Leo Pharma (Denmark)

Disease of a subgroup of patients with atopic dermatitis (AD) does not show sufficient improvement with current systemic therapies, highlighting the heterogeneity of the chronic inflammatory skin disease and the need for novel treatments. In this study, we investigated the pathogenic contribution of the IL-22/IL-22 receptor (IL-22RA1) axis to AD skin inflammation in in vitro, ex vivo, and in vivo models to evaluate the therapeutic potential of blocking this axis. IL22RA1 expression in AD skin was assessed by in situ hybridization. Inhibition of the IL-22/IL-22R signaling cascade was evaluated in a human AD in vitro model (3-D skin equivalents) and a phorbol 12-myristate 13-acetate (aka TPA) mouse model using temtokibart, a humanized antibody directed against IL-22RA1. IL22RA1 was highly expressed in the epidermis of lesional AD skin versus nonlesional control skin; expression correlated positively with epidermal thickness and negatively with the barrier integrity marker loricrin. IL-22 stimulation in 3-D skin equivalents induced a specific molecular signature associated with lack of terminal differentiation, altered lipid metabolism, and increased immune response. Inhibition of IL-22RA1 with temtokibart showed significant improvements in skin barrier integrity at the histologic and molecular levels. IL-22RA1 inhibition in a skin inflammation mouse model with Zymo, a surrogate murine anti-IL-22RA1 monoclonal antibody for temtokibart, reduced local expression of Cxcl1 and S100a9. These findings suggest that the IL-22/IL-22RA1 axis functionally contributes to AD pathogenesis. Thus, blocking IL-22RA1 represents a potentially valuable new therapeutic option.

Results Objectives To describe the sociodemographic and clinical characteristics of patients living with CHE in the United States (US). To identify sociodemographic variations within the different CHE severity levels.

Introduction: Clinical trials of up to 52 weeks showed that tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, was efficacious and well-tolerated as monotherapy and combination with TCS. Here, we evaluate the long-term safety of tralokinumab in an integrated analysis of seven phase 3 parent trials (PTs) (NCT03131648, NCT03160885, NCT03363854, NCT03562377, NCT03526861, NCT03761537, NCT04587453), and the ongoing, up to 5-year extension study (ECZTEND; NCT03587805).
 Methods: Two datasets were analyzed: placebo-controlled (initial 16-week period of the PTs), and all-tralokinumab combining PTs with ECZTEND including patients from first dose until end of tralokinumab exposure or data cut-off (April 30th, 2022). In the all-tralokinumab dataset, periods on placebo were disregarded. Treatment-emergent adverse events (AEs) were recorded. AEs of special interest (AESIs) were predefined. Proportions of patients with events and incidence rates (IR) per 100 patient-years of exposure (PYE) were calculated. PYE was defined as time until first event or exposure end, whichever came first, and incidence was defined as first event.
 Results: 2693 patients (≥12 years) received tralokinumab for up to 238.5 weeks (≈4.5 years) with a median exposure time of 76.5 weeks in the all-tralokinumab dataset. Median age at baseline was 33.0 years (min-max; 12-92). 10.4% of patients were 12-17 years. 2307 patients experienced an AE (IR=202.0), most (97.3%) of which were mild-to-moderate. Serious AEs (SAEs) were reported in 226 patients (IR=4.5); SAEs were considered possibly or probably related by the investigator in 50 patients (IR=0.9). No preferred term level SAEs were reported with an IR≥0.1. Discontinuation of treatment due to AEs was low (IR=2.8). AEs leading to drug withdrawal with an IR>0.1 were dermatitis atopic (IR=0.5) and injection site reaction (ISR) (IR=0.2). Frequently reported AEs in the all-tralokinumab dataset were consistent with the placebo-controlled dataset, including nasopharyngitis (IR=18.4), upper respiratory tract infection (IR=6.9), conjunctivitis (IR=5.0), ISR (IR=3.6), conjunctivitis allergic (IR=2.7), and injection site pain (IR=1.5). AESIs, including eye disorders, skin infections requiring systemic treatment, eczema herpeticum, and malignancies, were observed in the all-tralokinumab dataset at rates similar to or lower than the placebo-controlled dataset.
 Conclusion: Long-term use of tralokinumab, for up to 4.5 years, was well-tolerated, and the pattern of AEs was consistent with the initial placebo-controlled treatment period with no new safety signals identified.