2019 Of Cells And Gene Therapy: The Challenge Of "Sky High" And "Patent" Behind Scenery

Two years ago, at the end of August, Kymriah, a gene therapy from Novartis, was approved by the US FDA for children and adolescents with acute lymphoblastic leukemia (ALL). This is the first CAR-T product to be approved in history. FDA defines it as a "cell engineering based gene therapy product". Novartis has set the price of Kymriah as high as 475 thousand dollars per time.

This is the highlight time of CAR-T therapy, plus two months later, Kite Pharma's CAR-T product Yescarta was approved by lymphoma indications, and in 2017 it was called "the first year of CAR-T".

The successive approval of CAR-T products and its "sky high" cost have triggered a worldwide outbreak of clinical research and a frenzied pursuit of capital. However, two years later, the "halo" has disappeared. The layout of hematoma is solid tumor, price and payment problem, R & D target gathering, patent infringement. The industry's confusion and focus on CAR-T and other cell and gene therapies remain unchanged.

Looking back at 2019, although the share of new technologies such as gene therapy and RNA based projects is still small in the market, the release of regulatory agencies such as FDA will continue to be regarded as one of the favorable trends in the industry. The domestic enterprises, which followed the international speed layout field early, will see the first stage of the coming year and face international counterparts. The same questions and challenges.

"Sky high" drug family

In December 19, 2019, Novartis released a notice on children's spinal muscular atrophy (SMA) on its official website, announced that it would launch a global "gift giving" plan in 2020: a total of 100 doses of drugs were provided free of charge to eligible SMA patients in the countries where its gene therapy product Zolgensma has been approved. The plan will be launched in January 2020 with 50 doses in the first half.

One of the reasons for Zolgensma's concern is the "sky high price" of this innovative gene therapy. In May 24, 2018, DA approved the listing of AveXis gene therapy Zolgensma in Novartis, but the controversy was its pricing of up to $2 million 125 thousand. This is also Novartis's first CAR-T gene therapy Kymriah, which is priced at $475 thousand, and another product that shocks the market with prices.

In April 2018, Novartis bought a rare disease gene therapy company, AveXis, for $8 billion 700 million. In November 2017, at the investor conference, Dave Lennon, President of AveXis, said that the new gene therapy for fatal disease spinal muscular atrophy (SMA) was very cost-effective for the medical system. Each patient could save 4 million to $5 million in medical costs, and the 10 year treatment cost of SMA therapy Spinraza was 4 million 100 thousand dollars.

Novartis, a Swiss pharmaceutical company, is the strongest "fan" of global gene therapy in recent two years. It is keen to prove the value of all kinds of gene therapy. Even so, it seems that Novartis has given some concession to the suffocating price, and its attitude towards hematoma and solid tumor has gradually blurred.

It was reported that Novartis announced that it was temporarily abandoning the CAR-T research in the solid tumor field in the early December 5th of the internal R & D meeting. However, some media said that Novartis denied this statement and said it would continue to promote the development of the therapy.

The giants' pursuit of new gene technology is far from being stopped. Novartis's "fellow townsman" Roche announced the completion of the acquisition of gene therapy company Spark Therapeutics in December 17th. Spark Therapeutics, headquartered in Philadelphia, is a company exploring, developing and providing gene therapy for the treatment of hereditary diseases including blindness, hemophilia, lysosomal storage disease and neurodegenerative diseases.

Spark Therapeutics also has an expensive gene therapy Luxturna that has been listed. At the end of 2017, FDA approved its treatment for patients with proven retinopathy of malnutrition associated with allele RPE65 mutations, which cost about $700 thousand per patient.

In some cases, gene therapy can save patients further costs, but the industry's doubts are how many countries such as the medical insurance system can afford. Evaluate Pharma predicts that 68 gene therapies will be launched by 2024, which will generate 16 billion US dollars in the current year, and only treat a small part of 6000 known single gene diseases. The biopharmaceutical giants and funds will continue to enter this field.

Another challenge for enterprises is the declaration and protection of intellectual property rights in CAR-T. In December 13th, a jury in California ruled that gilid paid $585 million to BMS and his partners, and the cost of infringement infringed by its subsidiary company 27.6%, totalling about $752 million.

The focus of CAR-T patent protection includes chimeric combination of sequences, treatment methods, T cells, various vectors and transfection methods. CAR-T several giants Juno, Novartis and Kite patents are used to protect nucleic acid sequences and antigen binding sequences.

This reminds Chinese enterprises to pay attention to the protection of CAR-T patents in the future. On the one hand, if domestic companies do not transform any related sequence, they will be regarded as infringement. On the other hand, the advantages of different companies in China can improve the existing technologies in many ways, including enhancing specificity and affinity, improving carriers and improving transfection efficiency. In addition, domestic R & D products will be faced with patent risks outside the country. The complexity of CAR-T preparation process will lead to the complexity of patent pattern.

Competition in the domestic market

In December 18th, Fosun Pharmaceutical's Fosun star Kate announced its first CAR-T industrial production base opened in Shanghai. At present, the base has been completed and accepted, and facilities and equipment verification and trial production are being carried out according to the plan. It is expected that commercial production capacity will be available around 2020.

Fosun Kate is a joint venture between Fosun medical group and Kite Pharma of the United States, founded in April 2017 in Shanghai, China. In the same year, Fosun Kate introduced the world's first CAR-T cell drug Yescarta (FKC876) approved for treatment of specific non Hodgkin's lymphoma from the US Kite Pharma, and was approved to register clinical trials in China.

CAR-T is a highly personalized method. Each person's cells and treatment are different. Many patients have received various treatments before receiving CAR-T treatment, such as bone marrow transplantation, chemotherapy, targeted therapy, etc., and the preparation and programming of T cells will also be different. In addition to PD-1/PD-L1, CAR-T is another product area where domestic enterprises are advancing and catching up with the world's major forces.

As of December 23rd, in twenty-first Century, the economic report reporters visited the world's largest clinical trial registry database ClinicalTrials.gov, showing that at present, there are 302 registered active CAR-T projects, up from 169 in China.

"Domestic well established enterprises are expected to be listed in 3-5 years. At present, all enterprises in China are on the starting line with little difference. Cell therapy brings opportunities for domestic enterprises to overtake corners, but it is still in the stage of cooperation. Yuan Jijun, a founding partner and general manager of Jikai pharmaceutical company, said in an interview with the twenty-first Century economic report, "from the layout, it is a trend to extend from hematoma to solid tumor. The key technologies are how to control the cost, reduce the price, and protect the intellectual property rights.

CAR-T technology involves two problems, including the construction of genetic engineering vectors and the preparation of CAR-T cells, including the collection and treatment of immune cells, cell culture, transfection, amplification and reinfusion. Because of the cost of reagents and other materials, the detection cost of CAR-T cell quality control, the cost of cell product GMP workshop operation, the third party certification and quality inspection fees are very high, the terminal cost is very difficult to fall, resulting in the high price of landing in the future. This is also the reason why Novartis and Kite Pharma make high cost of treatment.

"We have no intellectual property rights in China as far as we know," Wu Yifang, President and CEO of Fuxing medicine and chairman of Fosun Kate, said in an interview with the twenty-first Century economic report. For the price, "CAR-T is a personalized medicine, separate production and separate distribution, its cost can be expected to be high." It is hoped that national health insurance, commercial insurance, including enterprises should contribute to enhance the accessibility of patients to the drug.

"The entire production process and process including product quality, without affecting the quality of the process, is estimated to have a breakthrough in cost, which may be difficult." Fosun Kate CEO Wang Liqun told the twenty-first Century economic report that when domestic companies want to declare to pharmaceutical companies, "the cost is similar to ours, because the products that China has not approved has been approved. If we drop a lot, we worry that the quality may be affected. We will declare the listing next year. At the same time, there is still more confidence in the application of CAR-T to solid tumors, and to which specific indications, we believe that the success of solid tumors should be gradual.

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