In 2006, Alnylam became one of the top five biotechnology companies in the world to demonstrate the research and development of new RNAi drugs

In the field of RNAi new drug development, Alnylam pharmaceuticals is a "star company" of great concern In 2018, the company's onpattro (paisiran) became the first FDA approved RNAi therapy This week, the FDA approved the company's givlaari, the second FDA approved RNAi treatment in the world In addition, inclisiran, developed by the company in cooperation with the medicines company, will also submit regulatory applications this year, which is expected to become the first RNAi therapy to reduce "bad" cholesterol next year After successive breakthroughs, Alnylam today held an R & D Day event in New York, which showed us its grand blueprint for realizing the potential of RNAi as a "Nobel Prize" technology application The company expects to obtain two FDA approved new RNAi therapies in 2020, with six late stage clinical projects, and 14 clinical development projects in four strategic therapeutic areas (STATs) Moreover, the company's R & D pipeline is expected to generate 2-4 preclinical therapies per year to support ind applications By 2025, the company hopes to become one of the world's top five independent biotechnology companies with more than 8 approved therapies and more than 10 late stage R & D projects! Let's take a look at how Alnylam is moving towards this grand goal RNA interference (RNAi) is a way of regulating gene expression in organism After RNAi mechanism was discovered, its potential in the development of new drugs soon got attention Because the advantage of this mechanism is that it can target any gene in the silenced genome and has a strong and lasting mechanism of action It is not only able to solve the problem that pathogenic proteins cannot be made into medicine, but also simpler in drug synthesis than screening small molecules or generating biological agents Source: reference [2] However, there are also unique challenges in the development of RNAi therapy This includes how to deliver RNAi therapy to the cells and avoid the side effects caused by Miss target effect Based on more than ten years of research and development, Alnylam has made great progress in targeted delivery of RNAi therapy and reduction of its toxic and side effects The approval of onpattro and givlaari is the best proof On the R & D day, the company further introduced the research progress in enhancing RNAi security and expanding its scope of application The side effects of RNAi therapy have always been one of the core problems that perplex the application of RNAi therapy in a large number of patients Alnylam's enhanced stabilization Chemistry (ESC) delivery technology platform can not only improve the stability of RNAi therapy, but also promote liver targeted delivery of RNAi therapy by GalNAc chemical modification of RNA fragments This technology has been used for the first time on the recently approved givlaari However, it is still possible for this therapy to silence other non target genes in the liver, leading to hepatotoxicity Alnylam's researchers found that one of the main reasons for RNAi's Miss target effect is that a part of the siRNA sequence that binds to the target mRNA may play the same function as microRNA (miRNA), which can combine with the 3-terminal UTR (3'UTR) of other mRNA to inhibit the translation and stability of mRNA In order to reduce this "Miss target effect", the researchers deliberately added a glycol nuclear acid (GNA) which could not match any base in the RNA fragment The addition of GNA can significantly reduce the possibility of RNAi therapy regulating other mRNA translation in the form of microRNA, and further improve the safety of RNAi therapy Alnylam calls this technology ESC + Source: reference [2] In human clinical trials, this technology has been verified by concept Vir-2218 (aln-hbv02), developed in cooperation with vir biotechnology, is a RNAi therapy to inhibit the expression of HBV protein Using ESC + technology, it can not only reduce the proportion of patients with hepatotoxicity from 2 / 18 (the highest dose of 3 mg / kg) to 0 / 31 (the highest dose of 10 mg / kg), but also reduce the level of HBsAg by 2.3 times ▲ ESC + technology gets concept verification (picture source: reference [2]) Now the technology of liver targeted delivery of RNAi therapy is becoming more and more mature How to deliver RNAi therapy to other tissues of the body? Alnylam also presented the initial results of its RNAi therapy targeting the central nervous system and ophthalmic targets The company's RNAi therapy targeting the mRNA encoding amyloid precursor protein (APP) in non-human primates, one intrathecal injection can reduce app mRNA levels in different tissues of the central nervous system by 50% - 75% However, intravitreal RNAi therapy can also reduce the expression of target protein in a dose-dependent manner ▲ performance of RNAi therapy targeting central nervous system and ophthalmic targets (picture source: reference [2]) In addition, the company's latest development of oral RNAi delivery technology in non-human primates also completed the concept validation experiment This breakthrough may lead to RNAi therapy that only takes 3 or 6 months for patients, and provide more options for drug development ▲ results of concept verification of oral RNAi therapy in non-human primates (picture source: reference [2]) The company is also developing other innovative RNAi technologies, including bis RNAi, which targets two different mRNA at the same time, and reverser, which can quickly and specifically reverse the gene silencing effect of RNAi The development of these technologies will provide more possibilities for RNAi technology platform Source: reference [2] In 2020, Alnylam expects two innovative RNAi therapies to be approved by FDA One of them is inclisiran, which works with the medicines company The latest clinical trial results of this therapy have been interpreted in detail by the content team of Wuxi apptec, and will not be repeated here Another promising RNAi treatment is lumasiran for primary hyperoxaluria type 1 (Ph1) Ph1 is a rare hereditary liver disease Due to the mutation of gene encoding human alanine glyoxylate aminotransferase (AGT), AGT is absent in patients This will cause excessive oxalate in the body of the patient, which can not be excreted in time in the kidney Severe Ph1 patients often need liver and kidney transplantation because of oxalate deposition in many parts of the body, which damages the kidney and related organs Lumasiran (aln-go1) is a subcutaneous RNAi therapy It targets the mRNA encoding the hao1 gene of glycolate oxidase (go) in the liver To reduce the production of oxalate in the liver by reducing the expression of go Action mechanism of lumasiran (picture source: reference [2]) The results of the open label extension study of the phase 1 / 2 clinical trial showed that the average urine oxalate level of patients treated with lumasiran was reduced by 76% compared with the baseline, and 68% of patients' urine oxalate level was reduced to the normal range ▲ results of lumasiran's extended study (picture source: reference [2]) At present, the top line results of the phase 3 clinical trial illuminate-a supporting lumasiran's application for listing will be obtained by the end of this year If the results are positive, Alnylam plans to submit a new drug listing application (NDA) in early 2020 On the R & D day, Alnylam predicted that from now to 2025, there will be 2-4 R & D projects in the company's R & D pipeline that can submit ind applications every year, which is expected to enter the clinical development stage In addition to targeted delivery of multiple therapies to the liver, Alnylam has also worked with regeneron to develop three targeted delivery to the central nervous system and two targeted delivery to the eye RNAi therapies Among them, there are a number of in-depth therapies that are expected to treat a large number of public diseases Source: reference [2] For example, aln-hsd targeting hsd17b13 mRNA is a RNAi therapy aimed at the treatment of nonalcoholic steatohepatitis (NASH) The loss of function mutation of hsd17b13 gene found in human genetics can reduce the risk of Nash and other chronic liver diseases, so it is an ideal target for RNAi treatment Aln-hsd can knock down the level of hsd17b13 protein by 90% through one injection in preclinical experiment Currently, Alnylam is conducting preclinical research in support of ind and is expected to submit an ind application in 2020 Source: reference [2] In non-human primate experiments, aln-app, which targets mRNA encoding app protein, can reduce the level of app β in cerebrospinal fluid by up to 80% in one injection The β - amyloid produced by abnormal cleavage of APP protein is considered to be one of the important causes of Alzheimer's disease Therefore, this therapy can be used to treat patients with early-onset Alzheimer's disease and other genetic diseases caused by APP gene mutations, such as hereditary cerebral amyloid angiopathy (HCAA) Source: reference [2] It is true that it is not easy to develop a successful RNAi therapy, which needs to overcome the challenges of side effects, delivery methods and other aspects However, Alnylam has different views on this On the R & D day, a picture of the company showed that the positive success rate of Alnylam's R & D project from phase I clinical progress to phase III clinical trial results reached 54.6%, far higher than the industry average of new drug development This is because all research and development projects are based on targets verified by human genetics, and the use of biomarkers is part of all research projects Once the challenges of side effects and delivery methods are overcome, the successful development of RNAi therapy becomes relatively simple At this time, the limiting factor of RNAi therapy development will be how to find the right target Source: reference [2] To this end, Alnylam has worked with biobank in the UK to discover gene mutations that have been reported in the scientific literature from its database The company said a search of the biobank database had found about 800 genes These genes have had homozygous or heterozygous loss of function gene mutations in human populations If these alleles with loss of function mutations are related to reducing the risk of specific diseases, they may be suitable targets for RNAi knockdown On the R & D day, Alnylam also introduced a number of other in-process therapies, including RNAi therapy fitusiran, which is authorized to Sanofi to develop jointly The treatment has recently been approved in China Due to the limited space, this article will not be repeated Click "read more" at the end of the article to read the PPT document (211 pages) of research and development day of Alnylam company Dr John maraganore, CEO of Alnylam, said that in the next six years, the company aims to become one of the five independent global biotechnology companies in the world Can Alnylam unleash the potential of RNAi therapy to achieve this ambitious goal? Let's see Source: reference [2] reference material: [1] Alnylam Announces 2020 Product and Pipeline Goals and Provides Updates at R&D Day Retrieved November 22, 2019, from http://investors.alnylam.com/news-releases/news-release-details/alnylam-announces-2020-product-and-pipeline-goals-and-provide