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)

Abstract

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, n¼18; PF-06700841, n¼16; placebo, n¼12) 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.

Frontal fibrosing alopecia shows robust T helper 1 and Janus kinase 3 skewing

“…54 Our study supports the rationale for larger studies to explore JAK inhibition in FFA, particularly JAK3 inhibition that showed significant clinical benefits in several clinical trials in moderate-to-severe patients with AA. 41,42,[55][56][57] The most striking difference between AA and FFA molecular signatures was the lack of downregulation of hair keratins in FFA, in contrast with their consistent suppression in AA, as previously reported. 35,48 The keratins include early, middle and late keratinization genes, such as KRT86 and KRT83, which serve as AA treatment response biomarkers.…”

“…In sum, the diminished but still present stem cells in FFA lesions and largely unaffected stem cells in nonlesional FFA, together with the strong upregulation of T-cell activation/ Th1/JAK-STAT-related pathways and their correlation with fibrosis, along with recent therapeutic success of immunebased therapies in AA models and patients with moderate-tosevere AA, [39][40][41] provide hope for testing and development of targeted therapies for FFA. We acknowledge that our study was limited by the relatively small number of patients, and lack of global profiling with RNA-Seq.…”

“…[35][36][37] The increased understanding of AA pathogenesis has led to testing of novel therapeutics, such as JAK inhibitors that target several polar cytokines, showing efficacy in early trials. [38][39][40][41][42] In contrast, the development of targeted therapeutics for FFA is lacking, largely owing to the lack of a complete understanding of disease mechanisms. Comparing the reversible, nonscarring AA with FFA may thus help to elucidate the molecular pathways specifically driving this scarring alopecia.…”

Phase 2a randomized clinical trial of dupilumab (anti‐IL‐4Rα) for alopecia areata patients

“…The sample size was based on the primary efficacy outcome, that is, change in SALT score at week 24 in drug compared to placebo. For patients with similar disease severity, a change in SALT of less than 5 units was observed in placebo 23 . Assuming that at week 24 dupilumab will induce a change in SALT of at least 25 with a standard deviation of 10, a total sample size of 54 patients randomized 2:1 dupilumab to placebo will provide 97% power to detect differences compared to placebo, based on a two‐sided Student's t ‐test with a type I error α = 0.05.…”

“…For patients with similar disease severity, a change in SALT of less than 5 units was observed in placebo. 23 Assuming that at week 24 dupilumab will induce a change in SALT of at least 25 with a standard deviation of 10, a total sample size of 54 patients randomized 2:1 dupilumab to placebo will provide 97% power to detect differences compared to placebo, based on a two-sided Student's t-test with a type I error α = 0.05. Assuming a 10% dropout rate, the planned sample size was a total of 60 patients.…”