Layout atopic dermatitis in progress

Atopic dermatitis (AD), also known as eczema, is a common chronic, recurrent and inflammatory skin disease, characterized by dry skin, eczema like skin rash and severe itching People without eczema may never feel the pain Eczema often occurs in children At present, there is a lack of reliable epidemiological data in the domestic market In addition, hospitals at all levels lack the cognitive and diagnostic ability of AD, which is easy to cause misdiagnosis or missed diagnosis According to rough estimation, the number of patients with atopic dermatitis accounts for about 10% of the total number of outpatients in dermatology department The incidence rate of children 15%-20% and adult 1%-3% is calculated on the basis of global scale, and the number of potential AD patients is about 66 million Considering that the correct diagnosis rate and standard treatment rate are still the main resistance of ad market, assuming that the treatment rate of ad is 90% and the treatment rate of ad is 10%, the potential population of ad in China is about 5.99 million From tens of millions to millions, although it reflects that ad as a chronic disease has not been given reasonable attention, it also indicates that the potential broad market of ad in China will be on the rise with the improvement of national awareness of disease diagnosis and early management In 2018, the global market for skin disease drugs reached US $29.4 billion, of which, there are two antibody drugs in the top 10 global sales, which are suitable for the IL family of psoriasis treatment However, the market scale of AD based on traditional drugs in China is only 7.78 billion yuan Subdivided into ad external drug market, in addition to local anti infection, ad local drugs are mainly non steroidal drugs (IMS includes PDE4, monoclonal antibodies, tacrolimus, etc.) and glucocorticoids, so it is used as a qualifier to retrieve sales data In 2018, the market scale of non steroidal anti-inflammatory drugs and local glucocorticoids reached US $6.06 billion, and the indications can be mainly divided into psoriasis (5 drugs), ad (4 drugs), and other skin diseases (6 drugs) Among them, psoriasis took the lead (79%, US $4.79 billion), ad ranked second (12.2%, US $740 million) In ad market, dupixent is the only McAb (1 / 4) targeting il4ra, which was approved in 2017 In 2018, the global sales reached US $80 million (AD indications only) If the market performance of the products in the field of asthma is added, the sales in 2024 is expected to reach us $8 billion In contrast, in the domestic market, the 2014 China specific dermatitis diagnosis and treatment guidelines did not include biological agents as recommended drugs, and no such indication biological drugs have been approved (skip and enbok cross indications, not detailed here) In contrast, there is a big gap between the domestic and foreign skin Market in drug use structure, and there is still a large development space in China Compared with small chemical molecules, the research and development heat of biological drugs in AD has been ignored until 2012 Since the approval of dupixent, the world's first targeted biological agent for atopic dermatitis in 2017, the era of ad targeted biotherapy has ushered in a spring, and the R & D model has gradually moved from the traditional drug model to the target biological model In view of the progress in the research and development of biological drugs in the field of atopic dermatitis, about 1 / 2 of them are monoclonal antibodies, which are still the main force at present The second generation of antibody drugs, bispecific antibody, has not been used in human trials and is in the preclinical stage In view of the important role of immune imbalance in the pathogenesis of atopic dermatitis, which is considered to be the leading allergic disease of Th2, in terms of target distribution of biological drugs, IL family is the key area of target distribution of domestic and foreign enterprises, with the largest proportion of il33 (6 / 69) At present, the treatment of ad is mainly due to conventional external drugs (glucocorticoids and / or calcineurin inhibitors), and if necessary, oral drugs or physical therapy It can be relieved gradually or recovered temporarily, but it can recur However, the application of long-term local chemical preparations can cause skin and systemic adverse reactions, often skin irritation represented by burning and irritation, which greatly reduces the compliance of patients with basic treatment A total of 95 biopharmaceuticals have been developed worldwide for the treatment of atopic dermatitis, with an end / no progress rate of 27% (26 / 95) Only one antibody drug, dupixent, was approved In contrast, in the domestic market, there are 10 biological drugs under research, most of which are in the early clinical stage (the early stage and the first stage), and only one drug is in the third stage, that is, the dust mite drops developed by our company for desensitization treatment of atopic dermatitis caused by dust mite allergy In the world, there are many types of drugs under study, but most of them are monoclonal antibodies Although there is a slight difference in the technical development and injection frequency between Zaiyuan / Sanofi, sinopharma, and Roche (later authorized to dermira) in the development of IL family monoclonal antibodies (Zaiyuan / Sanofi is twice a month, the rest once a month), according to the analysis of open clinical data, the three drugs have little difference in efficacy - the IgA score 0 or 1 after treatment is 30% - 40%, easi-7 5 in 50% - 60% Other types, such as cell therapy and oligonucleotides, although a few of them are in phase 2 or 3 clinical practice, their efficacy is not as good as that of monoclonal antibodies Fusion proteins, peptides, recombinant factors, etc., are mostly in the preclinical stage and have not been applied to human body Table 1 Comparison of representative biopharmaceuticals under research of overseas enterprises In view of the shortcomings of domestic R & D strength, domestic enterprises often take fast follow and me too as common strategies to keep up with the trend of overseas new drugs By analogy, in the field of AD, domestic enterprises have fast follow products with IL4 monoclonal antibody as the direction Because dupilummab has been declared for listing in China on December 25, 2019, it is expected to be approved for listing in the first half of 2020, and its domestic patent expires in 2031, it is preliminarily judged that domestic fast Cbp-201, a follow product with medium market value, can occupy a certain market share by virtue of its price advantage and speed advantage ahead of generic drugs In addition, there is a double target antibody layout with IL family as the guide, which is ahead of overseas enterprises Although it is in the early stage of clinical application, it is still a while away from being applied to human body, but it is speculated that its development purpose is to solve the defect of single target poor efficacy / safety / onset time / administration frequency (the reason for speculation can be seen below) According to the clinical table of previous double antibody in other indications Now, the product is still very worthy of expectation Table 2 Comparison of representative biological drugs under research in domestic enterprises The editor collected the experience evaluation of overseas dupilumab users and found that: 1) The mean score of dupilumab patients after use was 7.3/10 2) The drug cycle was mainly 1-6 months 3) The main factors that hinder patients from using the product are the side effects (such as blurred eyes, astringency, itching, etc., redness and dryness of lips), the effect is not up to the expectation, and the effect time is defective Referring to the defects of above-mentioned IL family McAbs, it also provides some ideas for drug research and development of enterprises, such as improving drug frequency and safety as the starting point Table 3 use evaluation of dupilumab (excerpt) According to a series of assumptions (due to word limit, detailed assumptions and estimated data can be obtained by harassing the editor), the sales volume of dupilumab ad indication after being approved for listing will be predicted and the NPV valuation will be discounted In 2030, the peak sales volume will reach 3.175 billion yuan, and the NPV of dupilumab ad indication will be about 3.635 billion yuan in China at present (this data is only limited to ad indications, and IL monoclonal antibodies often develop asthma indications synchronously, so the market prospect is very big.) According to the preliminary search at this stage, there are only a few enterprises in the field of ad in China, which are in the late stage of R & D although the market of ad biological medicine is still in its infancy in China, with the cultivation of Sanofi dupilumab in the domestic market, it is believed that in the next few years, this subdivision field will gradually become another hot chronic disease after the "three highs" Before the expiration of dupilumab's domestic patent, domestic enterprises take fast follow or me too as the direction, enter the market quickly, take advantage of the price advantage and the market advantage of local enterprises, and strive for a share of the ad biological drug market However, as the number of entrants increases, it will inevitably become a bloody red sea market At this time, how to avoid the project approval of their own products being hit by "dimension reduction" has become a practical problem that has to be considered In order to avoid the embarrassment of project initiation or failure, we can analyze the three-dimensional competition pattern of ad products through the three-dimensional value evaluation model, so as to realize the secondary track upgrade switch and product upgrade within the track during the project initiation Specific target selection, patent layout, access conditions and other Breakthrough Strategies, welcome to harass the editor, and look forward to in-depth discussion with colleagues.