Source: CBN, Cell and Gene Therapy, Cell and gene therapy

Cell and gene therapy can essentially treat a variety of diseases and achieve therapeutic effects that are difficult to achieve with general clinical means, which is an important driving force leading the innovation of future medical means. Gene therapy drugs mainly include plasmid DNA drugs, viral vector based gene therapy drugs, bacterial vector based gene therapy drugs, gene editing systems and in vitro gene modified cell therapy drugs (for example, CAR-T, CAR-NK, gene edited iPSC therapy). Cell therapy mainly includes stem cell therapy (such as hematopoietic stem cell therapy, mesenchymal stem cell therapy, iPSC therapy, etc.), immune cell therapy (such as NK cell therapy, T cell therapy, TIL therapy, DC therapy, etc.) and other cell therapies.

In recent years, cell and gene therapy has become a key area of competition for major pharmaceutical giants and biotech startups. Astrazeneca subsidiary Alexion is buying U.S. drugmaker Pfizer's portfolio of early-stage rare disease gene therapies for up to $1 billion to bolster its capabilities in genomic medicine.

In the first 7 months, more than 50 domestic CGT drug IND applications have been accepted

In China, the development of cell gene therapy drugs is becoming increasingly hot. Last week, the official website of the Center for Drug Evaluation (CDE) of the China National Food and Drug Administration announced that two CGT products of Janssen and Ruijian Medicine obtained the implied approval of clinical trials; Shanghai Pharmaceutical's application for clinical trial of chimeric antigen receptor autologous T cell injection B019 targeting CD19 and CD22 has also been accepted by CDE.

According to statistics, as of the end of July this year, CDE has accepted more than 50 IND applications for cell therapy drugs this year, including 18 CAR T drug IND applications, 19 stem cell drug IND applications, and 10 NK cell drug IND applications. In addition, at present, at least 25 domestic AAV gene therapy drug IND applications were approved, of which 3 entered phase III clinical.

On June 30 this year, the official website of the China State Drug Administration (NMPA) recently announced that the BCMA-targeted CAR-T product Ichiolencel Injection jointly developed by Reindeer Biology and Xinda Biology was approved for the market for the treatment of recurrent or refractory multiple myeloma (MM) adult patients. This is also another CAR-T therapy approved in China after Fosun Kate and Yaoming Junuo, and it is also the first CAR T therapy independently developed and produced in the whole process in China.

Cellular gene therapy is already generating revenue for multinational pharmaceutical giants, although the share of revenue is still small. Gilead Sciences reported that in the first half of this year, sales of cell gene therapy products exceeded $900 million, an increase of 43%. The BCMA CAR-T cell gene therapy cooperated by Johnson & Johnson and Legendary Biology sold nearly $200 million in the first half of the year; BMS's two CAR T-cell gene drugs had sales of about $450 million in the first half of this year; Novartis' CAR T cell gene products had sales of $260 million in the first half of the year.

The field of cell gene therapy in China started late, the medical payment ability is limited, and the development of the industry is still facing a series of challenges. Manufacturing cost is an important bottleneck restricting the development of cell gene therapy. In the United States, the most expensive cell gene therapy costs millions of dollars a dose, and in China, the price of a shot of CAR-T therapy is also more than one million yuan.

"The production process of cell gene therapy drugs does not bear any resemblance to modern manufacturing methods of traditional drugs, so companies need to establish entirely new production models." Since the industry is still in the early stage of development, it is impossible to reduce costs and increase efficiency through large-scale production. So says Roland Berger, a consultancy, in its latest report, "Reducing the production Costs of Gene therapy".

Roland Berger believes that gene therapy has opened up a new and highly profitable area in the pharmaceutical sales market, and although only 13 and 16 gene therapy products have been approved in the United States and the European Union, respectively, since 2016, it has already brought huge revenue to the company. The agency also estimates that non-cancer gene therapy sales account for a major share of the gene therapy market, and that global sales of non-cancer gene therapies will grow 20% to $4.2 billion by 2028.

Technology is moving faster than manufacturers can adapt

The slow pace of drug production is also one reason for the increased costs, and companies still need to use laborious methods to manufacture the vector. Vectors are one of the two main components of gene therapy (e.g., CAR-T therapy, CAR-NK therapy, AAV gene therapy) and can deliver therapeutic material (usually DNA) into cells. There is currently no universal carrier for all scenarios, so each carrier has its own manufacturing process. In addition, the pace of development of technology in the field exceeds the ability of manufacturers to adapt, which means that manufacturers are always in a state of "passive catch-up" in terms of manufacturing strategy.

"Vectors are a major driver of gene therapy manufacturing costs, and actual costs vary significantly depending on the type of vector or subtype required." "The manufacturing of gene therapies, and in particular the manufacturing of vectors, has become a key factor in determining the commercial and clinical success of new therapies," Roland Berger project leader Stephan Fath wrote in the report.

There are currently five viral vectors being used for gene therapy. Adeno-associated viruses (AAV) hold the largest market share at about 45%, followed by lentiviruses (LV) and adenoviruses (AV) at 20% and 16% respectively. AAV vectors have been shown to be effective mechanisms for gene therapy and gene editing vectors. Astrazeneca's Alexion hopes to acquire several new adeno-associated virus vectors through its acquisition of Pfizer's cell therapy products.

Mass production is another obstacle. The Roland Berger report states that the maximum scale that can be produced depends on the carrier technology and expression system chosen. For example, in adeno-associated virus (AAV) vectors, the commonly used batch size is usually limited to 500 liters, as virus transfection efficiency becomes less efficient at larger volumes. Since the batch size directly affects the raw material consumption per unit of production, this leads to higher raw material costs. Smaller batches also have higher quality control costs and lower yields than a single larger batch.

In addition, the dose of the drug presents a cost challenge. Both the indication of treatment and the target organ will have a key impact on the determination of the dose, and some multi-organ indications may require up to 100 times higher doses than those used for eye diseases, the report said.

At the same time, the level of investment in biotechnology is also falling. Roland Berger cited data showing that venture capital investment in biotech fell 45 percent between 2021 and 2022, largely because of concerns about return on investment. And as the number of gene therapy products on the global market increases, health care negotiations become more complicated.

Roland Berger points out that gene therapy has a lot of potential for improvement, both in terms of cost and efficiency. For example, by optimizing the expression systems and instruments required for production, the process development speed can be increased, the lead time can be shortened, and the risk of contamination can be reduced. Using new bioreactor technologies, cell density can be optimized, or medium formulation can be optimized during batch culture to increase yield.

Automation is also a major trend in the production of cellular genetic drugs. For example, high-throughput screening enables testing of new vectors and subtypes under a variety of conditions, helping to reduce the use of raw materials to optimize yields; Maintenance of automated cell cultures ensures better batch consistency; Automated purification processes allow for scale and time savings; Robot technology can also play a role in drug encapsulation.