Globally, tumors, respiratory and infectious diseases, neurological diseases, chronic diseases in the field of cardiovascular and metabolic fields are all diseases that threaten human health and put great pressure on the medical security system. Human beings have never stopped looking for and developing ways to overcome these diseases. With the expansion of policy support and the increase of R&D investment, we have reason to believe that the progress and breakthrough of the subdivision of medicine and biotechnology will make greater contributions to the diagnosis and treatment of the above major diseases.
In the previous issue, the sharing of Huaxing Medical and Life Sciences teams focused on the diagnostic and life sciences track. This issue will share a summary of the 2021 pharmaceutical and biotechnology track, and stay tuned to share it in other areas.
The results of epidemic prevention and control in 2021 have achieved initial results, and the new policy has been introduced to encourage innovation, and the total transaction volume and number of transactions in the pharmaceutical and biotechnology industries have both exceeded that of 2020. In particular, in the third quarter of 2021, the transaction volume hit a new high since 2018, with more than $5.4 billion in a single quarter.
However, the optimism looms: the secondary market breaks frequently, the pace of the primary market slows down, the market heat cools down, the concept speculation withdraws, and the head effect is more prominent. This reminds us that future innovation should closely follow national policies and overall planning; progress is greater than valuation, indications are more important than targets, prevention is better than treatment, diagnosis and treatment integration; and ultimately need to implement innovation through hard work.
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The 14th Five-Year Plan puts forward new overall goals for the development direction of the medical industry
In March 2021, the 14th Five-Year Plan for National Economic and Social Development and the Outline of Long-term Goals for 2035 were released. The 14th Five-Year Plan emphasizes the need to strengthen original and leading scientific and technological research, starting from the urgent needs and long-term needs of the country, and concentrating superior resources to tackle key core technologies such as emerging infectious diseases and biosecurity risk prevention and control, medicine and medical equipment. Among them, brain science and brain-like research, genetics and biotechnology, clinical medicine and health and other subdivisions are listed among them.
Local governments have successively issued relevant support policies to implement the central guidance, which is good for cell therapy, gene editing, synthetic biology and other tracks
The local governments of Beijing, Shanghai, Jiangsu and other provinces and cities have actively responded to the national policies and policies and actively laid out on the relevant tracks.
On November 24, 2021, the Beijing Municipal Committee of the Communist Party of China and the Beijing Municipal People's Government issued the "Beijing International Science and Technology Innovation Center Construction Plan for the 14th Five-Year Plan Period", which aims to promote the research and development of cutting-edge biotechnology technologies in key areas such as new antibody technology, gene editing, new cell therapy, stem cells and regenerative medicine.
On November 29, the leading group of the Zhongguancun Demonstration Zone in Beijing issued the "Development and Construction Plan for the Zhongguancun National Independent Innovation Demonstration Zone in the 14th Five-Year Plan Period", which pointed out: "Support the development of brain science and brain-like research, gene editing, stem cells and regenerative medicine, single-cell multi-omics, synthetic biotechnology, biological breeding and other life science and technology research." Strengthen the transfer and transformation of achievements of colleges and universities, in the field of biomedicine, give play to the role of medical device engineering platforms, biological sample banks, biocompatibility evaluation platforms and other technical platforms, and build cell and gene therapy, biological drugs, recombinant protein drugs pilot production platforms, AI innovative drug incubation platforms, etc. ”
On July 6, 2021, the General Office of the Shanghai Municipal People's Government issued the Notice on printing and distributing the 14th Five-Year Plan for the Development of Advanced Manufacturing in Shanghai. The notice pointed out that it focuses on cutting-edge biological fields such as brain science, gene editing, synthetic biology, cell therapy, stem cells and regenerative medicine, carries out major scientific and technological research, and promotes the research and development and innovation of key raw materials, high-end raw materials and auxiliary materials, important pharmaceutical equipment and consumables, precision scientific research instruments and other equipment and materials. On July 21, the General Office of the Shanghai Municipal People's Government officially released the "14th Five-Year Plan for the Development of Strategic Emerging Industries and Pilot Industries in Shanghai", which proposes that in terms of innovative drugs and high-end preparations, focus on the development of antibody drugs, gene therapy, cell therapy and other high-end biological products; in terms of biotechnology services, promote the development of artificial intelligence-assisted drugs, digital medical solutions and other related guidance plans.
In September 2021, the General Office of the Jiangsu Provincial Government released the "14th Five-Year Plan for Scientific and Technological Innovation in Jiangsu Province". The "Plan" pointed out that the focus is on the development of therapeutic antibodies, new vaccines, nucleic acid drugs, recombinant protein polypeptide drugs, genetic engineering drugs, cell therapy products, bacterial drugs and oncolytic viruses.
In addition to Beijing, Shanghai, jiangsu, including Zhejiang, Guangzhou, Shenzhen, Tianjin, Dalian, Yantai, etc., a number of provincial and prefecture-level governments have successively issued relevant pharmaceutical industry development guidance plans in 2021, tilting the development resources of many subdivisions such as cell therapy, gene editing, and synthetic biology, which is good for prominence.
Focus on major disease areas such as CVRM and CNS
Standing at the historical point at the beginning of the "14th Five-Year Plan", we must focus on the national strategy and return to the essential needs of treatment. Among them, major disease areas such as tumors, respiratory system and infectious diseases, nervous system diseases, chronic diseases in the field of cardiovascular and metabolic fields are the focus of national policy attention and industry efforts.
Over the years, research on oncology and immune diseases has received a lot of capital support. The outbreak of the new crown epidemic has led to an unprecedented increase in the attention of RSD (respiratory and infectious diseases). Faced with the high complexity of the CNS (nervous system disease), many pharmaceutical companies have been hit hard in this field and lost confidence; but in June 2021, Aducanumab was approved for listing in the controversy. Chronic diseases CVRM (cardiovascular, renal and metabolic diseases) have a large patient base and deserve more attention.
There are more than 500 million people with cardiovascular disease in the world, and cardiovascular disease is still the leading cause of death in the world; about 850 million people have kidney disease worldwide; more than 460 million adults worldwide have diabetes, and the incidence of diabetes has reached 9.3%. There are about 330 million patients with cardiovascular diseases in China, and the number of deaths due to cardiovascular diseases exceeds 5 million every year, which is the highest cardiovascular mortality rate; the prevalence of chronic kidney disease is as high as 10.8%, and the number of patients exceeds 100 million; the number of diabetic patients is about 140 million, accounting for a relatively high proportion of the global diabetes population. The global prevalence and burden of CVRM diseases are rising, and CHINA's CVRM has become a major public health problem.
In the face of these major disease areas, Novartis, Roche, AstraZeneca, Eli Lilly and other large MNCs have begun to lay out CVRM (cardiovascular, renal and metabolic diseases), CNS (nervous system diseases), RSD (respiratory diseases), etc., and expand the integration of diagnosis and treatment and the next generation of treatment platforms, which is worthy of benchmarking and reference for domestic enterprises.
The prevention and control of major diseases and the integration of diagnosis and treatment are the core areas of the development of the healthcare industry
On July 15, 2019, the State Council issued the Opinions of the State Council on the Implementation of the Healthy China Action (hereinafter referred to as the "Opinions").
"Prevention and control of major diseases" is the core area of R&D investment in the health care industry, and the diagnosis and treatment of major diseases such as cardiovascular and cerebrovascular diseases, cancer, respiratory system, diabetes, and infectious diseases is the core disease that the "Opinions" put forward to focus on diagnosis and treatment. These five major diseases are the most common diseases in the mainland, the most far-reaching impact on the health of residents, the most stressful to society, the most expensive medical insurance, and the main areas where the mainland medical industry has continued to increase investment in research and development in recent years. The "Opinions" once again clearly stated the importance attached to these major diseases, encouraged investment in related diagnosis and treatment fields, and programmatically led the core areas of the development of the healthcare industry.
With the development of technologies such as genomics and proteomics, human beings have entered the era of precision medicine, and the prevention, diagnosis, precision treatment and rehabilitation of diseases such as CVRM have risen to a national strategy. Especially for single-gene hereditary cardiovascular diseases with clear etiology, early prevention, screening and intervention of diseases should be actively carried out, and a precise health management system integrating diagnosis and treatment should be established.
New technologies for small molecules and large molecules are emerging in an endless stream, and new products return to the essence of clinical demand
In the field of small molecules, breakthroughs have been made in challenging the "undruggable" target through disruptive design and mechanisms of action. For example, targeted protein degradation (TPD) is an emerging strategy for drug development, which only requires small molecules that can specifically bind to the target protein (not necessarily functional), and combines ubiquitinated enzymes or lysosomal degradation pathways to theoretically degrade these "undruggable targets" (mainly including transcription factors, proteins that only play the function of the skeleton, etc.), with great medicinal potential.
In 2021, TPD technology represented by protein-targeted degradation chimeras (PROTAC), molecular glue (molecular glue) and lysosomal degradation has received unprecedented attention, and major pharmaceutical companies have launched layouts. In July, ARVINAS, a star company in PROTAC therapy, announced a more than $2 billion deal with Pfizer to advance the development of a potential "first-in-class" therapy, ARV-471; in August, Bayer announced a $2 billion acquisition of Vividion Therapeutics, an emerging protein degradation therapy company, and Eli Lilly also partnered with Lycia, which develops innovative protein degradation technologies Therapeutics reached approximately $1.6 billion in collaborations, and in November, Novartis and Dunad Therapeutics reached a more than $1.3 billion research and development cooperation agreement to develop a new generation of oral targeted protein degradation therapies.
The macromolecule field is at a turning point, and the global antibody drug market size will exceed $200 billion for the first time in 2021. Through deep-ploughing mechanism research, differentiated molecular design, clinical innovation exploration, target combination and combination therapy to return to clinical value, we will expand the disease field of "untreatable". The development of a new biological drug is not a single molecule, but a whole set of technologies, with "drugs" as the specific manifestation; this drug can be a protein macromolecule, or it can be a cell or vector delivered mRNA or DNA, through the target to act.
New methods and technologies such as multi-specific antibodies, ADCs and nanoantibodies, cell and gene therapy, and next-generation delivery technologies can expand more "untreatable" disease areas.
Cell and gene therapy is on the fast track, bringing new hope to diseases that are difficult to cure
Cell and gene therapy-related products, although relatively small in the entire biological industry at this stage, are one of the fastest growing areas in the global biomedical market in recent years. 2021 is the first year of Chinese cell therapy, and two CAR-T cell therapies targeting CD19 from Fosun Kate and WuXi Juno have been approved for listing, breaking the gap in this therapeutic field in China. Seven drugs based on CAR-T therapy have been approved in the blood tumor worldwide, establishing the status of CAR-T therapy in the treatment of a variety of hematologic malignancies; similarly, CAR-T therapy also has a huge clinical demand in the field of solid tumor treatment, Claudin 18.2, GPC3, MSLN, HER2, EGFR and other CAR-T targets to treat solid tumors are widely carried out.
From the perspective of technology iteration and accessibility, universal cell therapy is an inevitable trend in future development.
The fastest-advancing UCART19 therapy was co-developed by Servier and Alllogene, but was halted by the FDA in October 2021 due to some safety risks in clinical trials, revealing that behind the high potential is extremely difficult to develop. In February 2021, Cytovia entered into a $760 million strategic research and development collaboration with Cellectis to develop iPSC NK and CAR-NK cells based on TALEN gene editing. In December 2021, the clinical trial application for new drug CTA101 UCAR-T (general-purpose CAR-T) cell injection product independently developed by Beiheng Bio was accepted, which is the first "spot" allogeneic source CAR-T product accepted in mainland China, which is of great significance.
Since 2018, the number and scale of private financing of immune cell therapy companies in mainland China have continued to grow, with the number of financing rising from 11 in 2018 to 40 in 2021, and the scale of financing has exceeded 1.1 billion US dollars, with a number of large-scale financings that have attracted attention. Since 2020, domestic cell therapy companies have begun to land on the secondary market.
In the field of gene therapy, products are moving from the laboratory to the ward, and research and development and production have also entered the fast lane. Almost all of the TOP 20 pharmaceutical companies in Europe and the United States have entered the field of gene therapy through mergers and acquisitions or cooperation, and the entry of international pharmaceutical giants has become a booster for the development of the industry. In clinical practice, the efficacy and safety of gene therapy have been verified in several types of genetic diseases.
Novartis' Zolgensma, which is used for spinal muscular atrophy treatment, generated sales of $634 million in the first half of 2021, up 69% year-on-year, and is expected to enter the "$1 billion club.". In November 2021, the FDA granted Bluebird Bio's priority review of the Zynteglo Bio's application for authorization (BLA) for β thalassemia gene therapy, making it the next gene therapy to be approved for marketing by the FDA. In the field of diseases, gene therapy has also expanded from genetic disease treatment to cardiovascular diseases (such as Tenaya Therapeutics, XyloCor Therapeutics, Rejuvenate Bio), metabolic system diseases (such as Kriya Therapeutics, Verve Therapeutics) and infectious diseases (such as Beam Therapeutics), Gene therapy will become an indispensable form of medicine.
With the unprecedented development of RNA platforms, the era of RNA therapy will eventually come
RNA therapies are booming in 2021, with more than 600 RNA therapies in development worldwide, and the market size is growing at 16.8% CAGR based on mRNA alone. Collaboration and transactions within the industry, as well as the increasing size of capital markets, have accelerated a new wave of RNA therapy development.
In August, Sanofi announced a $3.2 billion acquisition of Translate Bio focused on mRNA vaccine development; in the same month, Abogen Biosciences announced the completion of more than $700 million in Series C funding to support the clinical development of its potential COVID-19 vaccine and expand its pipeline of other vaccines and treatment candidates, refreshing the amount of a single pre-market financing for Chinese biopharmaceutical companies. In October, Hexion Pharmaceuticals announced a more than $1.3 billion collaboration with Silver Therapeutics to develop siRNA drugs for three targets, and a $450 million collaboration with OliX Pharmaceuticals to develop asymmetric small-interfering RNA therapies for key targeted indications; in November, Novo Nordisk announced a $3.3 billion acquisition of Dicerna focused on RNAi drug development Pharmaceuticals is expected to apply RNAi technology to diabetes, obesity, cardiovascular disease and NASH and other fields; in December, Sirnaomics, the first share of domestic RNA therapy, landed on the capital market.
RNAi technology can regulate extracellular and intracellular protein expression by directly targeting the base pairs of mRNA and other targeted RNAs in the cytoplasm, preventing the production of disease-related proteins, promoting targeted degradation, and thus forming effective targeted gene silencing. Alnylam Pharmaceuticals, a pioneer in RNAi treatment, was approved the world's first RNAi drug ONPATTRO (patisiran) in 2018, and the second Givlaari (givosiran) and the third OXLUMO (lumasiran) RNAi drug were also approved in 2019 and 2020. At present, Alanylam is promoting RNAi therapy to more disease areas, including genetic diseases, cardiometabolic diseases, infectious diseases, central nervous system diseases and eye diseases.
RNA-based therapies are showing excellent application potential, not only to expand the range of targets of pro-drug drugs, but also to personalize drugs to bring effective targeted therapies to diseases that are currently difficult to cure. At present, RNA therapy has been extended from mainly targeting rare genetic diseases to more common clinical indications, such as cancer, cardiovascular disease and neurological diseases, and the era of RNA therapy will eventually come.
Next-generation drug delivery technology enables the development of more products
Drug delivery technology has enabled the development of many products, from small molecules and macromolecules to cell and gene therapy. With the continuous advancement of small molecules and antibody modifications, antibody-drug conjugate (ADC) has evolved, and ADCs combine antibodies with cytotoxic small molecules to be able to administer drugs in a highly targeted manner while providing synergistic immunomodulatory functions. Oligonucleotide drugs have the great advantage of programmed design, which has been widely used in the research of targeted gene therapy, and there are currently 8 antisense oligonucleotide (ASO) and 4 small interfering RNA (siRNA) drugs on the market, and multiple candidate therapies are in Phase 3 clinical trials, mainly for genetically defined rare diseases. With the gradual maturity of stem cells, gene editing and other technologies, stem cell-derived engineered red blood cell technology has developed rapidly, through the reprogramming of hematopoietic stem cells in vitro, with gene editing technology to encode the target gene of the drug into the hematopoietic stem cells, followed by culture, differentiation and maturation, so that red blood cells loaded with drugs can be directly generated. New treatments present additional challenges, particularly in terms of stability (proteins and peptides), intracellular delivery requirements (nucleic acids), and manufacturing and scalability (cell therapy).
AI and synthetic biology empower the development of life science and technology
"AI+Medical" brings more possibilities for healthy living and medical services, and "AI+Pharma" optimizes the processes and methods of traditional pharmaceuticals. Many international pharmaceutical companies have carried out cooperation with AI pharmaceuticals, and domestic Internet giants have also competed to lay out the AI pharmaceutical industry. At this stage, the main value of AI pharmaceuticals is to reduce the evaluation cost and iteration number of later stages through low-cost and high-quality inputs in the early stage; and the core of AI pharmaceuticals is not only to improve efficiency, but more importantly, to improve the success rate of the clinical stage. In the long run, AI is an indispensable and important element in the development of new drugs in the future.
Synthetic biology has entered a period of rapid development in recent years, and its core idea is to transform life (cells, etc.) through engineering methods or to build a living system from the source. Synthetic biology can not only use prokaryotic cells to regulate effector molecules in response to environmental stimuli, but also equip eukaryotic cells as chassis cells with biosensors to detect disease targets and activate downstream signaling pathways. At present, synthetic biology has been increasingly applied to medical health, agriculture, chemicals, energy, consumer goods, food and beverages and other fields, and the manufacturing capacity of complex organisms has expanded the boundaries of biological applications and leveraged huge economic value.
prospect
Standing at the beginning of 2022, under the background of the continuous introduction of policies by the state to encourage industrial innovation and development, the pharmaceutical industry is accelerating into the "fast lane" of transformation and upgrading with a rapid and unstoppable trend. In addition, with the accelerated process of internationalization and the trend of differentiation and homogenization, the pharmaceutical and biotechnology industries are facing challenges but also nurturing new opportunities.