core point
1. Gene therapy, cure from the root, has broad prospects
Gene therapy, cure from the root, just needs strong. The indications are mainly rare diseases and face huge unmet clinical needs.
Compared with traditional drugs, gene therapy has both clinical and R&D advantages. Clinical advantages: Directly targeting DNA therapy, without the dilemma of “undruggable” targets. R&D advantage: The synthesis of nucleic acid sequences is less difficult.
Policy assistance, capital mania, and broad prospects. The total global CGT investment and financing has grown rapidly from about 5 billion US dollars in 2014 to about 23 billion US dollars in 2021; it is estimated that the global and China scale will reach 30.54 billion US dollars and 17.89 billion yuan in 2025, and the CAGR will be as high as 71.2% and 276.0% in 2020-2025.
2. Gene therapy can effectively cure rare diseases, and viral vectors are the key to gene therapy
Gene supplementation technology is relatively mature. Six products have been approved by FDA/EMA. The research pipeline is very rich, and many overseas products have entered the stage of planning/BLA. The overall progress in China is relatively slow, and the indications are concentrated in ophthalmic genetic diseases and hemophilia. The research pipelines at home and abroad are mainly based on the in vivo route and are based on AAV vectors; there are few in vitro routes, most of which are based on LV vectors.
Gene editing is “powerful” + “targeted and precise”, and CRISPR, which won the “Nobel Prize” in 2020, leads a revolutionary breakthrough. Gene editing can achieve “gene knockout” and “gene insertion”, and “targeted and precise” editing of the target site. The core advantage of CRISPR/Cas9 lies in the positioning method. The synthesis of sgRNA is easier than that of protein, so it is efficient, convenient and low-cost. Overseas pipelines are basically covered by the “Big Three”, and CTX001, the fastest-growing CRISPR, is expected to submit BLA by the end of 2022. The domestic pipeline is still in the early clinical stage.
Viral vectors are the key to gene therapy, of which AAV is the most widely used for its safety advantages. A key advantage of recombinant viruses is their high native transduction efficiency. AAV core advantages: safety, do not integrate the host genome to avoid carcinogenic risk, natural AAV serotypes provide tissue targeting specificity.
3. CGTCDMO solves the bottleneck of large-scale production of viral vectors and boosts the commercialization of gene therapy
The upstream of the gene therapy industry chain leads the production of viral vectors, which is the core of commercialization. The price of gene therapy products is high, and viral vectors account for one-third of the research and development costs. Therefore, controlling the production cost of viral vectors is the key to reasonable pricing of end products.
The large-scale production of viral vectors faces many technological + capital barriers, and the production capacity is extremely short. The production of viral vectors involves multiple processes, and the steps are cumbersome. In order to establish plants and equipment that meet cGMP standards, heavy capital investment (hundreds of millions of dollars) is required. The global average waiting time for CGTCDMO is even as long as 2 years, and the current capacity gap is at least 1-2 orders of magnitude.
CGTCDMO solves the production bottleneck of viral vectors and is an indispensable participant in the industrial chain. CGTCDMO reduces costs and increases efficiency, and its production outsourcing penetration rate of 65% is much higher than that of traditional medicines, which is 35%.
4. Three-dimensional analysis of the challenges and trends of gene therapy (technology + production + commercialization)
Gene therapy faces multiple challenges in technology & production & commercialization. (1) Technical challenges: The technical challenges of delivery vectors include transduction efficiency, targeted tissue specificity, AAV vector capacity, and immune barriers. The most critical technical challenge of gene editing is the safety issue caused by off-target effects. (2) Production bottleneck: how to reduce plasmids required for transfection, how to increase cell culture density, and how to remove empty virus, etc. (3) Commercialization challenges: The rare disease patient base is small, and the commercialization price is extremely high.
From the perspective of technology & production & commercialization, the development trend of gene therapy is prospected. (1) Technology trends: delivery vector dimension, “gene expression cassette engineering” and “capsid engineering”, etc., improve safety + effectiveness + durability; gene editing dimension, modify Cas protein or sgRNA sequence to reduce off-target probability. (2) Production optimization trend: “stable transfection + suspension culture”, cost reduction + capacity expansion. (3) Commercialization trend: from rare diseases to common diseases, to achieve “single treatment”; the insurance payment system is increasingly improved.
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