Topical pan-JAK inhibitor mitigates inflammatory biomarkers in frontal fibrosing alopecia

Phase 2 results showed that pan-JAK inhibition with delgocitinib reduced the inflammatory markers interferon-gamma (IFN-γ), chemokine ligand (CXCL)9, and CXCL10 in frontal fibrosing alopecia (FFA). Also, a significant decrease in FFA Severity Score (FFASS) was observed at 12 weeks in participants treated with delgocitinib.

Previous profiling of gene and protein expression in lesional and non-lesional scalp tissue of patients with FFA revealed a significant upregulation of IFN-γ, CXCL 9, CXCL10, STAT1, and JAK3 [1,2]. Compared with alopecia areata, Th1 was more overexpressed and STAT1 and JAK3 more upregulated. These findings formed part of the rationale for Prof. Maryanne Senna (Harvard Medical School, MA, USA) and colleagues to investigate the topical pan-JAK inhibitor delgocitinib as a possible therapy for FFA [1].

The exploratory, randomised phase 2 study (NCT05332366) enrolled 30 women with FFA who were randomised 1:1 to delgocitinib cream 20 mg/g twice daily or a matching vehicle over 12 weeks. The primary endpoint was defined as a change from baseline to week 12 in IFN-γ, CXCL9, and CXCL10 levels. At baseline, the study cohort had a mean age of 64.4 years, their Lichen Planopilaris Activity Index (LPPAI) was 2.79, and FFASS was 12.14.

RNA sequencing and Th1 biomarker assessment detected numerical reductions in IFN-γ and CXCL10, and a statistically significant decrease in CXCL9 (P<0.05). Prof. Senna said that this suggests an attenuation of key inflammatory scalp biomarkers in FFA by delgocitinib cream. “Transcriptomic analysis showed that delgocitinib lesions had a 4% improvement towards non-lesional scalp skin compared with the vehicle-treated patients, who actually had 33% worsening of their transcriptomic profile,” she added. At week 12, the FFASS decrease was significantly superior to the vehicle (P=0.023) and LPPAI showed numerically greater changes on delgocitinib.

In an open-label extension phase until week 24, all participants continued on the study drug. An exploratory analysis found hair regrowth to some extent for all participants on delgocitinib at week 24. An average of 6.9 new hairs was observed in trichoscopy of 1 cm² scalp of the participants treated with delgocitinib at week 12, in contrast to a loss of 11.1 hairs in the vehicle group.

The safety assessment deemed delgocitinib cream in FFA well tolerated with only 1 treatment-related adverse event (i.e. moderate hand dermatitis) in the vehicle group.

“If we could recapitulate this data in larger clinical trials, this could potentially be a promising therapeutic option for this patient population,” Prof. Senna concluded.

1. 
   
   1. Senna MM, et al. Randomized vehicle-controlled clinical trial with the topical JAK inhibitor delgocitinib in patients with frontal fibrosing alopecia demonstrates biomarker and clinical efficacy. D3T01.4F, EADV Congress 2024, 25–28 September, Amsterdam, the Netherlands.
   2. Del Duca E, et al. Br J Dermatol. 2020;183(6):1083-1093.

Copyright ©2024 Medicom Medical Publishers



Posted on 6 November 2024