Inventory: JAK inhibitors

There are 4 members of the tyrosine kinase (JAK) family: JAK1, JAK2, JAK3, TYK2, which play an important role
in the signaling cascade of multiple type I and II cytokine receptors.
The mediated signaling pathway, JAK-STAT pathway, mediates physiological processes such as cell proliferation, differentiation, apoptosis, and immune regulation, and is involved in the pathogenesis of tumors, hematological diseases, and a variety of autoimmune diseases
.

Figure 1: JAK-STAT mediated cytokine signaling network

(Source: DOI: 10.
1016/j.
autrev.
2019.
102390)

At present, there are many types of JAK inhibitors, which are mainly divided into two categories: first-generation non-selective inhibitors and second-generation selective inhibitors
.
At present, there are 173 global drug research and development of JAK inhibitors, 460 clinical trials have been carried out worldwide, and 10 original drugs have been listed (data from Pharmarongyun, as of October 17, 2022).

Table 1: Status of JAK inhibitor approvals

1.
The first generation of JAK inhibitors

●In 2011, the United States approved the world's first oral JAK inhibitor drug, ruxolitinib (trade name Jakafi).

It is a reversible JAK1/2 inhibitor, jointly developed by Incyte/Novartis, entered the Chinese market in 2017 and is currently available in
more than 20 countries.
At present, ruxolitinib has been approved for a number of indications, respectively, for the treatment of myelofibrosis (the first), polycythemia vera, graft-versus-host disease, its ointment formulation is approved for the treatment of vitiligo and atopic dermatitis, and as many as a dozen indications are in
clinical development.

●Pfizer's JAK1/3 inhibitor Tofacitinib (trade name Xeljanz) is the world's second JAK inhibitor, which was first marketed in the United States in 2012 and entered the Chinese market with tofacitinib citrate tablets in 2017, and is also the first JAK inhibitor drug
in the Chinese market.
Tofacitinib is the first JAK inhibitor for the treatment of rheumatoid arthritis and is currently approved for RA, psoriatic arthritis, ulcerative colitis, juvenile idiopathic arthritis and ankylosing spondylitis
.
Data show that tofacitinib sales reached $2.
455 billion in 2021, making it the frontrunner among JAK inhibitors
.

●Baricitinib (trade name Olumiant), a JAK1/2 inhibitor jointly developed by Eli Lilly/Incyte, was first approved by the EU in 2017 for the treatment of RA, and is currently available in 12 countries including China, and was approved by the EU in October 2020 for the treatment of atopic dermatitis, and was approved by the FDA in May 2022 for supplemental oxygen therapy for adult COVID-19 patients.
In June 2022, it was approved by the FDA for systematic therapy for alopecia areata (first).

At present, the clinical trial indications of baricitinib include uveitis, juvenile arthritis, biliary cirrhosis and systemic lupus erythematosus
.

●Peficitinib (trade name Smyraf), a JAK1/2/3/TYK2 inhibitor developed by Astellas, was first approved for the treatment of RA in Japan in 2019 and has entered the application stage
in China.
Currently the indications under study worldwide are ulcerative colitis and psoriasis
.

●The JAK1/2/3/TYK2 inhibitor Delgocitinib (trade name Corectim) developed by Japan Tobacco was approved in Japan in 2020 for the treatment of atopic dermatitis and has not yet been studied
in China.
The indications currently under research include eczema, discoid lupus erythematosus, psoriasis and alopecia areata
.

Figure 1: First-generation non-selective JAK inhibitors

2.
Second-generation JAK inhibitors

●Upadacitinib (trade name Rinvoq), a JAK1 selective inhibitor developed by AbbVie, was approved by the United States in 2019 for the treatment of RA, is the first second-generation JAK inhibitor, and entered the Chinese market
in 2022.
Upatinib is currently approved for non-radioactive axial spondyloarthritis, ulcerative colitis, atopic dermatitis, ankylosing spondylitis and psoriatic arthritis in addition to RA, and indications in clinical trials include Crohn's disease, vasculitis, vitiligo, and systemic lupus erythematosus
.

●The JAK2/FLT3 inhibitor Fedratinib (trade name Inrebic) developed by Celgene was approved in the United States in 2019 for the treatment of myelofibrosis and has not yet entered the Chinese market
.
Clinical trial indications include polycythemia vera, solid tumors and liver disease
.

●Gilead's JAK1 inhibitor filgotinib (trade name Jyseleca) was approved by the EU and Japan in 2020 for the treatment of RA, and in 2021 it was approved by the EU for the treatment of ulcerative colitis, and is currently in the clinical phase 3 stage
in China.
Clinical trial indications for fegotinib include Crohn's disease, ankylosing spondylitis, psoriatic arthritis, cutaneous lupus erythematosus, etc
.

●The JAK1 inhibitor Abrocitinib (trade name Cibinqo) developed by Pfizer was approved by the United Kingdom for the treatment of eczema in 2021 and approved by the United States and China in 2022 for the treatment of atopic dermatitis, and the current clinical trial indications include hypersensitivity reactions and kidney disease
.

●Bristol-Myers Squibb's TYK2 inhibitor Deucravacitinib (trade name Sotyktu) was approved in the United States for the treatment of psoriasis in September 2022, and the current clinical trial indications include psoriatic arthritis, Crohn's disease and systemic lupus erythematosus
.
It is worth noting that deuterium celestinib is the first oral drug for the treatment of psoriasis and the first approved TYK2 inhibitor
.

Figure 2: Second-generation selective JAK inhibitors

3.
Domestic original JAK inhibitors

▲At present, all JAK inhibitors developed by Chinese pharmaceutical companies are in the clinical trial stage, and only Zejing Pharmaceutical's new JAK1/2 inhibitor Jaktinib hydrochloride submitted a new drug marketing application for the treatment of medium- and high-risk myelofibrosis to the National Medical Products Administration (NMPA) on September 28, 2022, and was approved on October 17, 2022, which is the first JAK inhibitor
in China 。 Jacktinib hydrochloride currently has entered clinical trials for many indications, including alopecia areata, atopic dermatitis, psoriasis and ankylosing spondylitis, among which the treatment of severe alopecia areata and myelofibrosis has also been approved
by the US FDA for clinical trials.

▲The JAK1 inhibitor SHR0302 (Ivarmactinib) developed by Hengrui Pharmaceutical currently has multiple indications entering the clinical trial stage, including alopecia areata, ulcerative colitis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, RA, vitiligo and Crohn's disease, most of which have entered the clinical phase 3 stage
.

▲The JAK1/2 inhibitor IBI-377 (itacitinib) jointly developed by Innovent Biologics and Incyte is currently in clinical phase 3 for a number of clinical trials, including graft-versus-host disease, solid tumors, B-cell leukemia and RA
.
IBI-377 has the most clinical trials in the United States, while clinical trials in China have only been shown for graft-versus-host disease
.

Figure 3: Chinese pharmaceutical companies with rapid progress in the development of JAK inhibitors

▲AstraZeneca/Dizhe Pharmaceutical's JAK1 inhibitor AZD4205 (Golidocitinib) has entered clinical trials in China, the United States, Australia and South Korea for the treatment of multiple indications, including peripheral T-cell lymphoma, non-small cell lung cancer, lung cancer and inflammatory enteritis
.

▲The JAK1 inhibitor WXFL10203614 developed by Wuxi Fuxin Pharmaceutical is currently in the clinical phase 2 stage
of the research on RA.

▲The clinical trial of JAK inhibitor KL130008 for alopecia areata and RA developed by Sichuan Colonbotai is still in the clinical phase 2 stage
.

▲The treatment of RA by the JAK3/1/TBK1 inhibitor CS12192 developed by Microchip Biologics is still in the clinical phase 1 stage
.

▲ The JAK2 inhibitor TQ05105 developed by CP Tianqing for the treatment of graft-versus-host disease, myelofibrosis and tumor is still in clinical trials
.

▲The JAK/TYK2 inhibitor TLL-018 developed by Gaoguang Pharmaceutical is currently in the clinical phase 1 stage
for the treatment of RA, psoriasis and urticaria.

▲The JAK/Syk inhibitor SYHX1901 developed by CSPC Group for the treatment of psoriasis, RA and systemic lupus erythematosus is in the clinical phase 1 stage
.

Table 2: Current status of domestic JAK inhibitor research and development

4.
When will JAK inhibitors replace Humirer's position as the drug king?

At present, the drug king in the self-exemption market is Adalimumab (trade name Trudexa), and will the next generation of drug king be JAK inhibitors?

JAK inhibitors are powerful and have diverse therapeutic
areas.
The current indications are not limited to a variety of diseases of the autoimmune system, but also include graft-versus-host disease, myelofibrosis, tumors, alopecia areata and other diseases
.

JAK inhibitors want to replace Humirer's position as the drug king, and they have to face its adverse effects
.
Several JAK inhibitor drugs are restricted to RA patients after TNF inhibitor failure, and in 2021 the U.
S.
FDA issued safety warnings for Xeljanz, Rinvoq, and Olumiant, stating that these JAK inhibitors "have an increased risk of serious heart-related events, cancer, blood clots, and death.
"
However, careful analysis will find that most of the JAK inhibitors that the FDA requires to add boxed warnings are first-generation non-selective inhibitors, which may be solved
by developing more specific second-generation selective JAK inhibitors.
In 2022, the year after the FDA issued the black warning, China and the United States passed a number of marketing applications for JAK inhibitors, including more indications for first-generation non-selective JAK inhibitors and multiple second-generation selective JAK inhibitors, which strongly demonstrated the strong market prospects
of JAK inhibitors.

With the joint efforts of major pharmaceutical companies around the world, Xiaobian believes that more new JAK inhibitors can be produced and more indications can be treated, and JAK inhibitors may not be an illusion to replace Humira as the next drug king!

Reference:

Medicine Cube pharmcube.
com

Wisdom buds pharmsnap.
zhuhuiya.
com