JAK inhibitors are accelerating in China!

On April 11, the official website of the China National Medical Products Administration (NMPA) announced that Pfizer's oral JAK1 inhibitor abrocitinib (abrocitinib, Chinese brand name Cipike) was approved for marketing in China, suitable for This is also the second JAK inhibitor approved by Pfizer in China for adult patients with refractory, moderate-to-severe atopic dermatitis who do not respond well to other systemic treatments (such as hormones or biological agents) or who are not suitable for the above treatments
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Abuxitinib is a once-daily oral inhibitor of JAK1, an intracellular enzyme that mediates signaling through the interaction of cytokines or growth factor receptors on the cell membrane, thereby affecting cellular hematopoiesis and immune cell function
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Abraxitinib reversibly and selectively inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site
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As early as February 2021, the CDE accepted the marketing application for abroxitinib and included it in priority review in March of the same year
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Intended for the treatment of patients 12 years of age and older with moderate to severe atopic dermatitis
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In addition, the approval status of abrucitinib in the United States and the UK is as follows: In September 2021, abraxitinib was approved for the first time in the United Kingdom for the treatment of adults and adolescents over 12 years of age with moderate to severe atopic dermatitis
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On January 14, 2022, abroxitinib was approved for marketing in the United States with recommended doses of 100mg and 200mg, and has been granted breakthrough therapy and priority review qualifications by the FDA
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01 There are 5 JAK inhibitors approved in China, and AbbVie Upatinib has won 3 indications in succession.
It is worth mentioning that since the beginning of this year, JAK inhibitors have accelerated their debut in China, and they have become another example of many pharmaceutical companies.
arena
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In addition to Pfizer's newly approved oral JAK1 inhibitor abrucitinib, AbbVie's JAK inhibitor upatinib has gained 3 indications in more than a month—— ♦February 24, 2022, NMPA official website Approved AbbVie's JAK inhibitor upadatinib extended-release tablets for systemic therapy in adults and adolescents 12 years of age and older with moderate to severe atopic dermatitis (AD)
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♦On March 22, 2022, NMPA's official website showed that AbbVieref (upatinib extended-release tablets) has been approved for the treatment of moderately ill patients with poor response or intolerance to one or more TNF inhibitors.
Adults with severely active rheumatoid arthritis
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♦On April 6, 2022, NMPA's official website showed that AbbVie's upatinib extended-release tablets have been approved for the treatment of active psoriatic arthritis in patients with poor response or intolerance to one or more DMARDs (PsA) Adult patients
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Up to now, according to the statistics of Sina Pharmaceutical, 5 JAK inhibitors have been approved in China, namely: Novartis' ruxolitinib, Eli Lilly's baricitinib, Pfizer's tofacitinib, AbbVie's The indications of Abrutinib and Pfizer abrutinib mainly cover rheumatoid arthritis, myelofibrosis, atopic dermatitis,
etc.
02 The development of JAK inhibitors is hot, and a large number of domestic companies are waiting in line.
In recent years, JAK inhibitors have grown rapidly in the domestic market
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According to the Yaorong Cloud database, in 2020, JAK inhibitors exceeded the 100 million yuan mark for the first time, reaching 200 million yuan, a year-on-year increase of 659%
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In the first three quarters of 2021, in-hospital sales have exceeded 500 million yuan, a year-on-year increase of 200%
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With the rising enthusiasm for the research and development of JAK1 inhibitors, although domestic JAK1 inhibitors have not yet been approved for marketing, a number of domestic manufacturers are chasing after them and deploying JAK inhibitors one after another, and the competition is becoming increasingly fierce.

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According to incomplete statistics from Sina Pharmaceuticals, there are currently more than 10 JAK inhibitors in China, among which pharmaceutical companies with rapid clinical progress mainly include: Hengrui Medicine JAK1 inhibitor - SHR0302, rheumatoid arthritis, atopic dermatitis, Rhon's disease, ulcerative colitis directions
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Innovent/Incyte's JAK1 inhibitor: itacitinib, in the direction of graft-versus-host disease
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Microchip CS12192 Capsules - JAK3 kinase inhibitor (also partially inhibits JAK1 and TBK1 kinases), rheumatoid arthritis direction
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Zejing Pharmaceutical’s JAK1/2/3 inhibitor, ankylosing spondylitis, severe alopecia areata, intermediate and high risk myelofibrosis, graft-versus-host disease, idiopathic pulmonary fibrosis,
etc.
Kelun Botai KL130008 Capsules - small molecule JAK inhibitor, clinical trials for severe alopecia areata
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Dizhe Medicine's AZD4205 capsules - a selective inhibitor of JAK1 for the treatment of peripheral T-cell lymphoma,
etc.
Gaoguang Pharmaceutical TLL-018 Tablets - TYK2/JAK1 dual inhibitor for the treatment of rheumatoid arthritis, psoriasis,
etc.
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.
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As more and more pharmaceutical companies are deployed and approved to enter the market, the market prospect of JAK inhibitors may be broader
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03 As the competition expands, a number of JAK inhibitors are approved around the world JAK1 inhibitors are one of the most popular targets, and research and development in foreign markets is also in full swing
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According to incomplete statistics from Sina Pharmaceuticals, the JAK inhibitors approved globally mainly include (with the first listing time as the axis): In 2011, the oral, ATP-competitive and reversible JAK1/2 inhibitor Rucoti was researched by Incyte/Novartis.
Ruxolitinib (Jakafi) approved by the US FDA for the treatment of myelofibrosis (MF)
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In 2012, Pfizer's JAK1/3 inhibitor tofacitinib (Xeljanz) was approved by the US FDA for the treatment of rheumatoid arthritis
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In 2017, baricitinib (Olumiant) jointly developed by Incyte and Eli Lilly was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment of rheumatoid arthritis
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In 2018, Astellas' peficitinib tablet was approved in Japan for the treatment of adult patients with relapsed/refractory acute myeloid leukemia with FLT3 gene mutation
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In 2019, AbbVie's JAK1-selective inhibitor upadacitinib (Rinvoq) was approved by the US FDA for moderately to severely active patients with insufficient response or intolerance to methotrexate (MTX-IR).
Treatment of adult patients with rheumatoid arthritis (RA)
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In 2019, Sanofi/Celgene's highly selective JAK2 inhibitor fedratinib (Inrebic) was approved by the US FDA for the treatment of myelofibrosis
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In January 2020, delgocitinib, co-developed by Japan Tobacco and Torii Pharmaceutical (Torii Pharmaceutical), was approved by Japan's PMDA for the topical treatment of atopic dermatitis
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This is the world's first JAK topical drug approved for adults with mild to moderate atopic dermatitis (AD) (proposed in Japan over 16 years old)
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In September 2021, Pfizer’s JAK1 inhibitor abrocitinib (Cibinqo) was approved by the UK Medicines and Health Products Administration (MHRA) for the treatment of adults and adolescents over 12 years of age who are suitable for systemic therapy.
Atopic dermatitis (AD) patients
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In January 2022, Pfizer announced that the U.
S.
FDA approved its JAK1 inhibitor Cibinqo (abrocitinib) for the treatment of adult patients with relapsing moderate-to-severe atopic dermatitis
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Among these approved JAK inhibitors, they are divided into - First-generation non-selective JAK inhibitors: ruxolitinib, tofacitinib, baricitinib , peficitinib, delgocitinib; second-generation selective JAK inhibitors: upatinib (Rinvoq) of AbbVie, fedratinib (Inrebic) of Sanofi/Celgene, Pfizer’s abraxitinib (Cibinqo)
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In general, the first-generation non-selective JAK inhibitors all contain similar structures of adenine in ADP, so they generally have the problem of low selectivity.
Adverse effects are largely predictable and include infection, anemia, neutropenia, lymphopenia, cardiovascular disease, gastrointestinal perforation, hyperlipidemia, and more
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Second-generation JAK inhibitors can selectively inhibit JAK family members, so they can inhibit specific disease-related signaling pathways while maintaining the function of other cytokines unaffected, which is based on research and development
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04 JAK inhibitors: one of the hot targets, angel or devil? However, the development of JAK1 inhibitors still faces challenges, and its safety and tolerability issues have attracted the attention of the industry and need to be resolved urgently
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The English name of JAK kinase is Janus Kinase, abbreviated JAK.
The name "Janus" comes from Janus, the two-faced god representing the beginning and the end in Roman mythology, because JAK kinase has two almost identical domains that transfer phosphate groups
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One of the domains exhibits kinase activity, while the other domain regulates the activity of the first kinase
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JAK kinases are a family of intracellular non-receptor tyrosine kinases that mediate cytokine production and pass on through the JAK-STAT signaling pathway
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The JAK-STAT pathway is one of the few immunomodulatory pathways that have been proven so far, so JAK inhibitors can play a role in the field of autoimmune diseases
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At present, JAK has found four family members: ♦JAK1: mainly associated with acute lymphoblastic leukemia, acute myeloid leukemia, solid organ malignancies; ♦JAK2: mainly associated with polycythemia vera, myelofibrosis, essential thrombocythemia ♦JAK3: mainly related to acute megaloblastic leukemia, T-cell leukemia, lymphoma and other diseases; ♦TYK2: mainly related to skin lymphoproliferative diseases and T-cell leukemia
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However, the potential dangers of JAK1 inhibitors are gradually being exposed
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Especially in the past two years, the FDA has issued a warning about the increased risk of serious heart-related events, cancer, blood clots and death caused by JAK inhibitors, and has repeatedly delayed the review of JAK inhibitor drugs.
attention to risk
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How to solve the problem of JAK inhibitor safety and drug resistance in the future will become a problem that pharmaceutical companies strive to solve
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