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225 An oral, selective inhibitor of tyrosine kinase 2, BMS-986165, improves molecular, cellular, and clinical biomarkers associated with efficacy in moderate to severe psoriasis
  1. Ian Catlett1,
  2. Sarah Hu1,
  3. Subhashis Banerjee1,
  4. Kenneth Gordon2 and
  5. James Krueger3
  1. 1Bristol-Myers Squibb
  2. 2Medical College of Wisconsin
  3. 3Rockefeller University Hospital, The Rockefeller University


Background Psoriasis, a chronic immune-mediated inflammatory disease dependent upon the interleukin (IL)−23/TH17 pathway, is thought to be initiated through plasmacytoid dendritic cell activation and induction of type I interferons. BMS-986165 is a novel tyrosine kinase 2 (TYK2) inhibitor that blocks signal transduction of IL-23, IL-12, and type I interferons. BMS-986165 selectivity for TYK2, compared with Janus kinases (JAKs) 13, is driven by binding to its pseudokinase domain, rather than the conserved kinase domain.

Methods BMS-986165 was evaluated in a randomized, placebo-controlled, dose-ranging trial in 267 patients with moderate to severe psoriasis. Dose- and time-dependent effects on laboratory parameters indicative of non-selective inhibition of JAKs 13 were assessed. In an optional substudy, 37 patients provided biopsies, which were assessed from healthy-appearing skin on Day 1 and from lesional skin on Days 1, 15, and 85 for changes in the IL-23, IL-12, and type I interferon pathways by QRTPCR, RNA sequencing, and immunohistochemistry.

Results All BMS-986165 treatment groups, except 3 mg every other day (QOD), achieved superiority versus placebo in the proportion of patients achieving Psoriasis Area and Severity Index 75 after 12 weeks of treatment (primary endpoint): 3 mg QOD, 9.1%; 3 mg daily (QD), 38.6%; 3 mg twice daily (BID), 68.9%; 6 mg BID, 66.7%; and 12 mg QD, 75.0% vs 6.7% with placebo. Mean levels of factors impacted with JAK 13 inhibition, including hemoglobin, total cholesterol, neutrophils, platelets, total lymphocytes, natural killer, and B cells, were not affected by BMS-986165. Markers of the IL-23 pathway including IL-17(A/F), S100A8/9, IL-22, and -defensin returned to non-lesion levels dose-dependently. Interferon and IL-12 pathway genes were normalized; keratinocyte dysregulation markers keratin-16 and 10, and late cornified envelope genes, returned toward non-lesion levels with effective doses.

Conclusions Clinical efficacy with BMS-986165 was associated with decreases in IL-23/TH17 and interferon pathway markers. TYK2 selectivity was confirmed by lack of effect on clinical biomarkers of JAK 13 inhibition. BMS-986165 has promising efficacy in psoriasis, and a distinct selectivity profile that warrants further investigation.

Funding Source(s): Bristol-Myers Squibb

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