Whose "100 billion cake" of hemophilia gene therapy

It has come to an end before it starts, who has the "100 billion cake" of hemise disease gene therapy?

Source: Yaozhi.com/Huang Zhongping

Before the birth of modern treatment, hemophilia was one of the most painful diseases known in the medical community at that time. Due to the lack of coagulation factors in the patient's body, minor injuries could lead to unbearable pain and life -threatening bleeding.

After a long medical exploration, scientists gradually understand the cause of this disease. The emergence of coagulation factor allows people to have the treatment of hemophilia. However, blood products with viruses have also brought more terrible risk of transmission of infectious diseases. Therefore, the research on more effective and effective hemophilia therapy drugs has never stopped.

Even now, under the effective control of the risk of infectious diseases, the venous injection of the year after year, the arm of the pinhole, and whether the complications accumulated over time have never stopped torture the patients.

Now, the hope of "healing" hemophilia has appeared, and the great goal of eliminating this terrible disease seems to be near.

"Treatment" therapy first

Recently, BiomarinPharmaceutical announced that the European Commission (EC) approved it for the treatment of ROCTAVIAN (VALOCTOCONEROXAPARVOVEC) for gene therapy A for hemophilia A for the treatment of adult patients for severe hemophilia A. This is the world's first genetic therapy for treatment of hemophilia A.

Image source: CISION website screenshot

It is reported that ROCTAVIAN is a genetic therapy that uses the AAV5 virus vector to deliver an expression factor VIII. Its advantage is that the patient may only need to receive treatment once, and hepatocytes can continue to express eight factor, so that long -term prevention of prevention of prevention of prevention.

The European Commission's decision is based on the results of the ROCTAVIAN Global Phase 3 clinical trial GENER8-1, which was published in "New England". The data shows that compared with the data before the group, after a single infusion of ROCTAVIAN, the use rate of coagulation eight factor of patients A patients A and ABRs that need to be treated were reduced by 99%and 84%, respectively. Generally speaking, 90%of the test participants do not need to treat bleeding events, or decreases from bleeding events compared with preventive treatment of coagulation eight factor.

In terms of security, ROCTAVIAN has good tolerance, without long -term treatment related side effects, and most of the side effects occur earlier, including adverse reactions related to infusion, mild liver enzymes, but no long -term clinical sequelae. Other side effects include nausea, headache, and fatigue. No patients with eight factors in the patient have no venous thrombosis, and no malignant tumors related to ROCTAVIAN have occurred.

Although this news has not yet caused much reaction, in fact, with the emergence of this gene therapy, the drug pattern of hemophilia A and even the entire hemophilia market has been completely changed.

The blood -based eight factor that will eventually be replaced

The above -mentioned gene therapy ROCTAVIAN's hemophilia A series is caused by the lack of coagulation eight -factor protein caused by patients. Due to the lack of coagulation eight -factor protein, the coagulation reaction chain of patients with hemophilia A is broken and the platelet condensate cannot be formed. Long -term, repeated joint bleeding and inflammation lead to high risk of disability in patients with hemophilia, and may endanger their lives.

In the past, an effective treatment plan was to combine the active coagulation eight factor proteins with the activated nine -factor protein by supplementing the octa factor of the coagulation, and then activated and produced the activated ten factor protein in combination with the ten factor proteins, forming a coagulantal activation. The coagulanticidal activation catalyzed coagulation converted into active coagulant under the action of calcium ions, transforming soluble fibrin in plasma into insoluble fibrin and formation of platelets and coagulation function.

Photo source: screenshot of Shenzhou Cell Filming Book

There are many patients with hemophilia in my country and have continued to increase. In 2014, the number of hemophilia patients in my country was 137,000, of which about 85%were patients with hemophilia A. By 2018, the number of hemophilia patients in my country increased to 140,000. The number of patients and patients will reach 144,000 and 146,000, respectively.

However, patients A patients in my country are unfortunate. The long -term supply of coagulation eight factor is small, and the treatment is extremely unsatisfactory. According to statistics in 2017, the consumption of the per capita coagulation of Chinese citizens is only 0.26iU, which is far lower than the United States' 9.57iU, Russia's 6.89iU, and the world average of 2.61iu.

The reasons for this situation are more complicated. Prior to 2021, China's domestic coagulation eight factor was mainly blood -ogenic coagulation eight factors, which were extracted from plasma. Since 2001, the country has not been newly batch of blood product manufacturers. The existing enterprises have increased production capacity by increasing the number of plasma stations. Overall the increase in coagulation eight factors has not increased greatly, and it is difficult to achieve a qualitative leap. In addition, because the blood -based coagulation is a blood product, there are potential threats such as virus bacteria cross infection, and it is easy to cause allergic reactions. Therefore, it is not an ideal treatment drug.

At present, the products that have been listed in China are Shanghai Rice, Hualan Biological, Green Cross, Shandong Thailand, Shanghai Emerging Pharmaceutical and other products. Domestic hemogenous coagulation eight factor has been listed on the market

Image source: "Eight Factors" is warm water, blood products giants are cooked frogs "-Jianxian Bureau

However, these blood product companies with a dedicated brand care for their care "lying" for too long, more or less forgiving problems, so that when the import reorganization coagulation eight factor impacts the domestic eight factor market, no one responded to fighting. Essence In 2011, Shanghai Rice has announced a pre -clinical study of the reorganization of the eight factor, which has been silent; Hualan Bio has never disclosed the reorganization eight factor plan. It can be seen that the special license is easy to nourish the development of enterprises.

The eight factors of the reorganized human coagulation are biological drugs. They do not need to use blood as raw materials, and do not need to use single -mining plasma stations as support points. There were earlier eight -factor products abroad, but they could not enter China for a long time. Since 1985, China has banned the import of blood products other than human leukin. Until 2007, considering domestic patients and product conditions, the reorganization of the eight factor was allowed to be imported. At present, imported products on the market include Best Bailin, Bayaki, Bayikch, Pfizer's Ren Jie, and the newly approved Nuo and Nord's Nordi.

An Jiayin's reorganization of the reorganization of the Shenzhou cells, An Jiayin, was approved, as if a spear stabbed the situation of foreign monopoly.

It is about to end before starting?

In July 2021, the eight factor (commodity name: Anjiain) of Shenzhou cell restructuring human coagulation (product name: Anjiain) was approved for the control and prevention of adults and adolescents (≥ 12 years old) hemophilia A. Anjiayin is the third -generation reorganized human coagulation eight factor products that are independently developed by Shenzhou cells, craftsmanship and preparations, and are the first domestic restructuring people to be approved for listing.

An Jialin has two core advantages: First, high production capacity, Shenzhou cells have established a variety of advanced technologies to form the core steps of high efficiency and high -specific downstream innocence process, finished preparation formula of gyin -free additives, and 4000 -liter cell culture The design capacity of the scale can reach 10 billion IU per year; the second is high stability. Among the real -time stability research under the conditions of 2 to 8 ゜ C conditions, the two specifications of 3 batches of finished products store 48 The product activity after the month has not seen a significant decline.

Picture source: Shenzhou Cell Official Website

The emergence of Shenzhou cell Anjiayin not only broke foreign capital monopolies, but also filled the domestic gaps. It is also more important that its crazy output is enough to subvert the market structure of the global reorganization eight factor, because the annual output of up to 10 billion IU is almost equivalent to the global global 2017 global Total consumption of eight factor.

However, this is just the beginning of localization. In June 2019, the State Drug Administration released the "Principles of the Technical Guidance of Reorganized Human Coagulation Factors ⅷ Clinical Test Technology" to encourage enterprises to develop and listed the reorganization of eight factors. Development of factor.

The Rongsheng Pharmaceutical, Thai Bangbang, Zhengda Tianqing, and Shengsi Biological of Tiantan Biological Holdings successively organized research and development and conducting clinical trials of reorganization of eight -factor. Among them, Zhengda Tianqing has submitted a listing application.

In addition to the above -mentioned coagulation factor treatment drugs, in the past ten years, the development of non -coagulation factor therapy drugs in the field of hemophilia treatment has begun. Non -coagulation factor therapy drugs include dual -antidote, RNAI therapy drugs, and gene therapy drugs.

In 2018, the State Drug Administration approved Roche's Emmy Saizab's import registration application. This drug is used for conventional preventive therapy for patients with hemophilia A who has the presence of coagulation eight factor inhibitors. It is currently the first preventive therapy drug that can be performed once a week.

Fitusiran, a RNAI therapy developed by Alnylam and Sanofi, is a new type of subcutaneous injection RNAI therapy that is developing to prevent the treatment of patients with type A or B -type hemophilia. According to the clinical research data of the 3 ATLAS-PPX clinical research data released at the 2022 conference in the 2022 conference of the 2022 conference, the monthly Fitusiran (80 mg) once a month can make hemophilia A and hemophilia B and B Patients' bleeding decreases by 61%. The clinical project has also been carried out simultaneously in China.

However, compared with the reorganization eight factor, the two -resistance and RNAI therapy is more obvious.

Gene therapy, as a therapy for "cure" various diseases, has become a commanding height of competition in biotechnology in various countries. In 2010, the genetic treatment of hemophilia in the world began, and China is expected to overtake in this field.

In May 2022, "Liuye Knife-Hematology" published the first liver targeting gland-related virus (AAV) hemophilia (AAV) hemophilic disease (AAV) hemophilia of hematopicians (AAV), which was published in "Liuye Knife-Hematology". The research results of gene therapy are exciting.

这项研究为单中心、单臂、1期注册临床研究（NCT041353000），自2019年10月正式启动，共纳入了10例重型/中重型血友病B（九因子凝血活性，即FIX:C <2IU/DL) Patients, after glucocorticoid pre-treatment, gives disposable venous infusion gene therapy products BBM-H901. The study completed a total of 58 weeks of follow -up. The results showed that the gene therapy had rapid results, relatively stable coagulation factor levels, significant clinical benefits, and good safety. Photo source: screenshot of Liuye knife official website

In addition, in February 2022, the clinical study of the original target genetic target genetic target therapy initiated by Sichuan Xie Shanwei New Biology passed the review of the Chinese Human Genetic Resources Management Office; in April 2022, Shanghai Tianze Yuntai Biological VGB-R04 Injecting liquid indication is the clinical trial application of congenital coagulation nine factors that the lack of hemophilia B clinical trial application has been approved.

The breakthrough of hemophilia A gene therapy in China is not far away.

Conclusion

A drug that can be "cured" is the luck of human beings, but at the same time, it is also the lament of all participating companies. Taking hepatitis C as an example, because the cure can be achieved, the future hepatitis C drug market will gradually shrink as the number of patients decreases.

Therefore, whether it is the eight factors of the blood -based coagulation or the reorganization of the eight factor, under the impact of the gene therapy that can "cure", it will inevitably decline. However, you don't have to worry too much. This should be a matter of many years. Whether the expensive price of gene therapy can be generally accepted for the time being. How will the follow -up development, Yaozhi.com will continue to pay attention.

Reference materials:

The annual report of Shenzhou cell, official website, prospectus, etc.

"Eight Factors" is warm water, and blood product giants are cooked frogs ", Kenji Bureau, 2021-9-14

"Global Hemophysical Gene therapy is approved! One -time infusion greatly reduces patient bleeding! ", Shengnuo family, 2022-8-26

"Cure" hemophilia? The results of the first genetic treatment in my country are here ", the blood channel of the medical community, 2022-6-19

"Heavy! Tianze Yuntai Bloody Friends AAV gene therapy VGB-R04 clinical trial application was approved by CDE ", how much is healthy, 2022-4-21

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