**: Briana***
Among the many types of nucleic acid drugs, small nucleic acid drugs have increasingly prominent clinical advantages due to their rich targets, short R&D cycle, and long-lasting efficacy. With the launch of Novartis' lipid-lowering drug Inclisiran, the clarion call for siRNA to enter the field of chronic diseases has officially sounded, and Roche's $2.8 billion bet has also pushed the research and development of siRNA drugs to a climax.
Overview of the field of siRNA and the advantages of proprietary drugs
According to the different structures, drug mechanisms, and targets, there are five main types of small nucleic acids, covering antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (microRNAs or miRNAs), aptamers (aptamers) and CPG oligonucleotides and aptamer, among which the research on ASO and siRNA are more popular.
siRNA is a class of artificially synthesized double-stranded short RNA molecules, which can combine AGO proteins to assemble into RNA-induced silencing complex (RISC), one of its strands is degraded, and the other strand is combined and cleaved through the principle of base complementarity pairing, and the mRNA that degrades the target gene, blocking the expression of the target protein, so as to achieve the purpose of ** related diseases.
siRNA is an extension of RNAi technology, which can be used to design modalities for a variety of diseases, such as genetic defects in diseases caused by one or a few genes, viral diseases, autoimmune diseases, and cancer. In view of the unique mechanism of action advantages of RNAi, siRNA also has unique druggable advantages.
High specificity: The binding of siRNAs to their targets is highly selective, identifying the target sequence and mediating its cleavage by using approximately the full length of the mRNA. The ability to distinguish sequences that differ by only one nucleotide makes siRNAs a suitable tool for disease**.
Unrestricted target selection: siRNA can silence the expression of almost any gene in the genome, which has a wide range of potential, and is expected to target "undruggable" targets in existing methods.
High efficiency: Since a single siRNA guide strand can be cycled through multiple rounds of mRNA cleavage, high efficiency can be achieved under the correct triggering conditions.
Up to now, 15 small nucleic acid drugs have been approved for marketing around the world, and in addition to 3 ASO products that were withdrawn due to low sales, there are 7 ASOs and 5 siRNA drugs that are still on the market. According to the relevant financial report data of various companies, the sales of 5 listed siRNA drugs have risen well, and the latest Q3 sales also show that on the whole, the sales growth rate of siRNA small nucleic acid has surpassed that of ASO small nucleic acid.
Global sales statistics of listed siRNAs.
Data**: Compiled based on publicly available data such as corporate financial reports.
Chronic diseases breed the next "hit" of small nucleic acids
At present, the small nucleic acid drugs on the market are mainly rare diseases, and Novartis' new lipid-lowering drug Inclisiran (Inkslane Sodium Injection) is the only small nucleic acid siRNA for chronic diseases.
Inclisiran binds directly to the mRNA encoding the PCSK9 protein, reducing mRNA levels through RNA interference, thereby preventing the liver from producing PCSK9 protein, and only needs to be received twice a year** after the initial injection and after the third month**. In August this year, Inclisran was officially approved for marketing in China, becoming the first siRNA drug to land in China, and the first batch of prescriptions was issued in China in October. At present, inclisran has been approved in 70 countries around the world, including the United States, the European Union, and China.
The current lipid-lowering market is more widely used statins, but the frequency of daily administration is a pain point, and later it was considered that the star targeted drug PCSK9 monoclonal antibody for lipid-lowering came out, although it has improved patient compliance, but still needs to be injected once every two to four weeks, the emergence of Inclisiran, has brought a new lipid-lowering **, compared with PCSK9 monoclonal antibody and traditional antihypertensive drugs, Inclisiran not only has a good effect, but also the administration method similar to the vaccine greatly improves patient compliance.
With its excellent efficacy and dosing advantages, Inclisiran performed well in the market after its launch, and according to Novartis' financial report, Inclisiran sales in 2022 were 1$1.2 billion;In the first half of 2023, its sales increased nearly threefold (+293%) to 14.2 billion US dollars, and 0900 million US dollars, achieving rapid growth.
Novartis revealed that Inclisiran is currently in the stage of high-speed volume, which is close to the volume rate of Novartis' current core drug Entresto, which will sell 29$1.5 billion.
According to iHealthcareAnalyst's latest analysis, the global dyslipidemia drug market share will exceed $39.8 billion by 2025, and the compound annual growth rate is expected to reach 99%, China is a big country with chronic diseases such as hyperlipidemia, and the Toubao Research Institute has estimated that the overall market size of domestic hypolipidemic drugs is expected to reach 50 billion yuan in 2024, and the compound growth rate in the next five years can reach 135%。
For more than 20 years since the first small nucleic acid drug was launched in 1998, only Lonis Biogen's Spinraza (nusinersen) has exceeded the $1 billion mark in annual sales, and the rest of the small nucleic acid drugs have also achieved sales growth, but the growth rate is small. Based on the broad lipid-lowering market, Evaluate Pharma has also estimated that Inclisiran's annual sales will exceed $3 billion, and Inclisiran is just around the corner to become a hit in the field of small nucleic acids that surpasses Spinraza.
SIRNA's chronic disease space has been fully opened, and domestic enterprises have launched a rapid attack
The successful launch of inclisiran has made the first collision between siRNA** and the lipid-lowering drug market spark, and also led to the research and development of siRNA** for chronic diseases.
On July 20 this year, Alnylam announced the results of the clinical trial of Zilebesiran, a siRNA drug for hypertension, and officially announced the clinical data of this new antihypertensive drug that only needs to be used twice a year.
As soon as the results were released, Roche reacted extremely quickly, only four days apart, on July 24, Roche quickly reached an agreement with Alnylam to jointly develop and commercialize Zilebesiran, the potential total value of the deal will be as high as 2.8 billion US dollars, Roche's operation is quite a shadow of Novartis spent a huge $9.7 billion to introduce Inclisiran from Alnylam.
Like hyperlipidemia, the population of hypertensive patients is also extremely large, and the existing antihypertensive drugs in the market generally cause large fluctuations in blood pressure due to the short half-life of the drug, so that the condition cannot be well controlled.
Roche and Alnylam both attach great importance to this siRNA antihypertensive drug, and are in full swing to promote clinical research, and the two have cooperated for less than two months, and on September 7, they jointly announced that the phase II clinical trial of zilebesiran was successful.
At present, the main common chronic diseases in addition to hyperlipidemia, hypertension, and hepatitis B, the global market size of these three chronic disease drugs is nearly 100 billion US dollars, Novartis and Roche's successful entry, siRNA ** in the field of chronic diseases in the field of imagination space has been constantly opened, this piece of hidden huge wealth of the blue ocean, domestic enterprises will not miss it, participating in the layout of Sirnaomics Pharmaceutical, Suzhou Ribo Biotechnology, Shengyin Biotechnology, Junshi Biotechnology, Hengrui Pharmaceutical, etc.
According to incomplete statistics, there are more than 12 new siRNA drug pipelines under development around chronic diseases in China, among which the pipeline of new siRNA drugs with high blood lipids includes RBD7022 and RBD5044 of Ribo Biotech, BW-00112 of Bowang Pharmaceutical, SGB-3403 of Shengyin Biotech, JS401 of Junshi Biosciences, etcThe pipeline of new siRNA drugs for hepatitis B includes HRS-5635 from Hengrui Pharmaceutical, AB-729 from Qilu Pharmaceutical, BRI835 from Brii Biosciences, RBD1016 from Ribo Biosciences, HT-101 from Fosun Pharma, etc., while the pipeline of new siRNA drugs for hypertension is BW-00163 from Bowang Pharmaceutical.
Recently, Huadong Medicine also announced that it has reached a strategic cooperation with Saint Bio to jointly develop siRNA drugs for chronic metabolic diseases based on Cause's Leadm (Ligand and Enhancer AssistedDeliverV) innovative technology platform.
With more and more companies at home and abroad devoting themselves to the track, siRNA chronic disease drugs have come to the early stage of the outbreak, or will lead a new drug revolution in the field of small nucleic acids, wait and see.
References: 1. "siRNA Industry Research Report", Chenyuan Venture Capital, February 13, 2023.
2. "Novartis Roche is betting on the next 10 billion drug", Pharmaceutical Vision, October 8, 2023.
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