What are the prospects for the development of JAK inhibitor safety warnings?

AbbVie today announced that it has submitted new indication applications for Rinvoq to regulatory agencies in the United States and Europe for the treatment of radiologically negative axial spondyloarthritis (nr-axSpA)
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Notably, AbbVie's Rinvoq received a safety warning from the FDA in December
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In the past two years, safety issues with JAK inhibitors have been common: In December 2021, the FDA used new safety warnings and restricted labels for AbbVie's Rinvoq, Pfizer's Xeljanz and Eli Lilly's Olumiant
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In September 2021, the FDA required Pfizer Xeljanz, AbbVie Rinvoq and Eli Lilly Olumiant to clearly identify patients with cardiac safety and cancer risk after receiving treatment
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In June 2021, AbbVie's Rinvoq was granted a second extension by the FDA for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS)
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In June 2021, the FDA's approval decision date for a regulatory application for Incyte's Jakafi for the treatment of steroid-refractory chronic graft-versus-host disease (GVHD) was pushed back by the FDA by three months
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In April 2021, the FDA extended the New Drug Application for the oral Pfizer JAK inhibitor abrocitinib for the treatment of adolescent and adult patients with moderate-to-severe atopic dermatitis (AD)
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Janus kinase (JAK) inhibitors are a class of drugs that inhibit the activity and response of one or more Janus kinases (JAK1, JAK2, JAK3 and TYK2)
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These enzymes often promote inflammation and autoimmunity
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Because of their unique roles in modulating signaling and pathogenic immune responses in many disease areas, JAK inhibitors can be used to treat cancer and inflammatory diseases such as myeloproliferative neoplasms by interfering with enzymatic signaling pathways.
, rheumatoid arthritis (rheumatoid arthritis), inflammatory bowel disease (inflammatory bowel disease) and psoriatic arthritis (psoriatic arthritis)
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JAK inhibitor drugs that have been marketed are currently FDA-approved for several classes of JAK inhibitors, including Pfizer’s Xeljanz (tofacitinib), Novartis’ Jakafi (ruxolitinib), BMS’s Inrebic (fedratinib), AbbVie’s Rinvoq (upadacitinib) and Eli Lilly Olumiant (baricitinib)
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In addition, Astella Pharma's peficitinib was approved in Japan in 2019, Pfizer's new-generation JAK drug abrocitinib was approved in the UK in 2021, and Gilead's filgotinib was approved in Europe in 2020
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Comparison of FDA-approved JAK Inhibitors and Biologics Biologics such as TNF blockers and JAK inhibitors belong to the family of disease-modifying antirheumatic drugs (DMARDs)
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These drugs stop or slow disease progression, not just treat symptoms
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There are four main classes of biologics: Tumor necrosis factor inhibitors, B-cell inhibitors, Interleukin inhibitors, and Selective co-stimulatory modulators.
stimulation modulators), each targeting a specific cell or cytokine
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JAK inhibitors: JAK inhibitors block inflammation inside cells
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These small-molecule drugs block enzymes called JAK1, JAK2, JAK3, and tyrosine kinases (TYK 2)
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When cytokines attach to cellular receptors, JAK enzymes send messages within the cell to trigger a cascade of signals that lead to inflammation
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JAK inhibitors can stop the process early, like removing the first domino in the reaction chain
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Compared with classical biologics, JAK inhibitors may have the following advantages
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In the case of rheumatism therapy, the first advantage is that it blocks a broad spectrum of cytokines that cover many existing and potential inflammation-causing factors
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From the experience with TNF blocker drugs, inhibition of a single cytokine does not guarantee a therapeutic effect in all patients with rheumatism
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Therefore, blocking multiple cytokines with one drug is of particular interest
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Second, JAK inhibitors are small-molecule drugs that are not prone to drug resistance, and their therapeutic effects may be more stable
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The therapeutic potential of a single biologic tends to be exhausted, and continued treatment may result in a secondary lack of efficacy, mainly due to the formation of antidrug antibodies capable of neutralizing the activity of the biologic
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Another possibility is that inhibition of a cytokine pathway may activate an alternative inflammatory pathway that does not use the currently blocked cytokine
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Third, JAK inhibitors are usually oral small-molecule preparations, which are much more convenient to administer than biomacromolecular drugs that require injection or infusion
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Safety of JAK Inhibitors Since the second half of 2021, the safety of JAK inhibitor drugs has been greatly questioned
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On December 6, 2021, the FDA decided to use new safety warning and restriction labels for AbbVie's Rinvoq, Pfizer's Xeljanz and Eli Lilly's Olumiant
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These new safety warnings require that the three drugs be used only in patients who cannot tolerate or respond poorly to TNF inhibitors such as AbbVie's Humira
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Safety concerns about JAK inhibitors stem from results from postmarketing studies of Xeljanz
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The study followed an analysis of data after taking Xeljanz in rheumatoid arthritis patients with cardiovascular risk factors
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The researchers noted that patients taking Pfizer's drug Xeljanz had an increased risk of blood clots, death from a major heart-related event, death, and cancer compared with patients taking TNF inhibitors
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Although safety concerns and red flags arose from postmarketing follow-up studies of Xeljanz, the FDA made it clear that it believes such safety risks are a common problem with JAK inhibitor drugs, including oral drugs in this class, and is calling for Rinvoq and Olumiant tags for a similar update
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In fact, before the latest label revisions, these three JAK inhibitor drugs already had boxed warnings for similar risk factors, but they were not compared with other TNF inhibitor drugs
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On December 15, 2021, the FDA approved AbbVie's Rinvoq for the treatment of psoriatic arthritis and Pfizer's Xeljanz for the treatment of active ankylosing spondylitis, following a label restriction update
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Future Clinical and R&D Directions JAK inhibitors have revolutionized the treatment of immune and inflammatory diseases
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As a newer class of drugs, many patients are likely to benefit from JAK inhibitors in the coming years
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Due to the doubts about its safety and the advantages compared to biologics, the future clinical and R&D directions are as follows
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More clinical experience is needed to determine the risk-benefit ratio of each drug in a specific indication
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Clinical vigilance of common and rare side effects of these drugs, including atypical infectious complications, withdrawal syndrome, potential cytopenias and liver dysfunction, lipid metabolism disorders, and the risk of thrombosis caused by certain drugs, need to be strengthened Skin surveillance for non-melanoma skin cancer
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All current JAK inhibitors require long-term efficacy data and post-marketing monitoring
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Explore combination therapy with JAK inhibitors
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Recognizing that dysregulated JAK-STAT signaling is not the only pathogenesis of diseases such as myelofibrosis and rheumatoid arthritis, the use of combination therapy may maximize therapeutic efficiency
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The drugs can be administered simultaneously or sequentially
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For example, a histone deacetylase inhibitor, pracinostat, and ruxolitinib were tested in patients with myelofibrosis, in which patients received ruxolitinib for 3 months followed by pracrinostat
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There is a need to understand the mechanisms of resistance and loss of response to JAK inhibitors, especially in relation to myeloproliferative neoplasms, and how to best mitigate drug resistance in patients
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Finally, underlying disease-related immune signatures may help clinicians choose which patients in which disease groups will benefit most from a particular JAK inhibitor
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Classifying different patients and selecting appropriate JAK inhibitors for personalized treatment will be a long-term trend in various therapies
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References: 1.
Current and future status of JAK inhibitors 2.
An Overview of JAK Inhibitors 3.
'The Great Debate': JAK inhibitors vs biologics following methotrexate failure in RA 4.
Biologics and JAK Inhibitors: What's the Difference?