Good to see Lupus mentioned.25 Mar 2024 12:57
Conclusions
The emergence of targeted anti-cytokine therapies has been a major breakthrough in the treatment of autoimmune and inflammatory diseases. Discoveries relating to cytokine signalling through addressable kinase targets led to the development of JAK inhibitors that showed evidence of efficacy, tolerability and safety across multiple indications. Although TYK2 is a member of the JAK family of receptor kinases, its actions are limited to a specific set of cytokines, predominantly signalling downstream of IL-12 and IL-23 and the type I interferons, and to some extent IL-10 and other cytokines, without affecting signalling downstream of classical type I cytokines or gp130 ligands such as IL-6. Recognition of the actions of TYK2, and the known efficacy of IL-12–23 blockade in psoriasis and PsA, as well as of type I interferon blockade in SLE, has spurred the development of TYK2 inhibitors in these indications. The TYK2 inhibitor deucravacitinib is now approved for the treatment of psoriasis on the basis of positive phase III trials, whereas preliminary evidence of the efficacy of deucravacitinib in phase II trials in PsA and SLE requires confirmation in the ongoing phase III trials. A potentially unique safety profile of TYK2 inhibition compared with other JAK inhibitors, on the basis of the finite list of cytokines in whose signalling it participates, was forecast and so far, upheld in clinical studies, at least with respect to laboratory evaluations. Whether the safety profile will be different from currently approved JAK inhibitors and biologic DMARDs with respect to the rarer events of MACEs, malignancy and VTE will have to await the results of much larger, longer-term studies and analyses. Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are at an early stage of development and have both shown preliminary evidence of efficacy. However, consistent with their binding to the ATP binding site of JAK and also inhibiting JAK1 and/or JAK2, initial data suggest that these drugs might be more similar to the approved inhibitors of JAK1, JAK2 and/or JAK3 than deucravacitinib in terms of safety. The potential application of TYK2 inhibitors in other indications, such as in cutaneous lupus as suggested by positive findings for skin disease in the phase II SLE trial38 and dermatomyositis as suggested by evidence from genetic studies and the type I interferon signature associated with dermatomyositis75, awaits further clinical trials in these conditions, as does potential application of TYK2 inhibition for the treatment of inherited interferonopathies.
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