gms | German Medical Science

Introduction: BMS-986165 is an oral inhibitor of TYK2, a kinase that activates cytokine signalling pathways involved in immune-mediated disease pathophysiology, such as in psoriasis, psoriatic arthritis and systemic lupus erythematosus (SLE). BMS-986165 binds to the regulatory domain of TYK2, which is unique and distinct from binding to the active domain by other tyrosine kinase inhibitors. This gives BMS-986165 high specificity for TYK2 over kinases (eg, JAK 1-3). In a randomized Phase 2 trial in 267 patients with moderate to severe psoriasis (NCT02931838), 67–75% achieved Psoriasis Area and Severity Index (PASI) 75 at Week 12 (primary endpoint) with doses ≥3 mg twice daily versus 7% with placebo (p<0.001) [1].

Methods: In an optional substudy of this Phase 2 psoriasis trial, 37 patients provided skin biopsies, which were assessed from non-lesional skin on Day 1 and lesional skin on Days 1, 15, and 85 for changes in TYK2-dependent interleukin (IL)-23, IL-12 and Type I interferon pathways by quantitative RT-PCR, RNA sequencing and immunohistochemistry. Changes were assessed for correlation with efficacy. Dose- and time-dependent effects on laboratory parameters indicative of JAK 1-3 inhibition were assessed in all patients.

Results: IL-23 pathway skin markers returned to non-lesion levels and Type I interferon and IL-12 pathway genes were normalized in dose-dependent manners with BMS-986165. Keratinocyte dysregulation markers returned toward non-lesion levels with effective doses. This correlated with clinical (PASI) improvements. BMS-986165 did not affect mean levels of blood parameters impacted with JAK 1-3 inhibition (eg, haemoglobin, neutrophils, natural killer cells, lipids).

Conclusion: BMS-986165 inhibited IL-23, IL-12 and Type I interferon signalling biomarkers in the skin that correlated with psoriasis clinical improvements. BMS-986165 only blocked TYK2-dependent pathways, demonstrating specificity for TYK2 versus JAK 1-3 in patients. This provides further rationale for ongoing investigations of BMS-986165 in psoriasis (Phase 3 trials NCT04036435 and POETYK PsO-1/2; NCT03624127, NCT03611751) and other immune-mediated diseases that could be TYK2-dependent. There are three ongoing, global, randomized, double-blind Phase 2 studies of relevance to rheumatologists: a study enrolling ~180 patients with active psoriatic arthritis (NCT03881059), one in ~360 adults with active SLE (PAISLEY; NCT03252587) and one enrolling ~78 patients with active lupus nephritis (NCT03943147).

Disclosures: IMC, LH, SB: shareholder and employee: Bristol Myers Squibb. KG: research support or consultation fees: AbbVie, Almirall, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Demira, Eli Lilly, Janssen, Novartis, Pfizer, Sun, UCB. JGK: grants paid to institution (Rockefeller University): AbbVie, Allergan, Amgen, Biogen MA, Boehringer Ingelheim, Bristol Myers Squibb, Innovaderm, Janssen, Kineta, Leo Pharma, Novan, Novartis, Paraxel, Pfizer, Regeneron, Sienna, UCB, and Vitae; personal fees: AbbVie, Acros, Allergan, Amgen, Asana, Aurigene, Biogen Idec, Boehringer Ingelheim, Escalier, Janssen, Leo Pharma, Lilly, Novartis, Pfizer, Roche, and Valeant.