What is the current status of ritlecitinib (Ritlecitinib) and upadacitinib (Upadacitinib) trials in the treatment of vitiligo?

Current Status of Ritlecitinib and Upadacitinib Trials in Vitiligo Treatment

Both ritlecitinib and upadacitinib have shown promising results in clinical trials for vitiligo treatment, with ritlecitinib demonstrating significant facial repigmentation in Phase 2b trials and upadacitinib showing effectiveness in small case series studies.

Ritlecitinib Trials for Vitiligo

Phase 2b Trial Results

• A randomized phase 2b clinical trial (NCT03715829) evaluated oral ritlecitinib, a JAK3/TEC inhibitor, in patients with active nonsegmental vitiligo 1:
  • 364 patients were treated with various dosing regimens
  • Significant improvements in Facial-Vitiligo Area Scoring Index (F-VASI) at week 24 compared to placebo:
    • Ritlecitinib 50 mg with loading dose: -21.2% vs 2.1% (placebo), p<0.001
    • Ritlecitinib 50 mg without loading dose: -18.5% vs 2.1% (placebo), p<0.001
    • Ritlecitinib 30 mg: -14.6% vs 2.1% (placebo), p=0.01
  • Continued improvement observed through 48 weeks of treatment
  • No dose-dependent trends in adverse events were observed

Biomarker Analyses

• Substudy of the phase 2b trial examined effects on skin and blood biomarkers 2:
  • Ritlecitinib treatment led to:
    • Downregulation of immune biomarkers
    • Upregulation of melanocyte-related markers (tyrosinase, Melan-A)
    • Significant reductions in CD3+/CD8+ T-cell infiltrates
    • Dose-dependent downregulation of T-cell activation markers
  • Changes in immune biomarkers correlated with clinical response

Efficacy Across Skin Types

• Analysis of ritlecitinib efficacy across different Fitzpatrick skin types (FSTs) 3:
  • Improved F-VASI scores at 24 weeks in both light skin (FST I-III) and dark skin (FST IV-VI) patients
  • Greater response in dark-skinned patients (placebo-adjusted difference -37.4% vs -15.2% in light skin)
  • Continuous repigmentation through week 48
  • Different immune responses observed between skin types, possibly explaining varied treatment responses

Upadacitinib Trials for Vitiligo

Current Evidence

• Limited studies exist specifically for upadacitinib in vitiligo treatment 4, 5
• A retrospective case series evaluated upadacitinib in non-segmental vitiligo 5:
  • Five patients received oral upadacitinib 15 mg daily for 4+ months
  • All patients achieved repigmentation
  • Biomarker analysis showed:
    • Decreased CXCL9 levels after treatment
    • Reduced ratio of CD4+CD3+/CD8+CD3+ T cells
    • Downregulation of Th1-like Tregs in peripheral blood
  • Treatment was found to be both effective and safe

Mechanism of Action

• Upadacitinib is a selective JAK1 inhibitor 4, 5
• JAK inhibitors work by blocking the JAK-STAT intracellular signal transduction pathway 6
• This pathway is important in the response to multiple cytokines involved in inflammatory disorders

Comparative Analysis

JAK Inhibitors in Vitiligo Management

• A scoping review of JAK inhibitors for vitiligo treatment found 4:
  • Various JAK inhibitors studied for vitiligo, with tofacitinib being most common
  • Ritlecitinib and upadacitinib were among the studied oral JAK inhibitors
  • Benefits may vary between JAK inhibitors based on receptor selectivity profiles
  • Concurrent use with phototherapy or sun exposure appears beneficial
  • Most common adverse effects: acne-related events, nasopharyngitis, upper respiratory infections, and headaches
  • No serious hematological or thromboembolic events were detected

Current Treatment Context

• Traditional vitiligo treatments include 6, 7:
  • Topical corticosteroids
  • Topical calcineurin inhibitors
  • Narrowband UVB phototherapy
  • PUVA therapy
  • Surgical options for resistant cases
• JAK inhibitors represent a novel approach targeting the underlying autoimmune pathways

Clinical Implications and Future Directions

Practical Considerations

• Dosing regimens in trials:
  • Ritlecitinib: 50 mg daily (with or without loading dose) showed best efficacy-safety profile 1, 2
  • Upadacitinib: 15 mg daily used in case series 5

Safety Profile

• Both medications were generally well-tolerated in the reported studies
• No serious adverse events were reported in the vitiligo-specific trials
• Common side effects included acne-related events, nasopharyngitis, and headaches 4

Research Gaps

• Larger randomized controlled trials for upadacitinib in vitiligo are needed
• Long-term safety and efficacy data beyond 48 weeks
• Head-to-head comparisons between different JAK inhibitors
• Combination therapy protocols with traditional treatments

Conclusion

Ritlecitinib has more robust clinical trial data for vitiligo treatment, with completed phase 2b trials showing significant efficacy. Upadacitinib shows promise based on limited case series data. Both medications represent an important advancement in vitiligo management by targeting the underlying immune pathways responsible for melanocyte destruction.