Search

Summary: Background: Janus kinase (JAK) inhibition is a promising approach for treating vitiligo. We aimed to assess the efficacy and safety of upadacitinib, an oral selective JAK inhibitor, in adults with non-segmental vitiligo. Methods: This was a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-ranging study completed at 33 clinical centres in the United States, Canada, France, and Japan. Eligible patients were aged 18–65 years with non-segmental vitiligo and had a Facial Vitiligo Area Scoring Index (F-VASI) ≥0.5 and a Total Vitiligo Area Scoring Index (T-VASI) ≥5. Patients were randomly assigned (2:2:2:1:1) using an interactive response technology to receive upadacitinib 6 mg (UPA6), upadacitinib 11 mg (UPA11), upadacitinib 22 mg (UPA22), or placebo (PBO; preassigned to switch to either UPA11 or UPA22 in period 2) once daily for 24 weeks (period 1). For weeks 24–52 (period 2), patients randomly assigned to upadacitinib continued their treatment, and patients receiving PBO switched to their preassigned upadacitinib dose in a blinded fashion. The primary endpoint was the percent change from baseline in F-VASI at week 24. Efficacy was analysed in the intention-to-treat population, and safety was examined in all randomly assigned patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT04927975. Findings: Between June 16, 2021, and June 27, 2022, 185 patients (including 115 [62%] who were female and 70 [38%] who were male) were randomly assigned to UPA6 (n = 49), UPA11 (n = 47), UPA22 (n = 43), or PBO (n = 46). At week 24, the LS mean difference versus PBO in the percent change from baseline in F-VASI was −7.60 (95% CI −22.18 to 6.97; p = 0.3037) for UPA6, −21.27 (95% CI −36.02 to −6.52; p = 0.0051) for UPA11, and −19.60 (95% CI −35.04 to −4.16; p = 0.0132) for UPA22. The LS mean difference versus PBO in the percent change from baseline in T-VASI was −7.45 (95% CI −16.86 to 1.96; p = 0.1198) for UPA6, −10.84 (95% CI −20.37 to −1.32; p = 0.0259) for UPA11 and −14.27 (95% CI −24.24 to −4.30; p = 0.0053) for UPA22. Ongoing treatment with upadacitinib induced continuous skin repigmentation over time without reaching a plateau through week 52. The rates for study drug discontinuation and serious treatment-emergent adverse events (TEAEs) were higher in the UPA22 group than in the UPA11 and UPA6 groups. Eight serious TEAEs, including one death of unknown cause and one case of infiltrating lobular breast carcinoma, were reported through 52 weeks; only two serious TEAEs (coronary artery arteriosclerosis [UPA6 (n = 1)] and non-fatal ischemic stroke [UPA11 (n = 1)]) were deemed by the investigator to have a reasonable possibility of being related to study drug. The one case of breast cancer in the UPA11 group was deemed unrelated to study drug, and the one death of unknown cause in the UPA22 group was reviewed and adjudicated and was deemed to be unrelated to study drug. The most common TEAEs were COVID-19, headache, acne, and fatigue. No new safety signals were observed. Interpretation: Upadacitinib monotherapy led to substantial repigmentation of both facial and total body vitiligo lesions and may offer an effective treatment option for adults with extensive non-segmental vitiligo. Based on these findings, upadacitinib 15 mg is being investigated in adults and adolescents with non-segmental vitiligo in an ongoing phase 3 randomised controlled trial. Funding: AbbVie Inc.

Identifying therapeutic oligonucleotides that are cross-reactive to experimental animal species can dramatically accelerate the process of preclinical development and clinical translation. Here, we identify fully chemically-modified small interfering RNAs (siRNAs) that are cross-reactive to Janus kinase 1 (JAK1) in humans and a large variety of other species. We validated the identified siRNAs in silencing JAK1 in cell lines and skin tissues of multiple species. JAK1 is one of the four members of the JAK family of tyrosine kinases that mediate the signaling transduction of many inflammatory cytokine pathways. Dysregulation of these pathways is often involved in the pathogenesis of various immune disorders, and modulation of JAK family enzymes is an effective strategy in the clinic. Thus, this work may open up unprecedented opportunities for evaluating the modulation of JAK1 in many animal models of human inflammatory skin diseases. Further chemical engineering of the optimized JAK1 siRNAs may expand the utility of these compounds for treating immune disorders in additional tissues.