Upadacitinib for Moderate to Severe Ulcerative Colitis

Introduction:

Ulcerative colitis (UC) is a relapsing, chronic inflammatory bowel disease (IBD) characterized by persistent colon inflammation that necessitates lifelong therapy due to the disease's remitting and relapsing course and causes major burden and disability in patients. Aside from traditional steroid or immunosuppressive therapies, inhibitors of tumor necrosis factor-alpha (TNFα) ), integrin, interleukin (IL) 12-23, and tofacitinib are currently available. Mesalamine, glucocorticoids, immunosuppressive agents, and biologics are currently available as treatments. However, the treatment choice seems ineffective in more than one-third of patients and can cause adverse outcomes, limiting their use. New treatments are required to improve symptomatic and endoscopic results in more ulcerative colitis patients. Apart from the therapeutic expansion of ulcerative colitis, in 46 percent of patients, both primary and secondary failure takes place, emphasizing the necessity for developing new drugs. Janus Kinase inhibitors (JAKi) are one of the new molecules currently under research for irritable bowel disease. These molecules are members of the small molecule drug (SMD) family and are already being used to treat various autoimmune conditions.

What Are Janus Kinase Inhibitors (JAKi)?

• JAKi is orally administered and targeted to act on the entire molecular pathway, the JAK or signal transducer and activator of transcription (STAT) pathway, separately by selectively obstructing the monoclonal antibody's single molecule mechanism.

• Intracellular tyrosine kinase TYKs include Janus kinases (JAK1, JAK2, JAK3, and tyrosine kinase [TYK] 2).

• They are activated by the binding of a cytokine ligand, which results in the recruitment, phosphorylation, and signal transducers activation and transcriptional activators, which control many functions of adaptive and innate immunity, hematopoiesis (formation of the blood cellular components), and cellular processes such as cell growth, survival, differentiation, and migration.

• JAK inhibition is becoming increasingly popular as a treatment plan for various immune-mediated diseases, including ulcerative colitis.

• Tofacitinib, a pan-JAK inhibitor, has been approved for treating ulcerative colitis after showing efficacy in three phases of 3 placebo-controlled studies in patients with moderately to severely active ulcerative colitis. This drug rapidly induces remission in patients with moderate-to-severe Ulcerative colitis. Moreover, there are still issues with its safety profile, as cases of thrombosis, dyslipidemia, and Herpes zoster reactivation have been reported.

What Is Upadacitinib (UPA)?

• Upadacitinib is given once-daily, oral, small-molecule therapy designed to be more selective for JAK1 than JAK2, JAK3, and TYK2.

• Upadacitinib (UPA) is a new selective Janus Kinase 1 inhibitor (JAK1 inhibitor) presently approved for managing various inflammatory diseases, such as rheumatoid and psoriatic arthritis, atopic dermatitis and is being analyzed for the treatment of ulcerative colitis and Crohn's disease.

What Is the Mechanism of Action?

• The JAK or STAT family contains four tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2, TYK2) linked with intracellular domains. When cytokines bind to the extracellular receptor of JAKs, the intracellular domain dimerizes and becomes activated.

• Once activated, JAKs phosphorylate themselves and travel to the nucleus, where they bind to DNA sequences and regulate gene expression. Various cytokines activate the JAK or STAT pathway; each cytokine receptor is connected with a JAK monomer.

• The primary cytokines interleukins- 6,10,12, 13,23 and interferon γ (IFNγ) activate the JAK or STAT pathway. Each of these cytokines plays distinct functions in the immune response and plays a role in the pathogenesis of Irritable bowel disease.

• JAK proteins comprise seven homologous domains (JH1–7). The JH5-7 domains are important for receptor binding, whereas the JH1 kinase region is a catalytic domain and is important for activating the pathway, with high homology between various isoforms.

• JAKi selectivity reduces with increasing doses because isoform selectivity is determined by the difference in concentrations required to inhibit 50 percent activation (IC50) for different JAK isoforms.

• As a result, Upadacitinib (UPA) is selective for JAK1, but at higher concentrations, it can inhibit JAK2 and, to a lesser extent, JAK3 and TYK2. Unlike monoclonal antibodies, UPA has a low molecular weight (typically less than one kDa), can travel easily through cell membranes into the intracellular space via the cell membrane, and is not produced by the body. Hence, it has a more stable structure.

• UPA is completely removed unchanged in 24 percent urine and 38 percent feces, with the remaining 34 percent excreted as metabolites. In patients with renal and hepatic deficits, no need for the adjustment of dose, and UPA is not advised in patients with severe hepatic impairment.

What Are the Indications and Usage of Upadacitinib?

The following are the indication of UPA:

1. Rheumatoid arthritis.

2. Psoriatic arthritis.

3. Atopic dermatitis.

4. Ulcerative colitis.

• Upadacitinib is recommendedfor adult patients having moderately to severely active rheumatoid arthritis, active psoriatic arthritis, moderate to severe atopic dermatitis, in active ulcerative colitis who did not respond or have become intolerant to one or more tumor necrosis factor (TNF) blockers.

• Limitations of Use: Upadacitinib should not be given with other JAK inhibitors, biological disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants such as Azathioprine and Cyclosporine.

What Are the Advantages and Disadvantages of Upadacitinib?

Advantages:

The following are the advantages of UPA.

• It is administered orally.

• It has a rapid effect.

• It is effective in biological naive or treatment.

• It has no immunogenicity.

• This drug saves time for the patient.

• This drug has rheumatological manifestations.

Disadvantages:

The following are the disadvantages of UPA:

• This drug cannot be used in elderly patients greater than 75 years.

• Not to be used in pregnancy and during breastfeeding.

Can Upadacitinib Be Used during Pregnancy?

UPA should not be used during pregnancy due to the possible teratogenic effects on the fetus and during lactation because of limited studies on pregnant mothers.

Conclusion:

UPA is a JAK1 or Janus kinase inhibitor with a fast onset of action and an oral route of administration. The FDA (Food and Drug Administration) approved UPA after phase 3 studies demonstrated its efficacy and safety in moderate-to-severe UC (ulcerative colitis) patients. Ulcerative colitis is a type of chronic inflammatory bowel disease. UPA can be administered to biologic-naive patients and those who have previously failed other treatments. Its effectiveness in other immune-mediated diseases makes it a promising treatment option for people with extraintestinal manifestations.