"Big pattern" in small fields: the present and future of drugs for the treatment of atopic dermatitis

Atopic dermatitis (AD), also known as allergic eczema, is a skin inflammation Ad is usually associated with other allergic diseases, such as allergic rhinitis and asthma It is believed that ad is related to the interaction of gene and environment, which promotes the dysfunction of skin barrier and immune system, and leads to the sensitization mediated by immune protein E (IGE) Ad usually occurs in childhood, with about 45% of infants at 6 months of age The study estimates that in industrialized countries, the proportion of children to adults is 15-30% and 2-10% respectively Due to the consideration of safety, the therapeutic effect of ad is often poor, and the treatment needs to be met are still very high Traditional therapeutic agents are the main drugs for AD, often used in combination with systemic therapy and phototherapy for severe AD patients The first treatment for ad is emolients, followed by topical corticosteroids if the effect is poor Long term treatment with topical corticosteroids can lead to skin atrophy and body absorption Topical calcineurin inhibitors, such as tacrolimus and pimecrolimus, are second-line drugs for local treatment, which can avoid the risk of skin atrophy In the process of systemic treatment of AD, oral steroid drugs, such as prednisone, have been approved by FDA, but considering its side effects, long-term treatment is generally avoided In addition, off label is often used in systemic therapy For example, cyclosporine, azathioprine, methotrexate, mycophenolate, interferon - γ and so on have shown good curative effect in the treatment of severe AD In conclusion, the use of systemic therapy drugs varies greatly in different countries due to the lack of long-term clinical data and medication guidelines Emerging therapy: with the approval of the first non steroidal external drug crisaborole and the first biological therapy drug dupilumab, the pattern of AD treatment drugs is gradually changing Crisaborole, developed by Pfizer, is a phosphodiesterase-4 (ped4) inhibitor; dupilumab, jointly developed by regeneron and Sanofi, is a monoclonal antibody that acts on the α chain of IL-4 receptor At present, the research and development of AD treatment drugs focus on phosphodiesterase-4 (ped4) inhibitors, interleukins monoclonal antibodies, JAK inhibitors and histamine antagonists, as shown in Table 1 Table 1 some drugs under development in atopic dermatitis note: click the picture to see a clear picture 1 Camp, an inhibitor of ped4, is an important immunoregulatory factor Ped4 can reduce the content of camp, which will lead to the disorder of immune function The inhibitor of ped4 is conducive to blocking this process The success of the first nonsteroidal topical drug, crisaborole, was due to two phase III trials (ad-301, ad-302) involving 1500 AD patients and controlled by excipients In addition, the mm36 developed by medimetriks has completed the clinical phase II The experimental results show that the mm36 is safe and well tolerated, and can quickly relieve the itch and pain of the adolescent AD patients Phase III trials will begin in the first quarter of 2018 2 At present, the cytokines secreted by type 2 T-helper cells (Th2), including IL-4, IL-13, IL-5, IL-31, etc., have become potential targets of AD treatment The main drugs under study are monoclonal antibodies Dupilumab, jointly developed by Regeneron and Sanofi, can inhibit IL-4R α and block the physiological process mediated by IL-4 and IL-13 by subcutaneous administration Three phase III clinical trials (solo1, solo2 and Chronos) have reached the clinical end point, and have been approved by FDA and EMA for use in adult patients with moderate to severe AD Meanwhile, the clinical trial of dupilumab for adolescent AD patients is under way In addition, medi-9314, developed by AstraZeneca, also targets IL-4R α, and its I clinical trial is underway IL-13 targeting drugs, such as tralokinumab and lebrikizumab, are all humanized monoclonal antibodies Tralokinumab, acquired by AstraZeneca from Cambridge anti technology in 2006, is used for severe asthma, ad and other treatments LEO has bought the global development right of Tralokinumab for the treatment of skin diseases At present, the III clinical trial for the treatment of AD is underway; Lebrikizumab, developed by Roche, in a phase II clinical trial, the combination of Lebrikizumab and external drugs can significantly improve the efficacy of AD Dermira acquired the global development rights of lebrikizumab for the treatment of skin diseases, and is ready to carry out the phase IIB trial for the treatment of ad in 2018 IL-5 can induce the differentiation and activation of eosinophils Mepolizumab, developed by GlaxoSmithKline, is an all human IL-5 monoclonal antibody In a phase II clinical trial conducted in 2017, mepolizumab can moderately improve the treatment of AD IL-31 targeting drugs, such as nemolizumab, developed jointly by Chugai & Galderma, humanized il-31r α monoclonal antibody, can significantly reduce the itch of AD patients in a phase II clinical trial, but only slightly reduce the inflammatory response, which may be related to the fact that IL-31 mainly regulates the nervous system rather than the immune system In addition, bms-981164 developed by BMS also acts on IL-31, but there is no latest progress in this project since phase I clinical trial in 2015 Of course, in addition to the above, there are many McAbs targeting other interleukin For example, anb-020 developed by anaptysbio, an IL-33 monoclonal antibody; tezepelumab developed by AstraZeneca, a TSLP monoclonal antibody, etc at present, these projects have entered the clinical stage 3 JAK inhibitor JAK-STAT signaling pathway has a wide range of functions, which is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation At present, researches related to diseases and drug innovation are focused on inflammatory diseases and tumor diseases Today, JAK inhibitors are candidates for the treatment of AD By Eli Lilly& Barictinib, developed jointly by company, is an oral reversible inhibitor of Jak1 and JAK2 In the phase II clinical trial of barictinib combined with external drugs, it can significantly improve the treatment effect of moderate to severe AD; upadacitinib, developed by abbvie, is a highly selective second generation oral inhibitor of Jak1 In a phase II clinical trial, after 16 weeks of treatment, upadacitinib will increase the severity of AD 90% reduction in pruritus and 69% reduction in pruritus As a result, upadacitinib has become the most expected JAK inhibitor Abbvie is preparing to launch phase III clinical trials of upadacitinib in 2018 4 Histamine, an antagonist of histamine, is a cell signaling molecule with rich expression and four known receptors Inhibition of histamine H4 receptor (H4R) reduces Th2 driven inflammation and pruritus Zpl-389 is such an H4R antagonist It was developed by ziarco & Novartis It is currently in phase II clinical practice Market structure: it is estimated that the global ad treatment drug market is about 3.3 billion US dollars, with a compound annual growth rate of 4% in the past four years Topical corticosteroids play a leading role, with annual sales of US $2 billion, accounting for 61%; systemic therapeutic drugs with annual sales of US $957 million, accounting for 29%; topical calcineurin inhibitors In hibitors, tacrolimus and pimecrolimus are two important patent protection drugs, with an annual sales volume of 344 million US dollars, accounting for 10%; crisaborile, the first non steroid external drug developed by Pfizer, has an annual sales volume of 11 million US dollars, accounting for 0.3% As shown in Figure 1 It is estimated that the AD drug market will reach US $6 billion in 2022, which is mainly due to the driving role of biopharmaceuticals represented by dupilumab For example, some predict that dupilumab's peak sales will reach US $2.5-4 billion However, biological agents are generally expensive and may eventually become second-line drugs for AD treatment Those low-cost, universal and effective external or oral systemic therapy drugs will become the first-line treatment products.