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PARIS — In a study that employed change in inflammatory biomarkers as a primary endpoint, hair regrowth with ritlecitinib, a dual JAK3/TEC inhibitor, was observed across three types of cicatricial alopecia that currently have no approved therapeutic options.

“The clinical improvement was often rapid, and the treatment was well tolerated,” reported Anusha Pasumarthi, MD, a fellow in dermatopharmacology at the Icahn School of Medicine at Mount Sinai, New York. 

Several inhibitors of the JAK family of tyrosine kinases are already approved for the treatment of various alopecias, although it is not certain whether, or the degree to which, differences in specificity for JAK subtypes affects either efficacy or safety, according to Pasumarthi.

Ritlecitinib (Litfulo, Pfizer) is a dual inhibitor of JAK3 and the TEC family of tyrosine kinases, which includes Bruton’s tyrosine kinase and interleukin (IL)-2 inducible T-cell kinase. In 2023, it was approved by the FDA for the treatment of severe alopecia areata in patients ages 12 years and older. 

In this study, “we started patients on a 200 mg daily dose of ritlecitinib for 8 weeks before reducing the dose to 100 mg for the remainder of the study,” said Pasumarthi, who presented the results at the European Academy of Dermatology and Venerology 2025 Congress.

Three forms of cicatricial alopecia — central centrifugal cicatricial alopecia (CCCA), frontal fibrosing alopecia (FFA), and lichen planopilaris (LPP) — were evaluated in this study. There is no approved treatment for any of these diseases. 

In this single-arm, open-label study of 50 patients, biopsies were taken from lesional and nonlesional skin at baseline, 8 weeks, and 24 weeks to monitor anti-inflammatory activity. Clinical effects and safety were secondary endpoints.

A substantial downregulation of inflammatory genes and biomarkers were observed in all forms of alopecia evaluated. Most were evident within 8 weeks, although the types of inflammatory markers and the degree of suppression differed between the 20 patients enrolled with CCCA, 15 enrolled with FFA, and 15 enrolled with LPP. 

“The most significant and robust immune downregulation across multiple axes was observed in the CCCA group,” Pasumarthi reported. This included IL2RA and IL2RB, which are genes mediating T cell activation; CCL13 and CCL22, which are genes mediating Th2 upregulation; and IL23R and S100A12, which activate T17/Th22 signaling. Genes associated with JAK/STAT and NK/T cell signaling were also upregulated.

Downregulation of COL1A1, a marker of fibrosis, was consistent across all three alopecia subgroups, but significant upregulation of hair keratin genes — including KRT85, KRT35, KRT83, KRT75, KRT86, and KRTAP1 — was only seen in the FFA group.

Likely reflecting the change in inflammatory genes, there was a substantial progressive reduction in disease activity as measured with Central Hair Loss Grading (CHLG) scores for CCCA, Frontal Fibrosing Alopecia Severity Index (FFASI) scores for FFA, and the Lichen Planopilaris Activity Index (LPPAI) scores for LPP. 

By week 24, there was nearly a 25% reduction from baseline (P < .05) in the CHLG score in the CCCA subgroup, and this continued to fall to week 48 when the reduction in the score from baseline reached nearly 50% (P < .01).

There were similar FFASI declines in the FSA subgroup, reaching about 22% (P < .001) at week 24 and slightly more than 40% at week 48 (P < .001).

The steepest reduction was observed for the LPPAI score in the LPP group. At 24 weeks, the reduction from baseline was more than 55% (P < .001), and at week 48, the reduction was nearly 65% (P < .001). 

“Clinical improvements were observed as early as week 4, and the improvements over time were clinically meaningful,” Pasumarthi reported. “The goal of therapy was to stabilize patients, but the fact that we did see hair regrowth is very encouraging.”

When disease duration was evaluated as variable in treatment response, there was a trend (P = .164) for those better outcomes at 48 weeks among those with a shorter history of alopecia (< 3.5 years) relative to those with a longer history when data was pooled for all three forms of cicatricial disease.

There were no serious adverse events attributed to ritlecitinib over the course of the study. This included any signal of thrombosis or other vascular events, which have been linked to other inhibitors of JAK subtypes. Pasumarthi reported that three patients discontinued therapy for reasons not thought to be related to treatment.

The reduction in key inflammatory markers and clinical improvement “were correlated” in regard to time on therapy, which led Pasutharthi to assert that the study was able “to bridge clinical and molecular endpoints.”

Controlled trials are now needed to confirm a meaningful benefit, while more work is required to provide more detail about the degree to which there is a relationship between the broad reduction in inflammatory markers Pasutharti displayed on a heat map and inhibition of JAK3, the TEC family of kinases, or both.

Other investigators have observed a relationship between cicatricial alopecias and JAK-mediated upregulation of inflammation. In a recent review of the experience with JAK inhibitors in cicatricial alopecia, Maryanne Senna, MD, who is affiliated with the Lahey Clinic in Burlington, Massachusetts, and is an assistant professor of dermatology at Harvard Medical School, Boston, cited several published studies, including a phase 2 trial with brepocitinib, a dual JAK1 and TYK2 inhibitor.

Asked to comment, she said that she considers these new data with ritlecitinib to be timely based on the growing interest of targeted antiinflammatory therapies for even the most severe forms of alopecia.

“I applaud this group for evaluating JAK inhibitors for scarring alopecia,” said Senna, referring to any drug with JAK inhibition as at least one mechanism of action.

“We and others have also shown significant benefit in reducing inflammation in these conditions,” she added. However, she noted that treatment early in this disease might be important because of the difficulty of reversing advanced scarring.

“The critical issue is ensuring that therapies of this nature are initiated early in the disease course to maximize benefit for patients. When introduced too late in advanced or severe cases with extensive hair loss, treatment may only halt further progression without providing any meaningful change in the damage already incurred,” Senna told Medscape.

The study was funded by Pfizer. Pasumarthi reports no potential conflicts of interest. Senna reports financial relationships with AbbVie, Immagine, Lilly, Leo, Pfizer, and Sun Pharmaceuticals.