TYK2 inhibitors may offer pathway for more comprehensive inflammation therapy
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The emergence of drugs inhibiting the JAK-STAT pathway has culminated in tyrosine kinase 2 inhibitors targeting psoriatic arthritis, lupus and other indications, noted a presenter at the 2022 Association of Women in Rheumatology conference.
“Now we have TYK2, which is involved in the pathogenesis of many immune-mediated diseases,” Grace C. Wright, MD, PhD, FACR, president of the Association of Women in Rheumatology, told attendees during the hybrid meeting. “What we are seeing, depending on how you disrupt that pathway, was a lack of serious adverse events associated with inhibition compared with other JAKs.
“The difference really is that if you’re binding the active site, then you are actually disrupting directly through that active site, and if you bind the regulatory site, you can fix it in a configuration in which the active site can no longer be active,” Wright added.
It is possible, she continued, that when binding the active site completely, the adverse events are absent as a result.
During the presentation, Wright discussed two tyrosine kinase 2 (TYK2) candidates, deucravacitinib (Bristol Myers Squibb) and brepocitinib (Priovant Therapeutics), which are regulatory and active site inhibitors, respectively.
“The potential involvement of TYK2 in the pathogenesis of immune and inflammatory diseases is vast,” Wright said.
The molecules have the potential to be involved in psoriasis, inflammatory bowel disease, rheumatoid arthritis and lupus, in addition to other neurodegenerative diseases including multiple sclerosis, she added.
“Now, suddenly, we see the far potential reach of modulating these kinds of responses,” Wright said.
Deucravacitinib is being evaluated in a phase 3 trial for psoriasis as well as phase 2 trials for PsA and systemic lupus erythematosus. Meanwhile, brepocitinib, a JAK1 and TYK2 inhibitor, is being investigated in phase 2 trials for psoriasis, PsA, alopecia areata, vitiligo, SLE, atopic dermatitis and hidradenitis suppurative. Although the molecules are in late-phase trials, they are still in the registration phase, Wright added.
“Look at all of the different ways in which you can now get a TYK2 to go across a vast array of things, from inflammatory skin, inflammatory joints and vitiligo, now coming in as an output of autoimmune and inflammatory mediation,” Wright said. “Perhaps now with better understanding of where these targets go, we can direct them based on the domains of activity for these patients who walk in with inflammation in areas we did not previously suspect.”
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Wright GC. TYK2: Pathological drivers and treatment targets in skin and joint conditions; Aug. 18-21, 2022; Hilton Head Island, South Carolina (virtual meeting).
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