JAK inhibitors: a target favored by major pharmaceutical companies at home and abroad, domestic track Hengrui leading

the | In the development of many targeted therapies, JAK is undoubtedly one of the most popular targets, favored by Pfizer, Lilly, Novaral, AbbVie, Gilead and other major pharmaceutical companies.
, 8 products have been approved for market worldwide, including rheumatoid arthritis, bone marrow fibrosis, psoriasis arthritis, ulcerative colitis, transplant anti-host disease and so on.
addition to multinational large-scale pharmaceutical companies, many local Chinese biological companies have joined the research and development team, such as Hengrui Pharmaceuticals, Xinda Bio and so on.
, however, most face safety challenges, both for approved JAK inhibitors and for candidates under development.
this area will develop in the future, and what potentials remain to be explored? 1. JAK-STAT signaling pathway JAK-STAT is an in-cell signaling pathway that is the signaling pathway through which cytokines, including lebinocytes (IL), interferons (IFNs), and other molecules transmit signals from the cell membrane to the nucleus.
the signal path has more than 50 liposomes, more than 30 subjects, 4 JAK family kinases, 7 STAT family proteins.
Figure 1: JAK/STAT signaling pathpographic pattern map (Source: Reference 1) Studies show that JAK-STAT signaling pathrapies are key signaling paths for inflammation and cancer, and are closely related to blood-related diseases such as erythropoies, thyroidism, leukemia, bone marrow fibrosis, and the occurrence of autoimmune diseases such as RA, strong scolitis, lupus erythematosus, psoriasis, and vitiligo.
JAK belongs to the non-receptor protein tyrosine kinase family, approximately 130kDa, consisting of JAK1, JAK2, JAK3 and TYK2 (non-receptor Protein Tyrosine Kinase-2).
JAK1 has become a target for inflammatory, cancer, immune and other diseases, JAK2 has become a target for blood system-related diseases, and JAK3 has become a popular target for autoimmune diseases.
, JAK inhibitors iteratives have been approved by the FDA since 2011, and so far, eight JAK inhibitors have been approved for market.
1, the international market research and development so far, a total of 8 JAK inhibitors have been approved worldwide, including 5 first-generation JAK inhibitors, namely Novaral/Incyte's ruxolitinib, Pfizer's Tofacitinib, Lilly/Incyte's Baricitinib, Astellas's peficitinib, Japan Tobacco's delgocitinib, and three second-generation JAK inhibitors, Fedratinib of New Base, Upadacitinib of AbbVie and Gilead's Filgotinib.
2: The world's first generation of JAK inhibitors with listed JAK inhibitors can have inhibitory effects on multiple JAK family members and have shown good results in the treatment of inflammatory and tumor diseases.
However, because the JAK family mediates the signaling of multiple cytokines, different subjects are associated with different JAKs, and the total suppression of the JAK family can bring a variety of side effects, including infection, anemia, neutral granulocytosis, lymphocyte reduction, cardiovascular disease, gastrointestinal perforation, hyperlipidemia, etc.
this also limits the clinical application of the first generation of JAK inhibitors.
unlike first-generation products, second-generation JAK inhibitors selectively inhibit members of the JAK family, enabling other cytokine functions to remain unaffected while suppressing specific disease-related signaling path path paths.
addition to the eight listed products mentioned above, dozens of JAK inhibitors are currently in clinical development, mostly next-generation therapies, with 10 products entering phase III clinical phase.
Pfizer and CTI BioPharma's Pacritinib have filed a new drug listing application (NDA) with the FDA.
3: JAK inhibitor research and development status quo 2, domestic research and development progress in China, there are currently 3 JAK inhibitors approved for market.
, Tofatib and barrettinib were approved for the treatment of rheumatoid arthritis, and reedcotinib was approved for the treatment of critical or high-risk bone marrow fibrosis.
several other products are in clinical development, mostly next-generation therapies.
China's JAK target innovative drug research and development started late, at present, Jiangsu Ruiheng, Xinda biology, micro-core biology and other enterprises have layout, of which the fastest research process is Hengrui SHR0302, is currently in the clinical phase II.
Medicine/Ruishi Bio: SHR0302 tablets of this product is a highly selective small molecule JAK1 kinase inhibitor.
, SHR0302's high selectivity may provide better safety and effectiveness than pan-JAK inhibitors, according to a press release.
currently, the product's oral tablets and ointments are being clinically developed for a variety of adaptations, including rheumatoid arthritis, specific dermatitis, vitiligo, baldness, Crohn's disease, etc.
the product has been registered in 16 clinical studies, including a Phase 3 trial for moderate to severe active rheumatoid arthritis and several Phase 2 trials.
/Incyte: Itacitinib is a new, efficient and selective small molecule inhibitor that inhibits jak1 signaling path.
previously, Cyda Bio had reached an exclusive licensing agreement with Incyte to advance the clinical development and commercialization of three new anti-tumor drugs, including itititinib, in Greater China.
November 2019, itcitinib, jointly declared by the two companies, obtained implied permission for clinical trials in China to develop an adaptive drug for the transplant anti-host disease.
microcore biology: CS12192 capsule this product is developed by micro-core bio-autonomous a JAK3 kinase inhibitor, but also partially inhibit JAK1 and TBK1 kinase.
June 2020, the product obtained two clinically implied licenses in China to develop an adaptive rheumatoid arthritis.
, JAK inhibitor development and challenge coexist, safety into a break key JAK-STAT pathopath not only mediates pathological signal pathology, but also mediates the normal signal transduction of the human body.
JAK2 is paired with itself, JAK1, or TYK2 and is essential for signaling of erythymocytoplasm, plateocytoplasm, and granulocyte collection stimulators, so inhibition of JAK2 can lead to plate reduction and anemia.
JAK3 is mainly expressed in lymphatic and hematologic tissues, and JAK3 inhibition can lead to inactive T, NK, and functional B cells, leading to severe combined immunodeficiency and life-threatening infections associated with clinical adverse reactions to JAK inhibitors.
Most JAK inhibitors approved by the FDA now have black-box warnings on their labels, and the Tofatinib manual is warned by the FDA that there is a "serious risk of infection, malignant tumors, and blood clots" in Upatinib and Barrettinib, as required by the FDA to increase the risk of thrombosis and death.
Solcitinib, developed by GlaxoSmithKline, was terminated early in Phase II clinical trials due to severe adverse events (elevated liver enzymes, increased drug rashes associated with increased acidoblasts and systemic symptoms) and interactions with statins.
Depernotinib, of Vertex, stopped the study because of a reduction in nexual granulocytes caused in Phase II./III. clinical trials.
Filgotinib was approved in the European Union and Japan, but the FDA refused to approve its listing, citing safety concerns.
Pfizer CEO Albert Bourla said at a recent JP Morgan conference that they were not concerned about the safety of JAK inhibitors, "I think the benefits of JAK inhibitors clearly outweigh any potential risks."
", due to the importance of JAK kinase, the corresponding inhibitors will produce certain toxicity, especially JAK1 and JAK2 inhibitors, JAK3 inhibitors have a smaller impact.
, " says Professor Fu Xinyuan, "but in the presence of the disease, it needs to be used in a comprehensive consideration of the patient's benefits."
according to feedback from most doctors, including clinicians in Huaxi, JAK inhibitors work well clinically, and doctors rarely see serious adverse reactions from patients.
" Although the efficacy and safety of several JAK inhibitors on the market are not satisfactory, recent studies of TYK2 selective inhibitors have shown satisfactory efficacy and safety, will not increase the incidence of shingles and cardiovascular events, blood cell count, lipids, creatinine or immunoglobulin and other laboratory indicators of the average is not significantly different baseline, so selective inhibition of TYK2 JAK inhibitors may be worth looking forward to.
30 years since the discovery of the conclusion JAK-STAT signal path, the drugs currently being developed are only the tip of the iceberg and have great potential.
intestinal dosing (intravenous or subsethic injections), high production costs, immunogenicity and other risks limit their use.
in order to overcome the shortcomings of biological agents, JAK inhibitors were born.
these small molecules are easier to synthesize, less costly to produce, and can be given or partially or by mouth compared to biologics.
to continue to lead to breakthroughs in this area, and some of the findings will undoubtedly translate into new treatment options.
But the development of JAK inhibitors remains a challenge, and their safety and tolerance issues need to be addressed urgently, and the successful development of highly selective inhibitors will hopefully reduce potential risks and lead to more next-generation therapies.
addition, STAT inhibitor research and development has also made some progress, whether it can eventually become a drug, we will wait and see.
References: 1,