544 Alopecia areata lesions show significant changes in immune and keratin biomarkers that correlate with clinical improvement with oral Janus kinase inhibitors PF-06651600 (JAK3) and PF-06700841 (TYK2/JAK1)

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Oral JAK3 (PF-06651600) and TYK2/JAK1 (PF-06700841) inhibitors were shown to be efficacious and well tolerated in patients with moderate to severe (≥50% scalp hair loss) alopecia areata (AA). A substudy of this Phase 2 trial (PF-06651600, n=18; PF-06700841, n=16; placebo, n=12) evaluated changes in lesional scalp biomarkers after 12 and 24 weeks of treatment using microarrays, qPCR, and immunohistochemistry. A total of 2264 genes were significantly up- or downregulated after 12 or 24 weeks of treatment across all patients and treatment groups (fold change >1.5; p<0.05). Significant gene-level changes from baseline in lesional transcriptomic profiles of 62% and 115% (12 weeks) and 162% and 104% (24 weeks) were obtained in the PF-06651600 and PF-06700841 groups, respectively, which differed significantly from those in the placebo group (week 12, 18%; week 24, 6%). With both treatments, patient-level T-cell activation, Th1, Th2, and IL12/23 pathways were significantly downregulated (p<0.05 at weeks 12 and/or 24) and hair keratins (KRT35, 40, 75, 83, 85, 86, KRTAP1) were significantly upregulated (p<0.05 at weeks 12 and/or 24). Most of these changes were significantly correlated (p<0.05) with clinical (Severity of Alopecia Tool score) improvements from baseline. No significant changes were seen with placebo. Greater improvements in clinical and transcriptomic parameters correlated with a shorter AA duration (<3.5 years). Overall, clinical improvements in patients with AA treated with PF-06651600 and PF-06700841 were associated with downregulation of Th1, Th2, and IL-12/23 immune responses and upregulation of hair keratins, with greater responses in patients with shorter disease duration.