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On October 21, AbbVie's marketing application for the new indication of "upatinib sustained-release tablets" was accepted by CDE, which is the fifth marketing application
submitted by upatinib in China.
According to the progress of clinical trials of upatinib in China, the author speculates that the indicated indication is moderate to severe active Crohn's disease
.
▲Organized according to the content of the CDE official website
Upadacitinib (Rinvoq) is a new generation of once-daily selective JAK1 inhibitors developed by AbbVie
, has been approved for multiple indications worldwide: (1) adult patients with moderate to severe active rheumatoid arthritis (RA) (FDA) with insufficient response or intolerance to methotrexate
2019/08)； (2) Adult patients with active psoriatic arthritis (PsA) who have insufficient response to or intolerance to one or more disease-modifying antirheumatic drugs (DMARs) (EMA).
2021/01)； (3) Adult patients with active ankylosing spondylitis (AS) who do not respond adequately to conventional therapy (EMA
2021/01)； (4) Adult patients with moderate to severe atopic dermatitis (AD) and adolescent patients aged 12 years and older (EMA) suitable for systemic therapy
2021/08)； (5) Adult patients with moderately to severely active ulcerative colitis (UC) (FDA) who have insufficient response or intolerance to one or more tumor necrosis factor (TNF) blockers
2022/03); (6) Adult patients (EMA) with an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs), elevated C-reactive protein (CRP), and/or magnetic resonance imaging (MRI) showing objective signs of inflammation in the axial axial arthritis (nr-axSpA).
2022/07)
。
It is worth mentioning that due to the safety risks of JAK inhibitors, Rinvoq's marketing applications for a number of new indications in the United States have been delayed
.
In December 2021, the Rinvoq US label was updated to include additional information on the risk of malignancy and thrombosis, as well as an increase in mortality and the risk
of MACE (defined as cardiovascular death, myocardial infarction, and stroke) in the boxed warnings and warnings and precautions sections.
At the same time, the indications for Rinvoq have also been updated as follows: Rinvoq is indicated for the treatment of adult patients
with moderately to severely active RA who have under-response or intolerance to one or more TNF blockers.
In addition, two phase III induction studies and one phase III maintenance study for the treatment of moderate to severe Crohn's disease (CD) with Rinvoq have achieved positive results, and clinical trials for giant cell arteritis (GCA) and Takayasu arteritis have also entered phase III clinical trials
.
Since its listing, Rinvoq's sales have climbed, entering the $1 billion blockbuster in 2021, its third year of listing, and is expected to enter the $2 billion list in 2022
.
AbbVie is very bullish on Rinvoq, expecting Skyrizi and Rinvoq when it announces its 2021 results
Sales will reach $15 billion
in 2025.
▲Sales of AbbVie's JAK inhibitor Rinvoq in recent years (US$ billion) as of October 2022
In China, upatinib (trade name: Ruifu) was first approved by the NMPA in February 2022 for refractory, moderate-to-severe AD patients in adults and adolescents 12 years of age and older who do not respond well to other systemic therapies (such as hormones or biologics) or are not suitable for the above treatment, and subsequently approved by the NMPA in March for adult patients with moderately to severely active RA who do not respond well to or tolerate one or more TNF inhibitors.
Approved by the NMPA in April for adults with active PsA who are poorly treated or intolerant to one or more DMARDs
.
In June 2022, upatinib will be on sale in China, and it is reported that the price is 6315 yuan / box (specification: 15
mg * 28 tablets).
At present, upatinib has entered the preliminary review list of the national medical insurance directory adjustment in 2022, and if it can successfully pass the medical insurance negotiation, upatinib is expected to achieve price exchange for volume and gain a foothold in the domestic autoimmune disease market
.
However, it is worth mentioning that Pfizer second-generation JAK1 inhibitor abxertinib has been approved in China in April this year for refractory moderate to severe AD adult patients who do not respond well to other systemic treatments (such as hormones or biologics) or are not suitable for the above treatment, and have also passed the preliminary review
of medical insurance.
If upatinib wants to enter medical insurance, it may face a fierce price war
.
The number of JAK inhibitors approved has reached 10, and 3 have submitted marketing applications
The number of JAK inhibitors approved has reached 10, and 3 have submitted marketing applicationsSince the discovery of the first JAK kinase in the early 90s of the 20th century, JAK inhibitors, as a new type of oral small molecule targeted drugs, have attracted much attention and attention
from pharmaceutical companies.
JAK kinase is a family of signaling molecules that interface the intracellular structure of type I and type II cytokine receptors, and belongs to the non-receptor class of tyrosine kinases
.
When the cytokine binds to the receptor outside the cell membrane, the cytokine receptor is activated, transmits the signal to JAK kinase, which phosphorylates and further phosphorylates the downstream molecule STAT, which can enter the nucleus as part of the transcription factor complex to control the transcription of cell genes, thereby affecting the biological function of cells, this cytokine conduction pathway is collectively known as the "JAK-STAT" pathway
.
The study found that JAK-STAT signaling pathway has a wide range of functions, is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation, and is closely related to blood-related
diseases such as polycythemia, thrombocythemia, leukemia, myelofibrosis, as well as the occurrence of autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, psoriasis, and vitiligo.
JAK kinase can be subdivided into four subtypes
: JAK1, JAK2, JAK3 and TYK2.
Based on the functional characteristics and special tissue distribution of each subtype in the JAK kinase family, JAK1 has become a new target in the field of immune, inflammation and cancer, JAK2 has become the exact target for the treatment and prevention of hematological-related diseases, and JAK3 and TYK2 have become popular targets for the treatment of autoimmune diseases
.
According to incomplete statistics, 10 JAK inhibitors have been approved worldwide (Jakafi/Jakavi and Opzelura have the same active ingredient and are regarded as one).
According to the selectivity of the target of action, JAK inhibitors are divided into two generations, of which Inrebic of Neoradical/BMS, Rinvoq of AbbVie, Jyselica of Gilead/Eisai, Cibinqo of Pfizer, and Sotyktu of BMS belong to the second generation
.
First-generation JAK inhibitors may have adverse reactions
such as infection, decreased hemoglobin, thrombocytopenia, gastrointestinal perforation, and nausea because they inhibit the kinase fraction of a variety of JAK proteins.
The second-generation JAK inhibitors mainly target JAK1 targets and TYK2 targets, and are better
safe and tolerated.
▲Data source: public information
▲Data source: company financial report
In terms of enterprises, Incyte, Pfizer and BMS each have two JAK inhibitors, of which Incyte has developed the world's first topical JAK inhibitor, Opzelura (Ruxolitinib cream), and Pfizer has developed a sustained-release formulation of
tofacitinib.
In terms of market performance, Jakafi/Jakavi performed best, AbbVie's Rinvoq is expected to become the second JAK inhibitor in sales in 2022, and Pfizer Xeljanz sales have declined significantly
.
However, in recent years, the market size of JAK inhibitors has continued to expand, from $1.
534 billion in 2015 to more than $9 billion
in 2021.
However, it is worth mentioning that the first generation of JAK inhibitors is facing a patent cliff, and more than ten domestic tofacitinib tablets and two domestic tofacitinib sustained-release tablets have been approved in China, and companies have submitted generic drug marketing applications
for baricitinib and ruxocotinib.
In addition, there are currently a number of JAK inhibitors under development worldwide, as detailed in the table below
.
Among them, Pfizer's JAK3 inhibitor Ritlecitinib (ritercitinib) has simultaneously submitted a new drug application
for the treatment of alopecia areata in adolescents and adults aged 12 and above in the United States, Europe and China.
Zejing Pharmaceutical JAK inhibitor jacktinib hydrochloride tablets have also submitted new drug applications
for medium and high-risk myelofibrosis in China.
Hengrui Pharmaceutical's SHR0302 and Innovent Biologics' Itacitinib have entered phase III clinical trials
.
It is worth mentioning that most of the JAK inhibitors under research are second-generation, and the target of action is mainly concentrated in JAK1
.
▲Source: Public information (incomplete statistics)
summary
summaryOverall, JAK inhibitor indications are mainly for autoimmune diseases, which are the third largest chronic diseases after cardiovascular disease and cancer, with a therapeutic drug market size of $109.
9 billion in 2018 and is expected to reach $152.
2 billion
in 2025.
With the advent of the new generation of JAK inhibitors and the increase in the indications and approved scope of marketed products, the market size of JAK inhibitors will continue to expand, and it is expected to soon exceed $10 billion and further consolidate its market position
in the field of autoimmune diseases.
