How To Solve The Problem Of Affordability Of "Skyrocketing Drugs" In Gene Therapy With A Single Needle Exceeding 10 Million Yuan?

"To develop a drug for a rare disease caused by genetic defects, what is the problem solved by such basic research and even applied research?" Recently, Dong Xiaoyan, founder and chairman of Wujiahe Gene Technology Co., Ltd., raised such a question in an interview with 21st century economic reporter.

——Solve the problem of no medicine.

"From no medicine to medicine, it solves a scientific problem. But when the drug comes out, if only one enterprise produces it, or only one or two varieties are aimed at one indication, it is obviously not enough. It will bring a series of economic and social problems Dong added.

The problem that Dong Xiaoyan refers to is a cyclical deduction: the scale is difficult to form industrial development, and the price of drugs will remain high, which will lead to the inability of ordinary people to use drugs, which in turn leads to the inability to recover the R & D costs of enterprises.

"To solve such problems, there is no doubt that we should greatly reduce the cost, improve the quality of drugs, and at the same time expand the scale of drug production. Let MAH (drug marketing license holder) who is engaged in the research and development of new drugs can complete the clinical and marketing of their developed gene drugs more efficiently and at a higher level, so that patients can use cheaper genetic drugs earlier. " Dong Xiaoyan pointed out to the 21st century economic reporter.

Gene therapy in fast lane

In recent years, with the development of science and technology, gene therapy has become the hope of curing genetic diseases. Gene therapy refers to the introduction of exogenous normal genes into target cells to correct or compensate for diseases caused by defective and abnormal genes, and finally achieve the goal of treatment.

In some indications, gene therapy has obvious advantages over traditional therapy. There are also several gene therapy products on the market in foreign countries. There are many clinical research projects, and some of them have achieved very good results.

Wang Xuyu, head of China region of sedolis biotechnology and Solutions Division, told the 21st century economic news that the global market for gene therapy, from glybera, the first drug officially approved by EMA in 2012, to luxturna and zolgensma, are all gene therapy drugs for rare diseases, The global market of gene therapy has entered a stage of rapid development since 2018.

Car-t therapy (chimeric antigen receptor T cell immunotherapy) is the most successful clinical application of "in vitro" gene therapy. Novartis was the first company to develop car-t therapy. In August 2017, FDA approved kymriah, the first car-t product.

In 2020, the sales revenue of Novartis car-t increased by 68% year-on-year to reach 474 million US dollars. Novartis currently has 290 qualified car-t treatment centers worldwide, and 27 countries have approved at least one indication for kymriah.

According to estimate Pharma, the market for gene cell therapy will grow from $1 billion in 2017 to $44 billion in 2024, with a compound annual growth rate of 65%.

Previously, FDA predicted that 40 kinds of gene therapy would be approved by 2022, and 10-20 kinds of cell and gene therapy products would be approved by 2025. Several products for hemophilia, thalassemia and other rare diseases have entered the advanced clinical stage.

According to the relevant data quoted by China Securities Construction Investment Corporation, by the end of 2020, the United States is the country with the largest number of clinical trials of gene therapy, with a total of more than 650. The second is China, with more than 300 items in total.

Wang Xuyu said that the whole process of gene therapy in China started not too late. At this stage, China also has a long time of accumulation. On the whole track of gene therapy, "we think that China has the opportunity to overtake in a corner and have more opportunities for innovation, which will also contribute to the overall development of global gene therapy in the future."

It is understood that at present, there are also in-depth layout of domestic kinsrui / legend biology, reindeer medical, yaomingjunuo, Fosun KITT, Jinlan gene, Faith Medicine, neufos biology, Hangzhou Jiayin, etc.

On June 22, China's National Drug Administration (nmpa) officially approved the car-t cell therapy product of Fosun KITT Biotechnology Co., Ltd., which is also the first car-t cell therapy product approved for marketing in China.

Bumps in the fast lane

Glybera, the first gene therapy drug approved by the European Union, costs more than 1 million euro and is also the most expensive gene drug in the year. The price of zolgensma, which was approved by FDA in 2019, reached US $2.125 million, which is a new price of the most expensive genetic drug.

"Expensive" is an unavoidable problem in gene therapy.

It is reported that in the five years since glybera went public, only one patient received treatment, and most of the cost of treatment was covered by insurance companies. But for patients and insurance companies, it is still a big burden. In April 2017, uniqure, the Dutch company that developed glybera, did not re apply for a marketing license until the sales license expired, which meant that the drug was delisted.

In order to avoid the embarrassment of delisting, the payment methods of the following approved gene therapy drugs were adjusted. In May 2016, GSK's strimvelis was listed in Europe, becoming the world's first gene therapy for adenosine deaminase severe combined immunodeficiency (ADA-SCID) in children, with a price of 594000 euros. GSK adopts installment payment mode and guarantees invalid refund. In December 2017, luxturna, a gene therapy drug approved by FDA, can pay according to the curative effect. If the drug fails to achieve the therapeutic effect, it will refund part of the treatment fee to the patient, and allow the patient to pay in installments.

In addition to the high cost of gene therapy, the "niche" nature of gene therapy itself also leads to limited market demand.

Taking car-t cell therapy as an example, Dong Xiaoyan said that because of the individualized treatment plan, the patient's own T lymphocytes need to be used, and then the lentivirus is used to gene modify it in vitro, so this batch of cells can only be used for this patient. This also limits the use of resources.

Gene therapy is a rare disease with a small population, and the research and development process of gene therapy needs a lot of capital investment. In order to recover R & D funds and obtain profits during the period of patent validity, enterprises set high prices, which leads to the inability of patients to pay.

The other is the problem of large-scale industrial production.

One of the important issues is the issue of standards. Wang Xuyu told the 21st century economic reporter that if any industry wants to develop, it needs to formulate more comprehensive standards to better support the industry. Wang Xuyu pointed out that in the same industry and field, the identification standards are not unified, and it is another data detected by different methods. If applied to human body, there will be great potential risks and safety problems.

In addition to the safety problems, due to the different selection of technology and technology, the identification standards are not unified, coupled with the consideration of confidentiality, it also greatly hindered the transformation from scientific research to large-scale industrial production. This obstacle will also lead to the rise of costs.

Looking for the way to break the game

"Some drugs for rare diseases may be" sky high "at present, but for patients, they also have the right to treat them. The cost seems to be very high, but this is the treatment of a disease." Song Ruilin, executive director of China medical innovation promotion association, pointed out to the 21st century economic reporter that the medication problems of such patients should not be ignored.

It is true that the price of cell therapy is high. In fact, the production, transportation and treatment of therapeutic cells are located in three different places, which also determines the high production cost of cell therapy.

CSCI believes that one of the solutions is to seek cdmo mode production.

Cdmo is an emerging R & D and production outsourcing organization, which mainly serves for the products of medical production enterprises and biotechnology companies, especially for the process research and development, preparation, process optimization, registration and validation of batch production and commercial customized R & D and production of innovative products.

Dong Xiaoyan told the reporter of the 21st century economic report that the technological process of the research and development of a gene drug includes determining the target cell of the gene drug, constructing the gene expression unit, making the recombinant virus, and passing the relevant tests and detection steps. This process involves different sub industrial chains of equipment, raw materials, reagents, consumables and related services.

At the same time, Dong Xiaoyan believes that a set of standardized production technology and quality system can not only find more suitable upstream development process points and process parameters in a short time, but also improve the recovery rate and efficiency of the downstream process, and finally build up the whole process flow and platform to realize mass production.

Car-t cell therapy, for example, is an individualized treatment with high cost. In Dong Xiaoyan's view, enterprises can choose to do universal car-t. the selected cells are a kind of universal cells, not the cells of a certain patient. After gene modification of the cell, it is applicable to all patients who can be treated with this strategy. Therefore, the conditions of mass production are available, so the cost will be reduced.

Dong Xiaoyan also reached a consensus in the industry.

Universal immune cell therapy, also known as allogeneic immunotherapy or spot immunotherapy, is a kind of therapy that extracts immune cells from healthy donors or uses peripheral blood, umbilical cord blood, pluripotent stem cells to prepare immune cells, carry out engineering transformation and amplification, and input into patients. Among them, the most widely used immune cells are T cells and NK cells.

At the 2021 Drug Information Association (DIA) China annual meeting held not long ago, he Xiaohong, founder and CEO of beiheng bio, introduced: "the universal car-t hopes to achieve immediate use through a series of genetic modification after donation of healthy immune cells, that is, it can be treated immediately according to the drug properties."

He Xiaohong said that at present, there are 8 domestic enterprises that take the general car-t as the main business layout, of which about 60% have entered the clinical research stage, and most of the enterprises mainly focus on the development and research of hematoma.

However, he Xiaohong also stressed that the whole process chain of donor's normal T cells, after gene editing, amplification, and then to the final product, seems simple, but at present, the whole industry is very new. If the upstream and downstream industrial chain is not yet sound, and there is no supporting system for aseptic production, enterprises need to develop themselves, so it is not easy to realize mass production.

At the same time, in Dong Xiaoyan's view, the localization of relevant chains is also one of the important factors to reduce costs.

As mentioned above, sedolis, as a leading enterprise in the industry, has done more localized production and services since the outbreak of the new epidemic last year.

"Cydolis began to increase investment in the production of disposable products last year, and has realized the local production of disposable products commonly used in biopharmaceuticals in Beijing. In addition to production, service is also developing towards localization. In April this year, a customer interaction center was set up in Beijing to speed up the acceptance of equipment by customers. " Wang Xuyu told the 21st century economic reporter.

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