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Autoimmune diseases, which are widely and mostly difficult to treat, are one of the important directions of drug development.
JAK-STAT pathways are proven and few immunomodulatory pathways, especially JAK inhibitors, and several drugs are listed worldwide, such as Tofatinib.
domestic aspect, the development of JAK inhibitors also has more than 10 varieties into the clinical stage, and jiangsu Hengrui led the track, the overall development of hot and clinical indications (such as bone marrow fibrosis, rheumatoid arthritis, baldness, etc.) is very much to look forward to.
1, JAK Inhibitors and Target Pathways Introduction Currently, 4 JAK family members (JAK1, JAK2, JAK3 and TYK2) and 7 STAT family members (STAT1, STAT2, STAT3, STST) were found in mammals AT4, STAT5a, STAT5b and STAT6), and further studies have shown that the biological effects of more than 50 cytokines and growth factors are mediated through the JAK kinase and its JAK-STAT pathways;
Figure 1.1: Intracellular-JAK-mediated different signal transduction pathways (picture source: s41575-020-0273-0) 2, the global listed drug introduction JAK target development time is less than 20 years, but there are nearly 7 varieties have been approved for market, adaptation is mainly tumor and autoimmune diseases, further refinement of the disease is mainly bone marrow fibrosis and rheumatoid arthritis.
below highlights the first FDA-approved JAK inhibitor for the treatment of patients with bone marrow fibrosis (reedinib) and the first JAK inhibitor (tofatinib) for rheumatoid arthritis treatment.
Ruxolitinib, jointly developed by Incyte and Novartis, was approved by the U.S. FDA in 2011 and is the first FDA-approved JAK1/2 inhibitor to treat patients with critical or high-risk bone marrow fibrosis.
, the species has been clinically developed in the areas of true erythrocyte growth and acute graft anti-host disease.
global sales, the annual sales of Reedinib in 2015 was US$1 billion and increased year by year, reaching US$2,799 million in 2019.
but surprising! Domestic registration declaration of this variety, in addition to the original Novartis has been approved for import, there is no domestic pharmaceutical companies to register the species declaration.
Tofacitinib, an oral small molecule JAK inhibitor developed by Pfizer in the United States with better JAK selectivity, and in November 2012, the FDA approved the use of the cesic tofatinib for use in adults with moderate to severe active rheumatoid arthritis patients who respond editing inadequately or intolerance to methotrexate treatment;
at present, in addition to approved indications, Tofatinib is also in the strong direct spina bifida, adhematitis, dry corneal conjunctivitis and Crohn's disease and other diseases in the efficacy of verification.
global sales, Tofatini's annual sales in 2017 were $1 billion, reaching $2.242 billion in 2019.
the domestic registration declaration of the variety, in addition to the original research Pfizer has been approved for import, the domestic pharmaceutical companies are daqing, Qilu pharmaceutical imitation varieties are registered with the chemical 4 categories of declaration, and has been approved for production.
Table 2.1: JAK inhibitors listed / NDA /III clinical varieties 3, domestic 1 innovative varieties and Hengrui lead the domestic current development of JAK kinase inhibitors, nearly 10 varieties have entered the clinical development stage, the track is the most advanced is the variety Ofs SHR developed for Hengrui -0302, which has now entered Phase III clinical phase, and the species entering Phase II are Zotiraciclib of Lee's Big PharmaceuticalS, Alkotinib, Jaktinib of Zei,AZD-4205 of Dizer Pharmaceuticals;
here mainly introduces the SHR-0302 of Hengrui Company, as well as the two Phase II varieties of Zezi bio.
SHR-0302 (Hengrui) Jiangsu Hengrui developed THE JAK1 inhibitor SHR-0302, currently in Clinical Phase III, for the treatment of rheumatoid arthritis;
January 2018, Jiangsu Hengrui entered into a cooperation agreement with Arcutis of the United States, which will receive SHR-0302 as a local external formulation for the treatment of skin diseases and will be exclusively clinically developed, registered and marketed in the United States, the European Union and Japan, while Hengrui will receive a down payment and milestone of US$200 million, plus a post-ipo sales commission.
the development of two JAK inhibitors by Jaktinib and Alkotinib (Zetsinbio) Biotech, which are now in the clinical stage in China.
Jaktinib, clinically developed for the treatment of bone marrow fibrosis and plaque, including bone marrow fibrosis, isoderitis, psoriasis, isoplastic pulmonary fibrosis, aggressive spinabitis and moderate and severe active rheumatoid arthritis;
Alkotinib, clinically developed in the direction of non-small cell lung cancer, further identified as the treatment of ALK-positive or ROS1-positive and failed treatment of first-line (chemotherapy or gramtinib). table 3.1 of the
: Domestic JAK inhibitor development 4, summary, that is, the global overall development of JAK kinase inhibitors.
the global listed drugs are mostly developed by large pharmaceutical companies, the market performance is gradually climbing, higher attention.
and domestic, for the development of related targets in this direction, are also very well-known innovative pharmaceutical companies in doing, and will soon enter the harvest period! In the future, it is not just the direction of JAK kinase inhibitors, I believe that the whole field of autoimmune diseases will be a global drug industry.
References: 1.JAK-STAT pathway targeting for the treatment of the simr. Nature Reviews . . . Gastroenterology and Hepatology.s41575-020-0273-0 2.JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycleprogression and leukemogenesis.3. Sciencedirect Database 4.Pharmacodia Database 5.Yaozh Database 6. Major official website information.