Are TYK2 inhibitors ‘ticked’ to be part of the JAK family?

Janet Pope, MD, MPH, FRCPC

Jun 01, 2022 4:34 pm

Are Tyk2 inhibitors JAK inhibitors?
Yes, no, maybe

Answer
Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family. These molecules regulate signal transduction downstream of receptors for L-23/IL-12 and type I interferon family, and TKY2 pairs with JAK2 or JAK1. They may have a differentiated clinical profile compared to JAK i. There may be designer TYK2 molecules with high potency and selectivity over off-target JAKi.¹

So you may still answer the same as before you read the above definition.

Are TYK2 inhibitors effective in PsA?
Yes, no, maybe, don’t know

Answer
There are currently 2 TYK2i that have been trialed in PsA.^2,3,4 Deucravacitinib data in PsA phase II RCT found ¼ reached MDA at 16 weeks in those who received either 6 or 12 mg daily.^2,3 Brepocitinib is an effective selective TYK2/JAK1 inhibitor where 1/3 of patients reached minimal disease activity (MDA) at 16 weeks and nearly half at 52 weeks.⁴ At EULAR2022, baseline biomarkers in PsA were shown to possibly predict the response of Deucravacitinib in PsA.⁵

Are TYK2 inhibitors safer than JAKi?
Yes, no, maybe, don’t know

Answer
This is the ‘million dollar’ question. TYK2i molecules may have less Herpes Zoster reactivation and may or may not be safer than JAKi. The safety profile thus far may be similar or better than traditional JAKi. There will need to be far more experience with these drugs in order to determine if TYK2i have a different overall safety profile compared to JAKi.

References

Gernstenberger BS, et al. Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases. J Med Chem. 2020 Nov 25;63(22):13561-13577.
Mease P, et al. Deucravacitinib ACR 2020, #L03
Deucravacitinib, an Oral, Selective Tyrosine Kinase 2 Inhibitor, in a Phase 2 Trial in Psoriatic Arthritis: Achievement of Minimal Disease Activity and its Components. EULAR 2022, POS1039
Mease P, et al. ACR 2021, #488
Baseline Biomarkers Predict Better Responses to Deucravacitinib, an Oral, Selective Tyrosine Kinase 2 (TYK2) Inhibitor, in a Phase 2 Trial in Psoriatic Arthritis. EULAR 2022 POS0005.