Probity Medical Research

Efficacious and well-tolerated systemic, oral treatments for psoriasis are needed. We report preclinical and phase 1c (NCT06808815) results for DC-806, a small molecule interleukin (IL)-17 inhibitor, for the treatment of mild-to-moderate psoriasis. Preclinical results demonstrated DC-806 targets IL-17AA and IL-17AF with secukinumab-like therapeutic efficacy. In the phase 1c trial, 32 patients consented to receive twice daily (BID) doses of placebo or DC-806 (200 mg or 800 mg) for 28 days. No serious adverse events (SAEs) or discontinuations due to treatment-related adverse events (TRAEs) occurred. In an exploratory analysis, adjusted mean percentage reductions from baseline in psoriasis area and severity indices (PASI) at Day 29 were 43.7%, 15.1%, and 13.3% for 800 mg BID, 200 mg BID, and placebo arms, respectively (800 mg BID vs placebo, P value = 0.0008). DC-806 was found to be well tolerated with an acceptable safety profile and preliminary signals of clinical efficacy in mild-to-moderate psoriasis. EudraCT Identifier: 2021-002888-21.

Patients with moderate-to-severe atopic dermatitis (AD) who discontinue dupilumab need additional therapeutic options. Lebrikizumab's distinct mechanism of action may provide that alternative treatment. We evaluated efficacy and safety of lebrikizumab in adults and adolescents with moderate-to-severe AD previously treated with dupilumab. In the open-label ADapt trial, patients who discontinued dupilumab due to inadequate response, adverse events (AEs)/intolerance, or other reasons received lebrikizumab 250-mg every 2weeks (Q2W) following 500-mg loading dose at baseline/week2, through week16, with optional topical therapy. From weeks16-24, responders (≥ 75% improvement in Eczema Area and Severity Index [EASI75] or Investigator's Global Assessment score 0/1 with ≥ 2-point improvement from baseline) received lebrikizumab every 4weeks; inadequate responders continued lebrikizumab Q2W. The primary endpoint was EASI75 at week16 in the intent-to-treat population; EASI75 was also analyzed by reason for dupilumab discontinuation. Secondary and exploratory efficacy endpoints were assessed throughout. Among the 86 patients enrolled, primary reasons for stopping dupilumab were inadequate response (n = 48, 55.8%), AEs/intolerance (n = 14, 16.3%), and other reasons (n = 24, 27.9%). Fifty-nine patients (68.6%) completed week16; 52 patients (60.5%) completed week24. At weeks16 and 24, respectively, response rates were 57.4% (35/61) and 60.0% (33/55) for EASI75; 53.2% (25/47) and 61.5% (24/39) for Pruritus Numeric Rating Scale ≥ 4-point improvement; and 83.0% (44/53) and 83.0% (39/47) for Dermatology Life Quality Index ≥ 4-point improvement. Most treatment-emergent AEs were mild/moderate. Serious AEs and discontinuations due to AEs were reported by 2 (2.3%) and 5 (5.8%) patients, respectively. Of the 10 patients who discontinued dupilumab due to eye-related events, facial dermatitis, or inflammatory arthritis, none reported similar events with lebrikizumab. Results suggest that lebrikizumab provides meaningful improvements in skin clearance, itch, and quality of life in dupilumab-experienced patients with moderate-to-severe AD, with a safety profile consistent with other lebrikizumab phase3 trials. ClinicalTrials.gov identifier, NCT05369403.

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by intense itching, redness, and eczema. It significantly impacts the quality of life of affected individuals, often requiring long-term management strategies. Abrocitinib, an oral Janus kinase 1 (JAK1) inhibitor, is approved for the treatment of moderate-to-severe AD. Phase 2 and phase 3 abrocitinib randomized clinical trials in the JAK1 Atopic Dermatitis Efficacy and Safety (JADE) clinical development program have demonstrated the efficacy and safety of abrocitinib in both adults and adolescents with moderate-to-severe AD. This review article explores the benefit-risk profile of a flexible abrocitinib dosing approach, tailoring dose based on individualized treatment of patients and highlighting the available supportive data from the JADE randomized clinical trials for healthcare professionals as part of joint provider-patient decisionmaking. Dosing flexibility and maintenance with the lowest effective dose is necessary to treat patients according to their individual disease course while minimizing safety risks. Safety data indicate that incidence of treatment-emergent adverse events is reflective of the current dosage, with no carry-over risk from a previous higher dosage. Overall, abrocitinib represents a valuable AD therapy that can be administered according to individual patient needs.Graphical abstract available for this article.

Introduction: Abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is approved in patients aged ≥12 years at the recommended doses of 100 mg and 200 mg for the treatment of moderate-to-severe atopic dermatitis (AD). JADE REAL (NCT04564755) was a global, open-label expanded access protocol initiated in 2020 (completed September 2024) to provide access to abrocitinib for patients with moderate-to-severe AD. This analysis evaluated dosing patterns and incidence of treatment-emergent adverse events (TEAEs) leading to a change in dose of abrocitinib inpatients with moderate-to-severe AD in an expanded access protocol simulating real-world use of abrocitinib. Procedure/Study: Eligible patients aged ≥12 years with moderate-to-severe AD initiated once-daily abrocitinib 100 mg or 200 mg (plus topical medication as needed). The dose could be changed throughout the treatment period. Initial dosing and the proportion of patients with continuous dosing, ≥1 dose change and >1 dose change were assessed. Safety was assessed via TEAE monitoring. Results: Of 312 patients, 120 (38.5%) and 192 (61.5%) patients initiated abrocitinib 100 mg and 200 mg, respectively (mean [SD] treatment duration: 379.1 days [203.3]). More patients of ages ≥12–18 and ≥65 years, Black/African American race, and with moderate AD initiated abrocitinib 100 mg, while more patients of ages ≥18–<65 years, Asian race, and with severe AD initiated abrocitinib 200 mg. Of patients who initiated abrocitinib 100 mg and 200 mg, 78 (65.0%) and 119 (62.0%) received continuous dosing, and 42 (35.0%) and 73 (38.0%) patients had ≥1 dose change, including 12 (28.6%) and 33 (45.2%) patients with >1 dose change, respectively. TEAEs led to dose reduction in 27 patients (8.7%), notably nausea (n=4 [1.3%]), thrombocytopenia (n=4 [1.3%]), acne (n=3 [1.0%]), fatigue (n=3 [1.0%]), and folliculitis (n=3 [1.0%]). TEAEs led to a dose escalation in 12 patients (3.8%); AD was the only TEAE that occurred in ≥1% of patients (n=10 [3.2%]) which led to a dose escalation. Conclusion: Most patients received consistent abrocitinib dosing throughout the study. TEAEs were not the primary reason leading to dosage reduction. These results may support clinical decision making around initial dose selection and dosage changes. JADE REAL demonstrated the potential benefits of flexible dosing and may simulate the real-world use of oral Janus kinase inhibitors. Funding/Disclosures: This study was funded by Pfizer.

Ixekizumab (IXE), an IL-17A antagonist, and guselkumab (GUS), an IL-23p19 antagonist, are common psoriasis treatments. This longitudinal analysis assessed gene expression profiles in IXE- and GUS-treated patients with plaque psoriasis through week 4. In IXORA-R (NCT03573323), a head-to-head phase 4 study, adults with moderate-to-severe plaque psoriasis were assigned 1:1 to receive IXE or GUS. RNA expression was assessed in lesional tissue (n=72) from IXE-treated patients, GUS-treated patients, and healthy control groups (199 samples in total). Empirical Bayes was used to model RNA-sequencing data; differential expression was analyzed by tissue type, treatment, and time point, correcting for random effects. At week 1, lesions from IXE-treated patients had greater numbers of differentially expressed genes (392 upregulated, 696 downregulated) than those from GUS-treated patients (0 upregulated 0 downregulated). By week 4, the numbers of differentially expressed genes increased in both groups (IXE: 1882 upregulated, 1649 downregulated; GUS: 318 upregulated, 131 downregulated). Molecular shifts from baseline to week 4 occurred earlier with greater magnitude in IXE- than in GUS-treated patients. Rapid normalization of transcriptomic changes in patients receiving an IL-17A antagonist reflected downregulation of key inflammatory genes in psoriatic epidermis. Differentially expressed genes involved in epidermal IL-17A and IL-36 responses correlated with PASI 100 response.