Ritlecitinib, an oral dual JAK3/TEC family kinase inhibitor, induces differential changes in immunological protein levels across Fitzpatrick skin types (FST) in patients with active nonsegmental vitiligo (NSV)

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.