In a randomized, placebo-controlled phase 2b trial in NSV, the efficacy of the oral JAK3/TEC family kinase inhibitor ritlecitinib with or without a 4-week loading dose (200/50mg, 100/50mg, 50mg, 30mg, 10mg) or placebo for 24 weeks was evaluated in patients with lighter skin (FST I-III) vs darker skin (FST IV-VI); 50mg dose groups (50mg) and 30/10mg (low dose) groups were combined for analysis. Treatment with 50mg ritlecitinib significantly reduced depigmentation extent at Week 24 [W24] vs placebo both in patients with FST I-III (% change from baseline [%CFB] in Facial-Vitiligo Area Scoring Index -15.2,P=0.004) and FST IV-VI (-37.4, P<0.0001). At Week 48, there was no difference in %CFB between FST I-III and FST IV-VI groups (-63.1 vs -66.8). Immune biomarkers were evaluated. Blood collected at baseline, Week 4 [W4], and W24 was analyzed by Olink proteomics cardiovascular, neurology, immuno-oncology, and inflammation target panels. At baseline, patients with FST I-III had elevated levels of serum proteins such as CLM-1 and CSF-1, and patients with FST IV-VI had elevated levels of NOS3. Following ritlecitinib treatment, patients with FST I-III in the 50mg groups had decreased CXCL11 levels from baseline (W24: P=9e-5), while patients with FST IV-VI had increased levels of CXCL11 (W24: P=0.05), IL-10 (W24: P=0.003), and IL-27 (W4: P=0.0007). These results suggest that NSV immune system dysregulation can vary, leading to differential molecular changes in response to JAK3/TEC family kinase inhibition.

In a post hoc analysis of a randomized, placebo-controlled phase 2b trial in NSV, treatment with the oral JAK3/TEC family kinase inhibitor ritlecitinib stabilized active lesions and repigmented stable lesions. This analysis compared melanocyte and immune biomarkers in active and stable lesions. Patients were randomized to daily ritlecitinib with or without a 4-week loading dose: 200/50mg, 100/50mg, 50mg, 30mg, 10mg, or placebo for 24 weeks; 50mg dose groups were combined for this analysis. Biopsies were obtained at baseline and Week 24. Samples were analyzed by RNA-seq, real-time qPCR, and immunohistochemistry for differential expression of markers associated with melanocytes, immune response, costimulatory molecules, and CD3+/CD8+ T cell infiltrates. At baseline, active lesions trended towards more T cell infiltrates than stable lesions. At Week 24, T cell infiltrates were reduced in both types of lesions in patients in the 50mg group. In the 50mg and 30mg ritlecitinib-treated groups, expression of melanocyte markers increased in stable lesions vs placebo (P<0.01 and P<0.05). Th1/Th2-related and costimulatory molecules decreased significantly in both 50mg group stable and active lesions (P<0.05). These data suggest ritlecitinib reduces immune infiltrates in vitiligo lesions, thereby stabilizing active lesions and promoting melanocyte recovery and melanin production in stable vitiligo lesions.