Observation on the Prospects of Nucleic Acid Drug Market and Blockmir Platform

Source: Financial News Network http://news.chnews.net/gcc/202306/563049.html

On the Market Prospects of Small Nucleic Acid Drugs   

1、 Small nucleic acid Drug development

The war between humans and diseases is inherent and has a long history. Is there a "perfect drug" that can be used anywhere, with minimal side effects... is this a real existence or just a dream? Small nucleic acid drugs can be said to carry the dream of such a human "perfect drug".

More than 80% of the pathogenic proteins related to human diseases cannot be targeted by conventional small molecule drugs and biomacromolecule preparations, and are considered non drug protein targets. RNA (ribonucleic acid) is an important bridge connecting genes and proteins, so nucleic acid drugs are not only not limited by their own structure, but can break the "difficult to form drugs"; It can also significantly expand the target range and break the "non fungibility". Traditional drugs are limited to around 500 producible genes, while RNA technology can carry out pharmaceutical research and development around over 2000 known target genes. It can be said that RNA technology has broadened the source and development direction of human drugs, theoretically inhibiting any gene. That is to say, genetic diseases and other difficult to treat diseases that currently do not have drugs are expected to find solutions through this approach.

In recent years, small nucleic acid drugs have been hoped to become the "third pharmaceutical wave" after small molecule drugs and recombinant protein/antibody drugs due to their design and development being not limited by the drug producibility and target of proteins. Nucleic acid medicine is also recognized as a "sharp weapon" against cancer, senile dementia, diabetes and other persistent diseases. The short research and development cycle and high success rate of nucleic acid drugs have also refreshed the investment community's impression of the traditional biopharmaceutical industry. Unlike the large-scale compound screening required for the development of small molecule drugs, the digital design of small nucleic acid drugs has led to faster early development speed and a breakthrough in clinical research and development success rate. Taking leading pharmaceutical company Alnylam as an example, its research and development project has progressed from phase 1 clinical development to phase 3 clinical development with a success rate of 59.2%, far higher than the pharmaceutical industry's average clinical development success rate of 5.5%.

With the continuous breakthroughs in core technologies, nucleic acid drugs have gradually unleashed huge market potential and are changing the treatment methods of diseases.

2、 Listing status of small nucleic acid drugs on the market

2.1 Listing and sales situation

In 2016, Spinraza developed by Lonis&Biogen and Exonys 51 developed by Sarpata Therapeutics were successively launched, marking the beginning of rapid development of small nucleic acid drugs. As of now, 16 small nucleic acid drugs have been approved for release globally (but early products such as Kynamro, Vitravene, and Macugen have been delisted), including 14 small nucleic acid drugs and 2 mRNA vaccines. Seven of them have annual sales exceeding $100 million, especially Spinraza, which achieved sales of $1.794 billion in 2022. According to the Q1 financial reports of various companies in 2023, the total revenue of globally listed small nucleic acid drugs has reached 1021.8 million US dollars (excluding the Japanese new drug Viltepso)

The market tends to believe that ASO (Anti sense Oligonucleotides) drugs are more mature in commercial development, with a share of nearly 80% in the overall small nucleic acid drugs. The ASO drug Spinraza is currently the most expensive small nucleic acid drug on the market worldwide. As the first FDA approved SMA treatment drug, Spinraza was jointly developed by Biogen and Ionis and officially approved by the US FDA in December 2016; Approved in the European Union in June 2017; Listed in China in February 2019. According to the official website of the National Center for Biological Information in the United States, Spinraza is priced at $118000 per injection, resulting in a treatment cost of $708000 in the first year and $354000 annually thereafter. According to the Chinese pharmaceutical information platform, the reference price for Spinraza injection is 69.7 million units.

In addition, on March 7, 2023, AstraZeneca Pharmaceuticals and Ionis' ASO type drug "Eplontersen" applied for listing in the United States for the treatment of hereditary amyloidosis of Thyroxine protein. The drug has been granted Orphan drug (ODD) qualification by the US Food and Drug Administration (FDA) in early 2022.

In 2020, the global sales of small nucleic acid drugs were around 3 billion US dollars, and in 2021, the global sales of small nucleic acid drugs were 3.25 billion US dollars. The global market size of small nucleic acid drugs has increased from 10 million US dollars in 2016 to 3.25 billion US dollars in 2021, with a compound annual growth rate of 217.8%. According to public data in 2022, the global market size of 15 approved small nucleic acid drugs has reached 3.784 billion US dollars, an increase of 14% year-on-year. It is expected that the global sales of small nucleic acid drugs will exceed 10 billion US dollars by 2025, with a compound growth rate of 66%. We have reason to believe that in the future, with the continuous verification and listing of nucleic acid drugs in the clinical stage, it will further drive the rapid development of the market, and the market for nucleic acid drugs with a scale of hundreds of billions is about to open.

In China, no other small nucleic acid drugs have been approved for marketing in China, except Spinraza, which was approved as a Orphan drug. However, there are also many domestic enterprises with layout, such as Sano Pharmaceutical, Ruibo Biology, and Yuekang Pharmaceutical (2


2. 2 Prospects for the Development of Traditional Chinese Medicine 

From the perspective of indications of listed drugs, they mainly focus on Rare disease. However, with the increasing application of small nucleic acid drugs in chronic diseases, hepatitis, tumors and other fields, they will have greater development potential and clinical value in many indications; There is no lack of clinical trials for major diseases such as tumor, diabetes and hepatitis B in the clinical research pipeline of small nucleic acid drugs, which will greatly make up for the lack of commercial blockbuster varieties, with huge potential. Once drugs are successfully launched in these fields in the future, the market space will undoubtedly increase exponentially.

The exploration in the field of small nucleic acid drugs is still in the front-end stage, but the advantages of small nucleic acid drugs such as short research and development cycles, long-lasting effects, high success rates in research and development, low susceptibility to drug resistance, and wide therapeutic fields have made them a new favorite in the pharmaceutical industry.

3、 Investment and financing situation in the field of small nucleic acid drugs

Now entering the market for antibody drugs and small molecule drugs, some future trends can be seen from the market value of the US stock market. The market value of AI Pharmaceutical's leading company is 1.7 billion US dollars; Market value of Synthetic biology head company: 4.8 billion US dollars; The market value of top nucleic acid drug companies is $27 billion, and several smaller nucleic acid companies also have a valuation of $9 billion. Bowang Pharmaceutical was established in 2021. After obtaining angel round financing in April 2021, it obtained over 400 million yuan in A-round financing in 2022 to promote the entry of RNA drugs into IND.

According to the Yaorong Cloud Database, there were a total of 10 investment and financing events in the field of small nucleic acid drugs in China in 2022.

3.1 Sino American Ruikang has completed nearly 200 million yuan of A+round financing

Financing time: January 27, 2022

Investment institutions: National Investment and Entrepreneurship Corporation, Nippon Eisai, LinkedIn Venture Capital, China New Capital, and Chengdao Xianghe

China-U.S. Ruikang is a platform based new drug R&D company based in China and facing the global market, committed to developing and commercializing RNA activation technology. China-U.S. Ruikang has built two key technology platforms, "Smart TTC" and "SCAD", with independent intellectual property rights, actively promoted more than 10 small activated RNA (saRNA) Drug development pipelines, and developed rapidly in Rare disease, tumors, central nervous system, liver targets and other fields, of which two key projects have entered the IND enabling development stage.

3.2 Aima Biology has completed angel round financing worth tens of millions of yuan

Financing time: February 7th, 2022

Investment institution: Dinghui Investment VGC Fund

Aima Biology focuses on the drug development of diseases whose clinical needs have not been met, especially the development of Synthetic biology self-assembled exocrine nucleic acid drugs in the fields of Central nervous system disease, infections and tumors. The company has a brand new third-generation small nucleic acid delivery system, which is expected to break through the delivery bottleneck of nucleic acid drugs, achieve targeted delivery of new multifunctional gene components, and strive to build a globally leading platform based nucleic acid innovative drug company.

3.3 Bowang Pharmaceutical has completed a round A financing of over 400 million yuan

Financing time: March 23, 2022

Investment institutions: Zhengxingu Capital, CPE Yuanfeng, Daoyuan Capital, Sany Innovation Investment, Jinsha River Joint Venture Capital

Bowang Pharmaceutical was founded in 2021 by experienced scientists in the development of digital siRNA drugs. The company is committed to developing a new generation of siRNA drugs to provide better treatment for patients worldwide. The team has many years of professional experience in the entire process of RNA drug development, including nucleic acid sequence design, chemical modification, GalNAc delivery technology, extrahepatic delivery technology, oligonucleotide synthesis, CMC, and other RNAi drugs.

3.4 Darui Biotech completed a Series A financing of $33 million

Financing time: April 7th, 2022

Investment institutions: Lilly Asia Fund, CMB International, Platanus, Fengchuan Investment, Lanting Capital

Established in 2021, Darui Biotechnology is committed to discovering and developing modular and programmable nucleic acid drugs to benefit patients around the world. With the support of blue chip investors, Darui Biotechnology has developed its own intellectual property RAZORTM platform to develop differentiated siRNA drug molecules from next-generation chemical modifications and novel biological insights.

3.5 Ruibo Biotechnology completed a $40 million E1 round of financing

Financing time: July 29th, 2022

Investment institutions: Panlin Capital, Sany Innovation Fund

Founded by senior overseas returnees and domestic expert teams in 2007, Ribo Biology is committed to the research and development of small nucleic acid Drug development with independent intellectual property rights, as well as the development and commercialization of clinical projects worldwide. The efficient and long-lasting RIBO GalSTARTM liver targeted delivery technology independently developed by Ruibo Biology has reached international level. The company's continuous development has gained the favor of many investors and has completed multiple rounds of equity financing with a total amount of over 1.5 billion yuan.

3.6 Onto Biotech completed nearly 100 million yuan of seed round financing

Financing time: September 19th, 2022

Investment institution: Xingze Capital

Founded in 2022, Onto Biotech is a drug development enterprise based on antisense nucleic acid technology. Based on the team's previous cutting-edge research in the industry, Onto Biology has built an internationally leading unique and efficient siRNA technology platform and an ASO technology platform for bidirectional regulation of protein expression, greatly expanding the range of treatable diseases. Ontop currently focuses on the research and development of innovative drugs based on new antisense nucleic acid technology, mainly developing nucleic acid drugs to treat liver targeted and extrahepatic targeted metabolic common diseases and severe Rare disease.

About Maijinjia Company

The first advantage: a tight and complete patent wall

Most domestic small nucleic acid companies are Sino foreign joint ventures, and the patents for excellent targets are basically in the hands of developed countries in Europe and America. Overall, the domestic small nucleic acid market is in a catching up stage.

McKinley also has the "Danish element", the support and participation of the inventor of locked nucleotides and the academicians of the Royal Danish Academy of Sciences and Letters. However, unlike many small nucleic acid companies, McKinley has developed Blockmir nucleic acid Drug development technology and Dosevo nucleic acid drug screening technology. The company has the global ownership of all relevant patents, rather than the right to use them for a period of time or in a certain region. At the same time, the company has applied for extensive patent protection for Blockmir technology in the world. It has a wide patent portfolio in Europe, North America, China and Japan, covering the entire platform (327 miRNAs and all their mRNA targets), the second generation Decorator pattern, and several individual BlockmiRs for specific targets. It also includes a method to screen Blockmir from large libraries with or without conjugation, forming a tight patent protection wall. The absolute control over the complete intellectual property rights of Blockmir technology patents has enabled the company to firmly grasp the initiative, which is of great importance for the company's next development. Previously, a well-known small nucleic acid pharmaceutical factory in Suzhou, also known as Suzhou Ruibo, the representative manufacturer of ASO (Anti sense Nucleic Acid Drugs) mentioned earlier in this article, withdrew its listing application due to the pipeline being authorized by a foreign biotechnology company. When submitting its listing application, the regulatory authorities questioned its innovative ability and ultimately withdrew it.

The second major advantage: the platform and product pipeline that can be quickly replicated are equally important

After the epidemic, the most popular biotech venture capital industry may be "platform" companies. Once the "platform" technology is validated, it seems to mean that the company can replicate successful experiences on a large scale, without worrying about pipelines and products, and without worrying about going public and returns. However, these overestimated companies also suffered the greatest impact in the capital cold winter after the COVID-19 epidemic. What is the reason? The important reason is that there are only "platforms" without "products". In short, the quality of research and development projects is more important than the quantity. If the project quality is low, the value of the platform will decrease with the expansion of scale. A valuable platform is one that can find a small number of valuable projects, rather than a large number of mediocre projects. It can be expected that companies with first in class or best in class potential will have both replicable platforms, ongoing research pipelines for key research, and "strong backers" for products awaiting regulatory approval.

Based on the research achievements of the Jesper Wengel academician team over the past 15 years, Maijinjia Company has established an efficient and tightly protected blockmir technology based drug screening platform. Many Animal testing have confirmed the effect of blockmir technology; The distribution test in the brain of Blockmir mice was completed, and it was confirmed that Blockmir drugs could reach almost all parts in the brain, and could enter various functional cells; Confirmed that Blockmir can indeed upregulate protein expression in mice (Aldo A target); Partially confirmed the half-life of Blockmir drugs, etc. Since 2007, various international research groups have conducted research on blockmir technology, and their research results have been recognized by top international journals. Currently, the cumulative number of relevant literature published internationally has exceeded 100.

In addition to the platform, Mai Jinjia has 8 pipelines under research, including cerebral cavernous malformation, acute respiratory distress syndrome, nonalcoholic fatty liver disease, Parkinson's disease, age-related macular disease, glucose transporter 1 deficiency syndrome, aging, hepatitis C, etc. Shenzhen Advanced Technology Research Institute of the Chinese Academy of Sciences is working with Mai Jinjia to develop a new treatment for protein diseases in rare neurodegenerative diseases based on the Blockmir technology platform, and will soon complete cell experiments and prepare for animal experiments. The First Affiliated Hospital of Sun Yat-sen University is also cooperating with Mai Jinjia in the research of nucleic acid drugs for acute respiratory distress syndrome (ARDS), which has entered animal experiments and has obtained positive data. In addition, the platform has established early research channels for liver and Central nervous system disease, and has selected targets for these research channels to find a direct link between genes and diseases.

Third major advantage: advanced technology to overcome difficulties

Firstly, the biggest challenge for small nucleic acid drugs in the industry is delivery technology. Simply put, it means that drugs are prone to rapid degradation in the bloodstream, making it difficult to reach the action site in the cytoplasm smoothly. Therefore, delivery system technology is crucial for drugs to enter cells and exert their effects, as well as ensuring the effectiveness and safety of nucleic acid drugs. Because of this, the development of small nucleic acid drugs also largely relies on the progress of delivery technology. Throughout the rise of each technological wave, delivery technology is an important driving force.

However, for the Blockmir platform owned by Mai Jinjia, the difficulties can not only be overcome, but also overcome: Blockmir technology mainly anchors antisense nucleic acid drugs, which can be independent of the delivery system, and can maintain the stability of small Nucleic acid structure structure through chemical modification. Antisense nucleic acid drugs can be less easily degraded in vitro (not including chemical drugs) and less easily degraded by RNA enzymes in the body. Therefore, local injection (central nervous system delivery) can reach the site of action and generate sufficient efficacy. Especially when administered by the Blockmir drug system, it can automatically target the liver and kidneys. Therefore, for liver and kidney related indications, Blockmir drugs no longer rely on delivery systems.

This is not a laboratory fantasy setting. The nine ASO (Anti sense Nucleic Acid Drugs) currently on the market are chemically modified and do not use delivery systems. It has been proven that ASO has a shorter chain length and does not rely as heavily on delivery systems as siRNA or mRNA vaccines.

Secondly, even if both are antisense nucleic acid drugs, Maijinjia's technology still has a key advantage, that is, Maijinjia is an upregulation protein technology and belongs to the scarce technology sector. Zhu Yingjie, Executive Director of Nell Neuroplasticity Nobel Prize Laboratory of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, also takes a special look at Blockmir nucleic acid drugs: This nucleic acid drug is very unique. Most diseases, including tumors, viral infections, immune diseases, metabolic disorders, etc., are related to miRNA abnormalities. Currently, drugs targeting miRNA all inhibit mRNA function, but Blockmir can upregulate mRNA function. A Blockmir only upregulates one mRNA function. This is equivalent to other drugs doing "subtraction" on the human body, which inevitably brings side effects, Blockmir nucleic acid drugs are additive, with higher natural specificity and fewer side effects.

Fourth major advantage: endorsement by Big Pharma (a well-known pharmaceutical company)

First, state two facts:

Firstly, Maijinjia has reached a milestone cooperation with French pharmaceutical company Servier, which involves a prepayment of nearly 2 million euros+35 million euros. Servier's feedback is that the patented technology can initially be used as medicine. At present, it has passed the mid-term acceptance of Servier's no to go agreement. The meeting minutes indicate that Servier recognizes Maijinjia's patented technology and expresses its intention to continue investing in research and development. Servier has currently provided its own machines as experimental equipment to the Danish laboratory of Mechin Jia, and dispatched technical personnel to assist on-site to accelerate research and development.

There are many biotech startups, but there are very few that can establish partnerships with well-known pharmaceutical companies during their initial stages; Many companies offer patents for free trial to pharmaceutical companies, while few large pharmaceutical companies are willing to pay for an unknown startup and even advertise it. This means that Maijinjia's original research technology has been recognized by French Servier.

Secondly, the Danish pharmaceutical company Santaris fought a lawsuit for six years to seize the Blockmir patent, but was reluctant to let go of it. Of course, the lawsuit ultimately ended with the victory of McKinley. Santaris is a company acquired by Roche, indicating that both Roche and Servier have taken a liking to MacKinga's technology platform. Although Mai Jinjia has only been established for three years, the team led by academicians of the Royal Danish Academy of Sciences and Letters has conducted basic research for 15 years. Mai Jinjia is equivalent to picking up a big bargain with his own eyes. This also indicates that due to the huge unmet clinical demand for protein upregulation technology, several major European and American pharmaceutical companies have begun to lay out nucleic acid pharmaceutical companies that upregulate proteins. Taking Mina Therapeutics as an example, this is a British company that can also conduct research and development on upregulation protein technology. It was only ten years after its establishment that it received the endorsement of its first pharmaceutical company, while Maijinjia received the endorsement of Servier three years after its establishment. Moreover, Maijinjia and Mina have a particularly similar history of prosperity - Mina's founder also had a unique early vision to buy all patents and start a business, And it has now partnered with large pharmaceutical companies for nearly $2 billion.

Fifth advantage: Strict experimental data management

Similarly, targeting unfamiliar proteins that have never been developed into drugs, why are some clinical developments relatively smooth, while others become a continuous pit? Why do some targets, the same molecules, cannot be achieved in the hands of Big Pharma, and the most suitable clinical development plan (indications, target population, combination, etc.) can be found on the meticulously crafted Biotech startup? Luck is certainly part of the reason, but whether to deeply explore the biological mechanisms of the target disease and obtain reliable and comprehensive data is perhaps the key winner or loser. An expert also mentioned this phenomenon in an interview: "Without careful pre clinical work, I just want to go directly to clinical practice. Once I went to clinical practice, I climbed to a relatively high dose and found that it was not effective. As for why it was not effective? The target is not yet fully understood

Maijinjia Company has extremely strict data requirements, which is different from some companies on the market using AI to "do" data or only using one or two positive data to generalize. The founder adheres to the scientific spirit and avoids the failure of industrialization implementation due to false positive data. This concept can even provide some inspiration for the dilemma of "investing early and investing small" or "investing later" in domestic innovative drug investment. If you want to avoid internal competition, explore a unique innovative target project, and minimize risks with sufficient certainty, then such projects that have entered the late stage of research and development and have more sufficient data are relatively better choices, especially when the research and development company has both positive preclinical data and its own in-depth and unique research on disease biology mechanisms related to translational medicine.



Sixth advantage: mature industrialization experience

For a long time, small and medium-sized Biotech companies have been the main driving force for the advancement of small nucleic acid drug technology. With the progress of the product in clinical development, the value is increasing Exponential growth. The value of hundreds of research and development stage projects is less than that of an approved heavyweight bomb product.

And Maijinjia happens to be an innovative Biotech company with industrialization experience. Dr. Zhai Jiajie, the founder of the company, is also the founder of another medical device company, Jiayue Meishi Biotechnology Co., Ltd. Jiayue Meishi Company was established in November 2016 and is a technology-based enterprise specializing in research and production of ophthalmic devices. It has received investment from the Guangzhou Development Zone Industrial Fund. On April 6, 2021, the button type artificial cornea developed by the company was included in the first batch of key catalogue of innovative services "innovative medical device projects". In February 2021, due to "clinical urgent needs, and no products of the same variety have been approved for registration in China", it was given priority by the Medical Device Technology Evaluation Center of the National Medical Products Administration. In September 2021, it obtained the Class III medical device registration certificate, and in October 2021, it obtained the Class III medical device production license. At present, the button type keratoprosthesis has become a routine ophthalmic surgery in many well-known ophthalmic hospitals or general hospitals in China, such as Sun Yat-sen University Eye Hospital, PLA 301 Hospital, Shandong Provincial Eye Hospital, etc.

Due to its rich experience in industrialization, Mai Jinjia has the confidence to promise to achieve systematic, reproducible, and scalable Blockmir patented technology from the date of full investment payment by the investor until March 11, 2026; From the date when all investment funds are fully paid by the investor to March 11, 2026, at least one target will complete the established treatment goals and achieve commercialization; Commercialization specifically refers to the exclusive authorization and licensing of self-developed product pipelines to other pharmaceutical companies for global or partial regional research and development, production, and commercial sales, or cooperation with other pharmaceutical companies for development. Authorization and/or cooperation agreements stipulate down payment, milestone payment, and potential sales ratio commissions for both parties; Or sell the entire self-developed pipeline to obtain a one-time profit. Develop a new drug compound for preclinical animal experiments from the date of full investment by the investor until March 11, 2026; From the date when the full investment price of the investor is fully paid in this investment to March 11, 2026, the company has obtained approval for at least one pipeline of the new drug clinical trial application.



In summary, the nucleic acid drug track is indeed a good track for the future long slope with thick snow. Maijinjia Company is currently on the high-quality track of nucleic acid drug segmentation, which has been verified by foreign companies, with a top enterprise valuation of 20 billion US dollars, and the domestic competition is still a blue ocean. On such a high-quality track, we should not give up on a startup company with such high certainty. In terms of investment timing, it is obvious that early (clinical or preclinical) investments can approach the balance point of considerable dividends and controllable risks.