JAK3/TEC Inhibition Through Ritlecitinib Effective, Safe for Cicatricial Alopecias

Ritlecitinib therapy has been linked with a favorable safety profile and rapid improvements in cicatricial alopecia clinical scores and molecular biomarkers, according to new data, supporting JAK3/TEC inhibition for this condition.1

These late-breaking findings on ritlecitinib’s use among patients with cicatricial alopecia were released during the European Academy of Dermatology and Venereology (EADV) 2025 Congress in Paris. They were presented by investigator Anusha Pasumarthi, MD, a dermatology resident at Mount Sinai Health System.

Cicatricial alopecias is is a set of alopecias that include lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and central centrifugal cicatricial alopecia (CCCA). These alopecias are chronic, scarring forms of hair loss that are known to progress over time and significantly impact patients' quality of life. Th1/JAK3 pathway activation evidence in these diseases has resulted in an investigation of ritlecitinib, a selective JAK3/TEC kinase inhibitor, as a potential therapy (NCT05549934).

Pasumarthi and coauthors' single-arm, open-label analysis involved the recruitment of 50 participants. They specifically enrolled 15 with FFA, 15 with LPP, and 20 with CCCA. All such patients were treated with ritlecitinib therapy over 48 weeks, beginning with 200 mg each day for the first 8 weeks. This dosage was then followed by 100 mg on a daily basis after 8 weeks.

In their assessment of ritlecitinib, the team determined there endpoints would be safety outcomes and shifts at Week 24 in Th1-associated biomarkers as well as fibrosis-related markers. Among their secondary endpoints were the Dermatology Life Quality Index (DLQI), clinical activity evaluations (LPPAI for LPP, FFASI for FFA, CHLG for overall hair loss severity), and the Physician Global Assessment of Improvement (PGA-I). Pasumarthi et al collected biopsies from both lesional and non-lesional scalp at baseline and at the 8 and 24-week points, with molecular changes being assessed via RT-PCR.

Ritlecitinib use led to mean improvements from baseline of 57% in LPPAI (P < .001), 24% in FFASI (P < .01), and 24% in CHLG (P < .05) among the 38 subjects with available data. 29 patients assessed were evaluated at the 48-week mark and these improvements rose among these individuals to 70% (P < .001), 41% (P < .001), and 52% (P < .01), respectively.

The investigative team's treatment course was shown to be generally well tolerated. The team did not observe any new safety concerns during the 48-week treatment period. Most of the adverse events (92%) were noted by Pasumarthi and colleagues as being mild to moderate in their level of severity. They added that only 9.6% were probably linked to ritlecitinib. In their molecular analyses, the investigative team confirmed significant down-regulation of CCL5 across all of the cicatricial alopecia subtypes at the 24-week mark (P < .05).

Reductions in inflammatory signaling were already evident by week 8. At week 24, key immune-related pathways showed significant downregulation, including general inflammatory markers (PDE4B), Th1 markers (CCL5, CXCL9, CXCL10), and cytotoxic/NK-T cell–related genes (IL2RA, GZMB) in FFA and/or LPP (all P < .05). CCCA demonstrated the broadest and most consistent suppression of immune activity, with significant decreases across multiple pathways: T cell activation (IL2RA, IL2RB), Th1 (CCL5, CXCL9, CXCL10, IL12RB1), Th2 (CCL13, CCL22), Th17/Th22 (IL23R, S100A12), and JAK-STAT/NK-T signaling (IL2RA, IL2RB, IL15RA, IL16, JAK1, JAK3, GZMB) (all P < .05).

While Pasumarthi et al concluded that fibrosis-related markers such as COL1A1 showed non-significant downward trends across the cicatricial alopecia subtypes, there was no consistent down-regulation identified for other fibrotic markers. In contrast, individuals with FFA displayed significant upregulation of their hair keratins (KRT85, KRT35, KRT83, KRT75, KRT86, KRTAP1; P < .05).

The investigators found the most robust molecular changes took place within the initial 8-week dosing period, though they noted similar patterns being maintained through the 24-week mark. CCCA had the most pronounced immunologic responses.

Prior findings highlighted in a previous HCPLive article pointed to positive results with ritlecitinib for alopecia areata.2 These new data suggesting positive responses among patients with cicatricial alopecias align with these findings and support continued evaluations of this drug.

References

1. Del Duca E, Lau M, Yassky EG, et al. JAK3/TEC Inhibition is Safe and Effective in Cicatricial Alopecias: Evidence from a Prospective Trial. Presented at the 2025 European Academy of Dermatology and Venereology (EADV) Congress, Sept 17-20, 2025.

2. Smith T. Phase 3 Findings on Long-Term Ritlecitinib in Adults, Adolescents with Alopecia Areata. HCPLive. July 24, 2025. https://www.hcplive.com/view/phase-3-findings-long-term-ritlecitinib-adults-adolescents-alopecia-areata. Accessed September 18, 2025.