JAK inhibitors could improve alopecia areata
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Patients with alopecia areata who were treated with ritlecitinib or brepocitinib had significant downregulation of immune biomarkers, according to a biopsy sub-study.
“Alopecia areata (AA) is a chronic, relapsing autoimmune disorder with an approximate 2% lifetime incidence among patients in the United States, affecting both adult and pediatric populations, and it has no sex predilection,” Emma Guttman-Yassky, MD, PhD, the Waldman Professor and System Chair of the Kimberly and Eric J. Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai, and colleagues wrote. “To date, there is no United States Food and Drug Administration-approved treatment for patients with moderate to severe AA, and available therapies, including intralesional steroid injections, contact sensitization and systemic immunosuppressants, show limited efficacy, are inconvenient for patients and/or are unsuitable for long-term use.”
Ritlecitinib, an inhibitor of Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma kinase family, and brepocitinib, an inhibitor of JAK1 and tyrosine kinase 2 (TYK2), are being studied in a phase 2a randomized, double-blind, placebo-controlled, multicenter clinical trial for the treatment of AA in patients with more than 50% hair loss.
“This is an important study because it’s the first time this mechanism is being studied in a placebo-controlled trial in relatively large numbers with a JAK inhibitor,” Guttman-Yassky told Healio.
Improvement in the Severity of Alopecia Tool (SALT) scores at week 24 is the study’s main efficacy endpoint, and patients could opt-in for an optional biopsy sub-study.
The sub-study used biopsies from lesional patients, who were completely void of hair, and nonlesional patients, who had available nonlesional scalp.
A mean SALT score improvement of 24.9 was recorded after 24 weeks in the ritlecitinib group and 38.8 for the brepocitinib group, compared with 7.6 for the placebo group.
The sub-study included 46 of the original 142 patients. Of these, 18 received ritlecitinib, 16 received brepocitinib and 12 received placebo. At week 12 biopsies were available for 13, 13 and 8 patients, respectively. At week 24, biopsies were available for 15, 12 and 8 patients.
Both treatment groups had a significant increase from baseline in mean expression of early, middle and late hair keratins, while placebo had no significant changes.
A significant improvement was also recorded in the hair keratin signature of those treated with brepocitinib at week 24 (P < .05) and the Alopecia Areata Disease Activity Index hair keratin composite for those treated with ritlecitinib (P < .05).
Improvements in scalp tissue and downregulation of immune biomarkers extending beyond the Th1 axis to Th2 immune axis was also found in both treatment groups.
Both groups showed a gradual shifting from lesional to nonlesional scalp phenotype over the treatment period, with those treated with brepocitinib experiencing the effect earlier at week 12. However, by week 24 both groups had improvements of more than 100% from baseline in the lesional scalp profile.
“This shows when you treat patients with a JAK inhibitor, you are improving not only the Th1 immune axis that was originally thought to be important in alopecia areata, but also the Th2 immune axis. This changes what we think of the pathogenesis of the disease a little bit,” Guttman-Yassky said. “I hope this study helps us understand the relationship between the clinical improvement and suppressing the inflammation, particularly Th2 and Th1 inflammation, as well as the third axis — the improvement in hair keratins that should increase with any successful treatment of alopecia areata.”