What is small nucleic acid
The occurrence of many human diseases is closely related to the changes in the structure, function and number of proteins, and the synthesis of proteins in the human body follows the central law.
The central law refers to the process of transcription and translation in which genetic information passes from DNA to RNA, and from RNA to proteins, and the process of replication in which genetic information passes from DNA to DNA. According to the central law, protein synthesis is directed and controlled by nucleic acids.
With the development of molecular biology, researchers have found that although some DNA/RNA is not transcribed/translated into proteins, but play an important role in the regulation of transcription/translation process, such as promoters and enhancers in DNA, Ribozyme, microrNA (miRNA), small interfering RNA (siRNA), small activating RNA (saRNA), etc.
Therefore, people have begun to design drugs at the nucleic acid level. Small nucleic acid drugs regulate the synthesis of proteins by directly acting on the RNA related to pathogenic proteins, so as to achieve the purpose of treating diseases.
The development history of small nucleic acid in the past 40 years can be divided into three stages:
In 1978, Harvard University scientist Zamecnik et al. found that a complementary nucleotide chain could inhibit the replication of RSV virus, and first proposed the concept of antisense nucleic acid (ASO). The first ASO drug was approved in 1998, the same year the mechanism of RNAi (RNA interference) was revealed. Three years later, RNAi technology was named one of the top 10 scientific advances of 2001 by Science magazine. In 2006 AndrewFire of the Carnegie Institution and CraigMello of the University of Massachusetts won the Nobel Prize in Medicine or Physiology for their discovery of RNAi mechanisms.
Since then, due to the instability of small nucleic acid drugs, potential immunogenicity and the lack of efficient in vivo delivery technology, the development of small nucleic acid drugs once fell into a low stage.
After 2013, the emergence of new technologies represented by GalNAc conjugate technology and enhanced stabilization modification technology has greatly promoted and promoted the rapid recovery of small nucleic acid drugs and accelerated the drug marketing. The FDA approved the first Rnai-based siRNA drug in 2018.
Up to now, 14 small nucleic acid drugs have been approved for sale worldwide, mainly for rare diseases and other fields. There are three applications for the market, 32 clinical phase 3, 115 clinical phase 2, and 113 clinical phase 1 pipeline under study, respectively. Among the 719 nucleic acid drugs in the world, ASO has the most varieties (253), and the rest are siRNA(229) and mRNA(72). According to Frost Sullivan, the global market size of small nucleic acid drugs has grown from USD 100 million in 2016 to USD 3.25 billion in 2021, at a CAGR of 217.8%. In the future, with the listing of more small nucleic acid drugs and the expansion of the patient population, the market will further accelerate the development.
A number of domestic small nucleic acid drugs have entered clinical practice
As a representative of the new generation of technology in the industry, a number of representative enterprises have emerged in the field of small nucleic acid drugs. Overseas, Ionis, Alynlam and Sarepta are becoming three major small nucleic acid drugs.
Among them, Alynlam is recognized as the hegemon of RNAi drugs. Currently, the four RNAi drugs on the market in the world are all developed by the company and its partners. In 2018, the company successfully launched Onpattro, the world's first approved RNAi therapy, which also means that the Nobel Prize achievement has been successfully brought from concept to practical clinical application. In 2021, Alnylam posted full-year revenue of $662 million and briefly topped $20 billion in market capitalization.
Ionis is a global leader in the research and development of antisense nucleic acid drugs, with a pipeline of more than 40 products in development. Its drug Spinraza (Nusinersen) has been approved for sale in many countries around the world, including the United States and China, and is the largest small nucleic acid drug in the world.
In addition, as the small nucleic acid drug discovery technology is becoming more and more mature, pharmaceutical giants Roche, Sanofi, Novartis have also come off the market, looking for the next "blockbuster" drug opportunities.
Overseas nucleic acid drugs are in full swing, and the domestic industry has also entered a period of rapid growth. In China, 24 small nucleic acid drug candidates have entered clinical trials, and most small nucleic acid drug companies are still in the early stage of development or rising.
Among them, the domestic enterprise with the most drugs in clinical stage is Rebo Biotics, which has 5 products into clinical.
SR062 is domestic first small nucleic acid drugs for type 2 diabetes treatment, developed by Ionis, rainbow biological research, development and cooperation for the treatment of type 2 diabetes, at present in domestic in phase 2 clinical stage, is expected to once every two weeks for medicine, greatly reduce the dosing frequency, such slow disease treatment for diabetes has important clinical significance.
RBD7022 injection is the first domestic PCSK9siRNA drug approved for clinical use. The drug is a GalNAc conjugate siRNA drug for hyperlipidemia, developed by Ribobio based on the RIBOGalSTARTM platform with proprietary intellectual property rights. Preclinical trial data showed that RBD7022 had good safety characteristics and strong lipid-lowering effect, and its lipid-lowering effect showed the characteristics of stable lipid-lowering level and long-lasting effect. After a single administration, the effect could be maintained for several months, and the inhibition of LDL-C could reach more than 50%.
RBD1016(SR016) is the first anti-hepatitis B siRNA drug based on GalNAc liver targeted delivery technology independently developed by Rebobio in China, which can effectively and long-term inhibit hepatitis B surface antigen and is expected to achieve functional cure of chronic hepatitis B. The current phase 1 clinical study is nearing completion.
SR063, the first ASO drug for the treatment of patients with AR-V7 positive prostate cancer, has inhibitory effects on both androgen-dependent and androgen-independent AR pathpath-related metastatic castration-resistant prostate cancer (mCRPC). Currently, it has completed phase 1 clinical study, and will carry out phase 2a clinical study in China.
In addition, in 2012, a joint venture company, Rebo Quark, was established between Rebo Bio-and Quark. In 2020, Rebo Bio-acquired Rebo Quark as a controlling subsidiary and renamed Rebo Gul. The subsequent research and development of SR061 in the licensed area is led and undertaken by Rebo Bio-. SR06 is a small nucleic acid drug with rapid development in China. It is an optic neuroprotective drug targeting Caspase2. Its first clinical indication is non-arteritis anterior ischemic optic neuropathy (NAION), and it is suitable for many ophthalmic indications related to optic nerve injury, including glaucoma. SR061 is currently being analyzed for phase 2/3 clinical data for NAION indications. For glaucoma indications, phase 2a clinical studies have been completed abroad.
In addition, STP705, a leader in the field of tumor RNAi therapy, is the most advanced product of Sunro, which has entered phase 2 clinical trials in the United States. It adopts two siRNA strategies that simultaneously deliver TGF-β1 and Cox-2 to target tumor tissues by intratulotumor injection. Previously published data from the phase 2 interim trial showed 100% complete clearance in the 180-μg dose cohort.
HT-101 injection is a GalNAc-siRNA drug developed by Xing Yao Kunze, a subsidiary of Fosun Pharmaceutical, for the treatment of chronic hepatitis B virus infection. In preclinical efficacy trials, a single dose reduced the expression of multiple key components of hepatitis B virus and sustained inhibition of viral replication for more than 70 days.
In 2021, through the acquisition of Tianlong Pharmaceutical, Yuekang Pharmaceutical began to actively layout mRNA vaccines and small nucleic acid drugs, and comprehensively cut into the nucleic acid track nucleus. Currently, the most advanced small nucleic acid drug CT102 is an antisense nucleic acid (ASO) drug targeting the human insulin-like growth factor type 1 receptor (IGF1R) gene for the treatment of primary hepatocellular carcinoma. The phase 1 clinical study was completed in January 2022, and the clinical 2a trial was initiated in March.
VIR-2218 is a subcutaneously administered siRNA targeting HBV introduced by Tensengbo. It is also the first clinical siRNA to include enhanced stabilization chemoplus technology to enhance stability and minimize off-target activity, indicated for hepatitis B.
