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Asymchem builds one stop siRNA drug CMC platform
2019-12-24 19:46

Since USFDA's approval for Vitravene,one antisense oligonucleotide in 1998 and A. Fire and C. Mello uncovering themechanism of RNA interference in 1998, nucleic acid drugs experience disruptiveprogress in recent years after 20 years’ pharmaceutical development. Seven nucleicacid drugs have been launched since 2016 (Chart 1), among which Spinraza was a$1.7 billion blockbuster drug. The first critical Phase III clinical study ofthe groundbreaking PCSK9 targeting Inclisiran, a lipid-lowering siRNA drug, isa great success, proving once again the technological advantages and potentialof the next generation nucleic acid drugs. The drug developer Medicineswas later acquired by Novartis for $9.7 billion, demonstrating thebright future of the siRNA drug market. Conservative estimates show that the siRNAdrug market will reach more than $10 billion by 2025.  

Chart 1. Nucleic acid drugs launched

Source: Cortellis database

Compared with traditional small molecular chemicals, proteins and antibody drugs, siRNA drugs enable more targeted gene therapies by targeting directly on hereditary materials. Take Figure 1 as an example, siRNA can be combined with proteins to form siRNA induced interference complex (RISC), then RISC combines with complementary mRNA to degrade the target gene mRNA and finally silence specific gene expression.

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Figure 1. RNA interference diagram

Source: Richard Robison from Wikipedia

The mechanism of siRNA drug contributes to the advantages of high specificity, high efficiency and long-lasting effectiveness, as well as short R&D period and more candidate targets. Currently siRNA drugs launched / in the clinical stage are indicated for rare diseases (amyotrophic lateral sclerosis, duchenne muscular dystrophy, spinal muscular dystrophy), tumors, viral diseases, kidney diseases, cardiovascular disease (hereditary antithrombin deficiency, dyslipidemia, etc.), inflammatory diseases (asthma, arthritis, colitis), metabolic diseases (diabetes, non-alcoholic steatohepatitis) and so on. siRNA drug is described as the dark horse in innovative drugs and expected to treat the genetic diseases that have no cure up to now, bringing great hope for the treatment of many diseases. (Figure 2). 

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Figure 2. Advantages of siRNA drugs  

Source: Asymchem

siRNA drug got into a difficult situation in the initial stage due to lack of good stability, poor drug delivery systems and toxic side effects caused by off-targeting. But continued progress has been made in gene sequencing technology, cost reduction and drug delivery systems, especially the liver targeting research platform represented by GalNAc and the application of lipid nanoparticle formulation technology (Figure 3, Figure 4). The results solved the fundamental problems that affected in vitro drug delivery performance, greatly enhanced the safety and efficacy of the drug. Thus siRNA drug went through the difficult time, and the whole industry has regained confidence.

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Figure 3. GalNAc structure and Conjugates

Source: Guangzheng Heng Sheng

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Figure 4. Lipid nanoparticle formulation technology

Source: Online information

More and more siRNA drugs for different indications will be approved for marketing, especially for cardiovascular diseases and hepatitis B, and the CDMO market accordingly will be emerging. The significant achievement is driven by technological breakthroughs made over past years by biotech companies represented by Alnylam, Ionis, Arrowhead, Dicerna, Wave, and Suzhou Ribo, plus the re-engagement of large pharmaceutical companies represented by Pfizer, Lilly, Merck and Novartis, as well as capital and expedited drug review. However, compared with small molecule drugs, regulations on siRNA drug registration still need to be improved, production process of raw material and formulation is more complex, either synthetic purification or quality control highly deepens on equipment, and large quantity of waste is generated (PMI> 10000). These factors rise higher requirements for the CDMO industry of siRNA drugs. 

With over 20 years’ commitment in the industry, Asymchem Laboratories (Tianjin) Co., Ltd. (SHE: 002821. SZ, “Asymchem”) has deep expertise in CMC for the small molecule drugs. Asymchem is widely recognized as a strategic partner or preferred supplier by over 400 pharmaceutical companies including global Top 10 and biotech companies worldwide due to its experienced professionals, cutting-edge green pharmaceutical technologies such as continuous reactions and biotransformation, established GMP and EHS system, and rich experience in project management. Asymchem continues to expand its CDMO success in small molecules to chemical macromolecules represented by peptide and siRNA and biomacromolecules represented by antibody.   

To further enhance the siRNA business, Asymchem has been devoted to improving the production process to be a qualified one-stop service provider of siRNA CMC(Chemical Manufacturing & Control)(Figure 5). Asymchem has formed a siRNA team of over 50 staff to conduct the process development, analytical development, and GMP production, including overseas PhD returnees and professionals with more than 10 years’ experience and over 60% staff with a master’s or /PhD degree. The investment on equipment approximately reaches 100 million Chinese RMB. Asymchem has provided CMC for several siRNA drugs in preclinical or clinical phase and expedited the pharmaceutical R&D process through professional services, improved management systems and mature supply chain.   

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Figure 5. Business scope for siRNA CDMO 

Source: Asymchem

Asymchem has always adhered to technology–driven development and continuously promotes the innovative development of green pharmaceutical technology and other new technologies. As a state certified “Green Factory” in 2017, Asymchem has developed a complete EHS system and can solve problems of waste generation in commercial production through effective waste treatment methods and device to achieve green and sustainable development of the industry. Asymchem sticks to its philosophy of “the customer always comes first”, as well as strict industry standards and superior production quality. Working in accordance with the sincerity and precision that defines our corporate culture and the principle of “Green, Safe, Reliable” in R&D and production, Asymchem is widely recognized by global clients. These excellent practices will continue to be carried out in siRNA business to provide best services with the highest delivery quality to our customers.

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