Two highlights of "Glassman" drug market: China's huge growth potential and a large number of breakthrough and heavy new drug reserves

In our life, there is a group of people who may accidentally bleed with a small scratch, suffer from joint pain or even necrosis due to a wrestling, and have gastrointestinal bleeding or urination without omen Such people are often called "Glassman" In fact, many "Glassman" in reality are hemophilia patients This disease basically belongs to X-linked recessive gene defect Hemophilia patients lack some coagulation factors or lack of activity to varying degrees, which leads to coagulation dysfunction In 2016, China rare disease development center (cord) released the reference list of rare diseases in China, which included hemophilia and 146 other diseases in the list of rare diseases in China According to the results of the 1986-1989 years of large sample survey in China, the prevalence of hemophilia in China is 2.73/100000 In view of the medical conditions at that time, the prevalence of hemophilia in China should be higher The incidence rate of hemophilia in male population is about 2.4, according to the Chinese expert consensus on haemophilia diagnosis and treatment (2017 Edition) According to the types of factor deficiency, hemophilia can be divided into hemophilia A (type a hemophilia, lack of coagulation factor Ⅷ) and hemophilia B (type B hemophilia, lack of coagulation factor IX), in which hemophilia A a accounts for 80% ~ 85%, hemophilia B for 15% ~ 20%, hemophilia a A and hemophilia B are X-linked defects In addition, there are rare hemophilia C caused by autosomal recessive defects According to different conditions, hemophilia A and hemophilia B can be divided into light, intermediate and heavy Light patients generally do not need routine treatment, but the middle or heavy patients often have large bleeding in small wounds, and spontaneous bleeding may occur in joints and other parts According to the consensus of hemophilia experts in 2017, products such as desmopressin, tranexamic acid and 6-aminocaproic acid can be used for the treatment of hemophilia, but the most important is still coagulation factor replacement treatment Global market: many "heavy bombs" have been produced since the 1960s The relatively purified coagulation factors (including human coagulation factor Ⅷ, prothrombin complex and human coagulation factor IX preparation) derived from healthy human plasma and inactivated by the virus have gradually replaced the cold precipitation of plasma, and are used in the replacement treatment of hemophilia At present, most blood product manufacturers can supply human coagulation factor Ⅷ and prothrombin complex, and some enterprises can also produce high-purity human coagulation factor IX preparations However, although blood clotting factor products have almost no effect on the spread of virus infection at present, due to the origin of human blood, it still can not completely avoid the risk of virus In addition, there are still some obstacles in plasma donation in many countries The content of coagulation factors in plasma is extremely limited, and the lack of plasma supply also leads to the deficiency of blood coagulation factors Compared with clotting factors from human blood, recombinant clotting factors from genetic engineering undoubtedly have significant advantages in product source and virus risk In 1992, recombinate of Baxter was listed in the United States as the first recombinant coagulation factor Ⅷ (RF Ⅷ) approved by FDA However, as the first generation of drugs, recombinate is still immature, especially when the specific activity is too low and human albumin needs to be added in the preparation process Subsequently, the new generation of products, such as advance of shire, kovaltry of Bayer, nuwiq of auctfarma and xyntha of Pfizer, went on the market successively and became the mainstream of the market In terms of recombinant coagulation factor IX (RF IX), currently there are limited varieties approved Pfizer's benefix was the only approved recombinant coagulation factor IX before 2013, but in recent years, several products have been approved, including shire, biooverativ, Novo Nordisk, beline and aptevo Although patients are limited, due to the long-term treatment and high cost, the global hemophilia drug market has reached more than 10 billion US dollars Among them, NovoSeven, kovaltry, advocate and some blood clotting factors have reached the rank of heavy bomb However, the domestic hemophilia drug market is still very limited China's China China market: awesome policy and high growth rate, the rate of hemophilia in China is much lower than that in Europe and America As a serious genetic disease, the management of hemophilia is widely adopted in the world However, the number of registered hemophilia patients in China and the United States is different from that of the 10/100000 in Europe and the United States The number of registered blood users in China is only 0.8/100 of the total population 000, because there is no significant difference in the prevalence of hemophilia patients between species, compared with Europe and America, the diagnosis and treatment rate of hemophilia patients in China is less than 10% The diagnosis and treatment rate of hemophilia patients in China is not only low, but also the per capita consumption is very low Hemophilia treatment in Europe and the United States is widely used in children and adults with severe cases Every week, 2-4 injections of coagulation factor are used for alternative prevention, while China's preventive treatment is only used in some developed areas for some children To this end, the latest 2017 version of China's hemophilia expert consensus stressed: "with the improvement of conditions such as medical insurance and drug supply, China has been equipped with various conditions for the prevention and treatment of hemophilia patients It is suggested that prevention and treatment should be carried out actively in order to reduce the disability rate and improve the quality of life of hemophilia patients in China " At present, hemophilia drugs in the domestic market mainly include blood source and recombinant coagulation factor Ⅷ for hemophilia A, prothrombin complex (PCC) and RF ⅸ for hemophilia B, and PCC and RF ⅶ a for inhibitors According to the statistical report of data issued by China's blood products batch in 2016, 988600 bottles of domestic clotting factors (all blood clotting factors) were supplied to the market in 2016 (calculated by 200iu / bottle, the same below), 685900 bottles of imported clotting factors (all recombinant), and 86700 bottles of pcc68700 According to the estimation of the product's bid price, the market scale was about 1.5 billion yuan Although the market size in 2016 increased by more than 20% compared with that in 2015, compared with Europe and the United States, there is still a huge market potential for hemophilia in China to be developed in the future With the increase of national medical investment and the increasing attention to rare diseases, at present, some developed regions have gradually incorporated hemophilia prevention and treatment (especially the prevention of hemophilia among children) into the local chronic disease management The 2017 version of medical insurance adjustment pays special attention to the needs of hemophilia patients In 2017, the adjustment of medical insurance increased RF ⅸ as a class B product of medical insurance, and reduced the restrictions on the use of medical insurance of RF Ⅷ In the latest medical insurance drug price negotiation, rfⅶ a, as the lowest decreasing variety among 36 varieties, entered the medical insurance with a price reduction rate of less than 10%, which made all the five drugs for hemophilia substitution treatment in China be included in the national medical insurance catalog, and a series of hemophilia drugs in research were included in the drug catalog for accelerated evaluation by the national drug regulatory department The above adjustment shows that the country attaches importance to hemophilia and cares for the patients with hemophilia The importance and policy implementation of hemophilia make us believe that the market of hemophilia drugs in China will maintain a rapid growth trend for a long time in the future Hemophilia new drug reserve: a large number of breakthrough and heavyweight new drugs and the latest research and development progress However, in the field of hemophilia drug market, the biggest highlight is not the huge market growth space in China, but a large number of breakthrough and heavyweight new drug reserves on the follow-up R & D line
Although there are abundant blood sources or recombinant coagulation factor Ⅷ and coagulation factor ⅸ on the market at present, and the supply of coagulation factor in some developed countries has been able to meet the clinical application, there are still some deficiencies in coagulation factor replacement therapy, mainly including high inhibitor problems, high frequency of injection and low compliance of intravenous injection At present, the products under research are mainly aimed at the above problems Make improvements Therefore, the author summarizes the latest progress of the four hot research directions One of the challenges in the treatment of hemophilia is that some patients will develop anticoagulant antibodies, commonly known as "inhibitors" after using alternative therapy The occurrence of "inhibitors" will reduce the effect of coagulation factors, while severe patients may lead to the inactivation of coagulation factors and induce more serious bleeding events It is generally believed that about 10% - 30% of hemophilia A A patients and about 5% - 10% of hemophilia B patients will have different degrees of hemophilia inhibitors in the treatment, among which the incidence of severe hemophilia patients is higher and the influence of inhibitors is more serious For patients with severe hemophilia inhibitors, although a few can be eliminated by immune-induced tolerance (ITI), more patients can only use bypass to stop bleeding The commonly used by-pass hemostasis drugs are blood derived coagulation factor complex containing F ⅶ, such as PCC (prothrombin complex) and FEIBA (f ⅶ inhibitor by-pass active agent), but due to the limited purity, the effect is often not ideal Because it is difficult to purify clotting factor ⅶ in plasma, NovoSeven, the first recombinant clotting factor ⅶ a product, was developed by NovoSeven through recombination technology, and the higher purity reduced the dosage of clotting factor However, NovoSeven has limited supply, high treatment cost and high frequency of administration, so better varieties need to be studied According to cortellis data, in addition to NovoSeven's biological analogues, there are currently four rfⅶ a in clinical research stage Among them, lr769 of LFB has completed the clinical research on clotting factor inhibitor This year, it is reported to FDA for listing, and is expected to become the second approved new rfⅶ a drug in the world The drug is similar to NovoSeven, but the updated process makes the production cost greatly reduced Beline's csl-689 is currently in phase III clinical practice, and its half-life is more than twice that of NovoSeven, which is expected to reduce the frequency of administration In addition, opko can further prolong the half-life of clotting factors by using its patented CTP fusion protein technology The mod-5013 developed by opko is currently in phase II clinical practice, and only needs to be injected once or twice a week For patients who are intolerant of F ⅶ or ineffective, there are other solutions In addition to the hot emicizumab mentioned later, there is a very special variety In 2016, shire's recombinant pig f Ⅷ, obizur, was approved by the FDA for use in patients with severe inhibitors of hemophilia A The principle of the drug is that the presence of antibodies in patients can reduce human f Ⅷ, but pig f Ⅷ is not affected by it, so recombinant pig f Ⅷ can achieve substitution Direction 2: change the way of administration As a gene deficient disease, hemophilia treatment advocates prevention first, and attaches importance to family independent administration However, unlike subcutaneous administration of insulin, all clotting factor products on the market need intravenous injection, which undoubtedly increases the difficulty of administration The development of recombinant coagulation factors for subcutaneous injection is a direction of research and development At present, the csl-640 of beline is the rapid progress of RF ⅸ subcutaneous injection preparation, while in the field of RF ⅸ subcutaneous injection, the fastest progress is the long-acting preparation nn-7170 At present, both of them are still in phase I clinical practice In addition to recombinant clotting factors, emisizumab, which is mentioned later, is also worthy of special mention The drug only needs to be injected subcutaneously once a week