A novel combination therapy approach using oral ritlecitinib with narrowband UV-B (nbUV-B) phototherapy has demonstrated significantly enhanced repigmentation outcomes in patients with nonsegmental vitiligo (NSV), according to results from a phase 2b clinical trial. The combination achieved a 69.6% mean improvement in facial repigmentation compared to 55.1% with ritlecitinib monotherapy alone.
JAK Inhibitor Shows Promise in Vitiligo Treatment
Ritlecitinib, an oral JAK3/TEC family kinase inhibitor with high selectivity over other JAK isoforms, has emerged as a promising therapeutic option for NSV. The drug, which received FDA approval for severe alopecia areata treatment in 2023, demonstrated efficacy in the phase 2b vitiligo study (NCT03715829) when administered at 50 mg daily with or without loading doses over 48 weeks of treatment.
Dr. Emma Guttman-Yassky from the Icahn School of Medicine at Mount Sinai, who participated in the clinical trial, noted that "ritlecitinib alone was effective in improving repigmentation, but when combined with nbUV-B, the efficacy results were even more significant."
The molecular analysis of skin biopsy samples revealed significant dose-dependent downregulation in T-cell activation, natural killer cell, cytotoxic, type 1 immune, and type 2 immune markers in response to ritlecitinib treatment. The drug demonstrated similar efficacy and safety profiles across all Fitzpatrick skin types I through VI.
Addressing Unmet Medical Need
NSV represents the most common form of vitiligo, an autoimmune condition that significantly impacts patients' quality of life through depression, anxiety, impaired personal and social relationships, negative self-esteem, and reduced quality of life. Currently, no systemic pharmacological treatments are approved specifically for NSV, creating a substantial unmet medical need.
The psychological impact is particularly pronounced among patients with darker skin tones, who may experience higher levels of discrimination and self-consciousness. Research has shown that patients often become self-conscious when looking in mirrors, highlighting the urgent need for effective treatment options.
Two-Step Therapeutic Approach
The enhanced efficacy of combination therapy stems from a strategic two-step treatment approach. The first step focuses on reducing inflammation and stopping melanocyte destruction, while the second step induces melanocyte growth and spreading. Ritlecitinib addresses the immunomodulatory component, while nbUV-B phototherapy contributes to melanocyte regeneration.
"In vitiligo, it can take up to 1 year of treatment to achieve meaningful repigmentation. Consequently, a 2-step approach is needed," explained Dr. Guttman-Yassky. "The immunomodulators are thought to affect step 1 therapy and the phototherapy would contribute to the second step."
Advancing Through Phase 3 Development
The promising phase 2b results have led to an extensive phase 3 program comprising three studies: Tranquillo (NCT05583526), Tranquillo LTE (NCT06163326), and Tranquillo 2 (NCT06072183). These studies are evaluating ritlecitinib at doses of 50 mg and 100 mg daily in adult and adolescent patients with NSV.
The main objectives include demonstrating statistically significant and meaningful repigmentation compared to placebo while maintaining a favorable benefit-risk profile. The studies are designed to provide comprehensive data on efficacy, safety, and tolerability across diverse patient populations.
Broader JAK Inhibitor Landscape
Ritlecitinib joins a growing class of JAK inhibitors being investigated for vitiligo treatment. Since July 2022, topical ruxolitinib has been the only FDA-approved JAK inhibitor for treating nonsegmental vitiligo in patients 12 and older. Other JAK inhibitors including upadacitinib, povorcitinib, baricitinib, and tofacitinib are also under investigation in various phases of clinical development.
The combination therapy approach represents a significant advancement in vitiligo treatment, potentially offering patients more rapid and clinically meaningful repigmentation outcomes. As Dr. Guttman-Yassky noted, "The combination therapy may provide rapid and clinically meaningful repigmentation, which could significantly improve patients' quality of life."
