently, small nucleic acid drugs mainly include two major technical paths: small interfering nucleic acid (siRNA) and antisense nucleic acid (ASO). Among them, antisense nucleic acids dominate the research and development of small nucleic acid drugs due to their early discovery. 9 drugs have been approved for marketing. The nucleic acid interference (RNAi) mechanism was discovered in 1998. Although it started late, it has more outstanding advantages in treatment efficiency, safety and long-term effectiveness. This has attracted more and more companies to join the market and gradually became the hottest nucleic acid drug track. Currently, five siRNA drugs from the industry flagship company Alnylam have been approved by the US and European regulatory authorities to enter the market, and most of the others are still in different clinical stages.

According to Ping An Securities, delivery technology is the key to the preparation of small nucleic acid drugs. Among them, the effective ASO has been modified in large quantities of chemicals, and the need for delivery of vehicles is not necessary. Since siRNA drugs are easy to decompose RNA molecules in the body, the use of high-efficiency transcellular membrane vector delivery technology is the mainstream trend and an important bottleneck in the research and development of this technology.

Lu Yang told First Financial News that "the breakthrough in delivery technology is extremely challenging". A qualified delivery technology needs to ensure accurate delivery, maintain drug activity and have high safety. However, due to individual differences, even the same drug delivery technology may have different effects in different humans and for different indications. Therefore, the real investment in nucleic acid drug delivery technology in clinical applications requires long-term technical accumulation and breakthroughs. At present, small domestic nucleic acid drug companies mostly adopt the fast-follow strategy, the main reason is that innovative breakthroughs cannot be made in delivery technology.

market is still in its early stage of development, and the application prospects of nucleic acid drugs are optimistic. Due to the limitation of delivery technology, the targets of small nucleic acid drugs are still mainly limited to liver tissue. The indications are more concentrated in genetic diseases, rare diseases and individual liver-related chronic diseases. The patient population is small, and the market is still in its infancy.

Ping An Securities statistics show that as of 2020, the global sales of small nucleic acid drugs were around US$3.5 billion, of which the highest sales was Spinraza, developed jointly by Ionis and Biogen. As the world's first drug approved for the treatment of spinal muscular atrophy, it achieved revenue of US$2.052 billion in 2020.

But the future market potential of small nucleic acid drugs is generally optimistic. Lin Wei, manager of Qingqiao Sunshine Fund, believes that even at the moment when it is limited to liver targets, the application prospects of nucleic acid drugs are incalculable, especially in the fields of chronic diseases such as lipid and blood pressure reduction. In terms of lipid-lowering, there may also be competition from other drugs such as monoclonal antibodies, but in the treatment of hypertension and and ATTR diseases, liver-targeted small nucleic acid drugs have unparalleled advantages. Once a breakthrough is made, it will open up considerable market prospects for nucleic acid drugs.

"The market size of about US$10 billion is roughly equivalent to the level that monoclonal antibody drugs have reached after ten years of development (2010). To this day, the market size of a single drug adalimumab alone has exceeded US$20 billion." Lu Yang said that small nucleic acid drugs are still in the early stages of development, and the expansion of market size also depends on people's awareness and acceptance of nucleic acid drugs, and at the same time, it is necessary to increase efforts to expand the coverage of indications.

Lu Yang introduced that the current clear expansion direction of siRNA drugs is mainly in the field of chronic diseases, such as the application in the fields of high cholesterol , hypertension, diabetes and other diseases. There are two breakthrough directions for the future development path of siRNA drugs. One is , central nervous system , which points to brain diseases, such as Parkinson's, Alzheimer's disease, and the other is to the field of tumor treatment. "So far, the clinical demand for tumor treatment has been far from met, and the demand for tumor treatment will exist for a long time, which leaves considerable market space for siRNA drug treatment."

Everbright Securities Previously estimated that the three major areas of infectious diseases, chronic diseases and tumors are combined with five indications. In addition to mRNA new crown vaccine and rare disease nucleic acid drugs, it is expected that the domestic small nucleic acid drug market size will reach 100 billion yuan by 2034.

The domestic nucleic acid drug industry is ushering in the second wave of development

For a long time, small and medium-sized Biotech companies have been the main driving force for the technological progress of small nucleic acid drugs. Currently, 15 companies around the world focus on the research and development of small nucleic acid drugs, including five domestic companies such as Shengnuo Pharmaceutical and Ruibo Biologic .

It is reported that the domestic nucleic acid drug industry has experienced two waves of development climaxes in the past 20 years. The first wave was after the small nucleic acid drug research won the Nobel Prize for in 2007. A large number of domestic biotechnology companies either entered the nucleic acid drug field through their own research and development, or through technology introduction, etc.; in 2018, the development of domestic innovative drugs ushered in the second wave of peak, with a large number of experts and scientific researchers returning to China to start businesses, and nearly 20 companies entered the nucleic acid drug field, but most of them were still introduced into projects through license in for development.

Lu Yang believes that although these drugs have been conducted clinical trials abroad, most projects still face challenges. By conducting domestic research in this way, the risk of failure is high. In contrast, some companies with global layout and promoting technical research at home and abroad and with relatively solid basic skills are more likely to succeed in this wave of nucleic acid drug development.

Lin Wei believes that in the field of nucleic acid drugs, the technical route, delivery technology generation difference advantages, and the first-mover position advantages are the key factors that constitute the core competitiveness of enterprises. When the delivery technology is not yet mature and has not formed a generation difference advantage, the selected technical route will constitute the core competitiveness of nucleic acid pharmaceutical companies. In comparison, companies with siRNA technology routes have more advantages.

Shennuo Pharmaceutical, led by Lu Yang, currently has multiple technology platforms such as polypeptide nanoparticles (PNP), new GalNAc siRNA and respiratory drug delivery, used to develop a wide range of tumor and fibrosis disease drugs. Among them, the company's research in the field of PNP is in the world's leading position.

Lu Yang said that the company pursues the expansion of nucleic acid drug indications to the field of tumor treatment through polypeptide nano delivery technology.Currently, research in this field adopts a robust strategy to gradually verify the accuracy of the target and the safety of the drug from relatively mild skin squamous cell carcinoma. Among the 16 candidates currently under development, the core product STP705 is a dual-target TGF-β1/COX-2 inhibitor. Its pipeline for non-melanoma skin cancer (NMSC) is currently in clinical phase IIb in the United States, and the pipeline for hyperplastic scars (HTS) has also launched a Phase IIa study in the United States.

Ruibo Bio is another leading nucleic acid drug in China, and has established a full technology chain integrated R&D platform for small nucleic acid drugs. On September 19, 2022, Ruibo Bio announced that its independently developed small nucleic acid drug (RBD7022 injection) targeted by PCSK9 was approved to conduct the first human clinical trial in China. This drug is a GalNAc-conjugated siRNA drug for hyperlipidemia.

In addition, BRII-835 introduced by Tengsheng Boyao (02137.HK) from Vir is a siRNA targeting HBV highly conserved DR2 region, which can inhibit the expression of a variety of hepatitis B proteins. It has been completed in phase II clinical practice; STSG-0002, which has independent intellectual property rights under development in Shutaishen (300204.SZ), is a shRNA drug targeting hepatitis B virus. It is currently in phase I and has completed part of the enrollment. No gene drug of the same target has been approved for marketing worldwide.

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