Background: This is the first report on the effects of abrocitinib, a Janus kinase 1–selective inhibitor, on the expression of skin biomarkers in patients with moderate‐to‐severe atopic dermatitis (AD).Methods: JADE MOA (NCT03915496) was a double‐blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once‐daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]‐12), epidermal hyperplasia (keratin‐16 [KRT16]), T‐helper 2 (Th2) immune response (C‐C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks.Results: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP‐12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose‐dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26.Conclusions: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate‐to‐severe AD.

Background: RPT193 is an orally administered small molecule antagonist of the human C‐C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T‐helper Type 2 (Th2) cells. We investigated single‐ and multiple‐ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate‐to‐severe atopic dermatitis (AD).Methods: This was a first‐in‐human randomized, placebo‐controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate‐to‐severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects.Results: In healthy (n = 72) and AD subjects (n = 31), once‐daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment‐emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193‐treated versus placebo‐treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures.Conclusions: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.

Background: Atopic dermatitis (AD) is a chronic pruritic inflammatory disease affecting children and adults. Upadacitinib and abrocitinib are selective Janus kinase 1 inhibitors approved for the treatment of moderate-to-severe AD. Although their efficacy and safety are described in phase 3 clinical trials, real-world data are limited. Objectives: We aimed to evaluate the effectiveness and safety of upadacitinib and abrocitinib treatment in a real-life adult population with moderate-to-severe AD throughout an extended observation period. Methods: This retrospective observational study was conducted by analyzing data from the electronic records of IRCCS Humanitas Research Hospital from January 2023 to December 2024. Patients were administered either upadacitinib (15 or 30 mg) or abrocitinib (100 or 200 mg). Effectiveness was evaluated by using clinician-reported scores (Investigator Global Assessment [IGA] and Eczema Area and Severity Index [EASI]) and patient-reported outcomes (peak pruritus numerical rating scale [PP-NRS]) at weeks 8, 16, 32 and 52. Statistical significance was set at a probability value (p-value) < 0.05. Adverse events were also collected. Results: In total, 129 patients were included in the study, and 84 of them reached 52 weeks. At week 52, the EASI 75, 90, and 100 responses were 88.9%, 70.8%, and 54.2% for upadacitinib, and 100%, 91.7%, and 75% for abrocitinib. An IGA score equal to 0 or 1 at 52 weeks was achieved by 84.7% of patients treated with upadacitinib and 100% of those receiving abrocitinib. A four-point reduction from baseline PP-NRS was reported by 86.1% for upadacitinib and by 83.3% of patients for abrocitinib after one year of follow-up. Conclusions: Our study showed comparable or even higher effectiveness outcomes in terms of EASI 75, EASI 90, and EASI 100 at week 52 compared to phase-3 clinical trials, with no new safety concerns, supporting the real-world effectiveness of abrocitinib and upadacitinib in moderate-to-severe AD.

The efficacy of ritlecitinib, an oral JAK3/TEC family kinase inhibitor, on active and stable lesions was evaluated in patients with active non-segmental vitiligo in a phase 2b trial (NCT03715829). Patients were randomized to placebo or daily ritlecitinib 50 mg (with or without 4-week 100-mg or 200-mg loading dose), 30 mg, or 10 mg for 24 weeks. Active lesions showed greater baseline expression of inflammatory/immune markers IFNG and CCL5, levels of CD103, and T-cell infiltrates than stable lesions. Patients with more active than stable vitiligo lesions showed higher baseline serum levels of CXCL9 and PD-L1, while patients with more stable than active lesions showed higher baseline serum levels of HO-1. At Week 24, ritlecitinib 50 mg significantly stabilized mean percent change from baseline in depigmentation extent in both active lesions and stable lesions vs. placebo-response, with stable lesions showing greater repigmentation. After 24 weeks of treatment, ritlecitinib 50 mg increased expression of melanocyte markers in stable lesions, while Th1/Th2-related and co-stimulatory molecules decreased significantly in both stable and active lesions. Serum from patients with more active than stable lesions showed decreased levels of ICOS and NK cell activation markers. These data, confirmed at transcription/protein levels, indicate that stable lesion repigmentation occurs early with ritlecitinib, while active lesions require stabilization of inflammation first. ClinicalTrials.gov: NCT03715829.