JAK inhibitors in iterations! A target favored by Pfizer, Lilly and other major companies.

JAK is undoubtedly one of the most popular targets in the development of many targeted therapies.
it is an important research and development direction in Pfizer's inflammation and immunology fields, including Eli Lilly and Company, Novartis, Celgene, AbbVie and Gilead Sciences.
of the seven JAK inhibitors approved for sale worldwide, the allergens include rheumatoid arthritis (RA), bone marrow fibrosis, psoriasis arthritis, ulcerative colitis, graft anti-host disease, etc.
, however, most of the approved JAK inhibitors and candidates under development face safety and tolerance challenges.
this unfinished clinical need has also spawned a new generation of JAK inhibitors.
present, in addition to many large pharmaceutical companies, many local Chinese biological companies have joined the research and development team, such as Xinda Biology, Microcore Biology, Hengrui Pharmaceuticals, Ze-Yu Pharmaceuticals and other companies.
is JAK inhibitors so popular? What other potentials remain to be explored in this area? Today, we will lead the reader to find out exactly.
jaus kinase, the jak signal path, is derived from a Roman mythical god named Janus, who has two back-to-back faces, one looking past and one looking to the future.
like this god, JAK has two faces.
on the one hand, it can activate the downstream path, on the other hand, it can negatively regulate its own phosphate level.
in terms of function, JAK is the path of the immune response, and when inflammation occurs, JAK is overactivated, which in turn promotes disease progress.
as a member of the cytoplasm tyrosine kinase family, JAK has four subtypes of JAK1, JAK2, JAK3 and TYK2, with overlapping binding objects between subtypes.
they play an important role in signal cascading of multiple type I and type II cytokine subjects, and the JAK-mediated signaling pathline is associated with processes such as cell proliferation, differentiation, apoptosis, and inflammation.
these cytokines or growth factors are combined with the corresponding subjects on the cell membrane to form a diogenesic body, causing aggregation of JAKs in the cytokines and activation of adjacent JAKs with mutual phosphate.
signals through type I and type II cytokine subjects (Photo source: Resources) The JAK-mediated signaling paths include the JAK-STAT path, mapK path and P13k-AKT path.
among them, JAK-STAT access is closely related to blood-related diseases such as erythropoies, plate small plate energies, leukemia, bone marrow fibrosis, and the occurrence of autoimmune diseases such as RA, severe spina brysitis, lupus erythematosus, psoriasis, and vitiligo.
, the JAK kinase family is an important target for the treatment of these diseases.
iterative upgrade of JAK inhibitors The current clinical success has been made with the development of first-generation JAK inhibitors such as Novaral/Incyte's ruxolitinib and Pfizer's Tofacitib Inib, Lilly/Incyte's Baricitinib, Astellas' Peficitinib, Japan Tobacco/Torii Pharmaceutical's delgocitinib, etc. have all been approved for listing.
these products have inhibitory effects on multiple MEMBERS of the JAK family and have shown good results in the treatment of inflammatory and tumor diseases.
, 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 have a variety of side effects.
this limits the clinical application of the first generation of JAK inhibitors.
Based on the biological function of type I and type II cytokines in signal transduction, the adverse effects of the first generation of non-selective JAK inhibitors on patients are largely predictable, including infection, anemia, neutral granulocyte reduction, lymphocyte reduction, cardiovascular disease, gastrointestinal perforation, hyperlipidemia, etc.
effects on different JAKs (Photo source: Resources) led to the launch of a new generation of modified JAK inhibitors in terms of safety and tolerance.
unlike first-generation products, second-generation JAK inhibitors selectively inhibit members of the JAK family, thus maintaining other cytokine function while suppressing specific disease-related signaling path path paths.
, for example, selective blocking of JAK3 is only associated with common gamma chain subjects and has the function of inhibiting T-cells, natural killer (NK) cells, and B-cells, while keeping hematogenesty and metabolic pathways unaffected.
2nd generation JAK inhibitors approved for sale in August 2019, the new base's highly specific JAK2 inhibitor Inrebic (fedratinib) and AbbVie JAK1 selective inhibitor Rinvoq (upadacitinib) were announced on the same day that they were approved by the FDA for the treatment of adult bone marrow fibrosis and RA patients, respectively.
two approvals also mark the official launch of a second generation of JAK inhibitors that are selective to the JAK protein kinase family.
addition, Inrebic is an oral JAK2 and FLT3 inhibitors that inhibit the activity of wild and mutant-activated JAK2 protein kinases and is more inhibitory to JAK2 than the other three JAK subsypes.
in China, Xinji is conducting a phase 3, multi-center, open-label, randomized study evaluating the use of fedratinib for bone marrow fibrosis after reedtinib treatment.
Rinvoq is a small molecule JAK1 selective inhibitor that is oral once a day.
In addition to treating rheumatoid arthritis, it has conducted clinical studies in a number of inflammatory adaptations, including psoriasis arthritis, Crohn's disease, ulcerative colitis, strong scoliosis, and endopathic dermatitis.
it is worth mentioning that the product has been approved in China a number of clinical.
It is worth mentioning that the JAK1 selective inhibitor filgotinib, developed jointly by Gilead Sciences and Galapagos, has previously submitted applications for the listing of new drugs in the United States and has received support from the European Union's EMA Commission for use in adult patients with moderate to severe RA.
, the product did not show a clear association with thrombosis risk or elevated plate plate plate levels in safe clinical trials.
was not approved by the FDA on the original PDUFA date.
addition to the above three products, there are currently a number of JAK1, JAK3, and TYK2 specific inhibitors in the clinical development stage.
Xinda Bio, Hengrui Pharmaceuticals, Microcore Bio, etc. are all under development 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.
particularly noteworthy is Pfizer, which has four JAK inhibitors under accelerated development in China.
the products that have attracted much attention in the antho-section of this article.
1, Pfizer: JAK series PF-04965842 (abrocitinib) is an oral-specific JAK1 inhibitor that has previously been recognized by the FDA as a breakthrough therapy for the treatment of moderate to severe specific dermatitis.
2019, the PF-04965842 has made significant progress in global development, including reaching the end of trials in three Phase 3 clinical trials.
in China, the product has registered six clinical trials, five of which are international multi-center Phase 3 clinical trials.
PF-06651600 is a JAK3 inhibitor that has previously been recognized by the FDA as a breakthrough therapy for the treatment of baldness.
, Pfizer is currently conducting two phase 2b/3 international multi-center clinical trials in China for bald subjects.
, the product will continue to be tested for the treatment of RA, Crohn's disease and ulcerative colitis.
PF-06826647 is a TYK2 inhibitor being developed by Pfizer and is now in clinical phase 2.
according to Pfizer's official website, the product is intended to develop adaptive disorders for inflammatory and autoimmune diseases.
, the product was approved for clinical trials in China to develop a moderate to severe ulcerative colitis.
PF-06700841 is a TYK2/JAK1 inhibitor.
the product has reached the main effective end point of promoting hair regeneration in clinical Phase 2 trials for the treatment of moderate to severe baldness.
in China, PF-06700841 was approved in two clinical trials at the end of 2019 with the following symptoms: adult active systemic lupus erythematosus.
2, Cyntaf/Incyte: Itacitinib is a new, efficient and selective small molecule inhibitor that inhibits jak1 signaling paths.
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.
3, Hengrui Pharmaceuticals/Ruishi Bio: SHR0302 This 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 external ointment two dosage forms are in the clinical development of a variety of adaptations, including ulcerative colitis, Crohn's disease, specific dermatitis and vitiligo.
, Phase 2 clinical trials on baldness completed the first patient in China at the end of July this year.
China Drug Clinical Trial Registration and Information Disclosure Platform, the product has registered 13 clinical studies, including a Phase 3 trial for moderate to severe active RA and several Phase 2 trials.
4, microcore biology: CS12192 capsule This is a JAK3 kinase inhibitor developed by microcore bio-autonomous, but also partially inhibit JAK1 and TBK1 kinase.
study found that CS12192 can not only effectively inhibit the inflammation mediated by over-active immune cells, but also reduce the tissue attack of immune cells by inhibiting TBK1, bring better efficacy and safety, and hopefully provide a new differentiated treatment option for the clinical treatment of autoimmune-related diseases.
june this year, the product obtained two clinically implied licenses in China to develop an adaptation to rheumatoid arthritis.
5, Zetsin Pharmaceuticals: Jack tini, this is Zetini Pharmaceuticals through its precision small molecule new drug research and development and industrialization platform of drug stability technology, independent research and development of JAK kinase small molecule inhibitors, belong to a new class of drugs, respectively, tablets and cream two dosage forms.
Currently, Zee-Pharma is conducting Phase 2 clinical trials for the treatment of active orthosis, severe baldness and medium- and high-risk bone marrow fibrosis, as well as two Phase 1 trials for transplant resistance to host disease and idiopathic pulmonary fibrosis.
conclusion From the research and development situation in China, JAK inhibitors are still in the hot stage, especially for the development of second-generation JAK inhibitors.
At the same time, people are also optimistic about the application of JAK inhibitors in the area of baldness, whether it is Lilly, Pfizer and other large international companies, or Ze-Yuan Pharmaceuticals, Hengrui Pharmaceuticals / Ruishi Bio and other Chinese pharmaceutical companies, have been involved in this field.
it is clear that JAK inhibitors have great potential to be discovered, both globally and in China.
, as with iterative upgrades to many products, if JAK inhibitors are addressed in terms of safety and toeration, they will lead to more next-generation therapies and benefit more patients.
we look forward to early progress in this area.
reference: swartz et al., (2017). JAK resedion as a therapeutic strategy for immune and appy diseases. Nature Reviews Drug Discovery.[2] Schwartz, D. M., Bonelli, M., Gadina, M. and O'Shea, J. J. Type I/II Cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12, 25–36 (2016). Wang Xuechuan, Li Wei, Liang Chengyuan. Advances in Drug Research Based on JAK-STAT Signaling Path path, Journal of Shaanxi University of Science and Technology, 2019, 37 (06): 79-86. The research progress of Xue Xiang, Liu Hongmei, Yan Danbing, etc.JAK/STAT signal path adjustment mechanism, etc.J., modern biomedical progress, 2015, 15 (11): 2161-2165. [5] Involvement of the JAK-STAT pathway and SOCS3in the regulation of ofadiponectin-generated reactive oxyge.