Bexley Hall

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.

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.

This study aimed to describe treatment patterns, frequency of comorbidities, and healthcare cost burden among patients with atopic dermatitis (AD) initiating systemic therapy (or re-initiating it after more than 12 months) versus matched controls without AD. Patients with AD initiating oral corticosteroids (OCS), immunosuppressants (SIS), or biologics between 1/1/2017 and 6/30/2022 (index=first treatment) were identified for analysis in the MarketScan claims databases. Patients were continuously enrolled 12 months before (baseline) and after index (follow-up). Direct and propensity score matching were used to adjust for baseline differences between cases and controls. Comorbidities and all-cause healthcare costs within service categories were compared between AD cases and matched controls during follow-up and treatment patterns were described for all patients with AD. A total of 20,503 patients with AD were identified. On index,12% initiated biologics, 86% OCS, and 2% SIS, and discontinuation rates were high during follow-up (SIS: 80%; biologics: 35%) The incidence of several comorbidities, including cardiovascular disease, atopic conditions, and mental health disorders, was higher in the AD cohort compared with matched controls (p<0.001). Patients with AD (vs. matched controls) also had significantly higher mean total all-cause healthcare costs (US$15,134 vs. $6832; p<0.001). Patients with AD who are initiating systemic treatment experience an increased risk of being newly diagnosed with several comorbidities and higher healthcare costs compared with matched controls, which places increased burden on patients and healthcare systems.

Abstract Introduction Obstructive (OSA) and central sleep apnea (CSA) are associated with higher prevalence of atrial fibrillation and other arrhythmias. Arrhythmia detection is possible with in-lab polysomnography (PSG) but not with home sleep apnea tests (HSAT) that typically lack the electrocardiogram (ECG). SANSA (Huxley Medical, Inc.) is a chest-worn monitor with HSAT and Holter ECG capabilities to simultaneously detect OSA, CSA, and arrhythmias at home. This study used this monitor to characterize nocturnal arrhythmias in patients with OSA and CSA. Methods Data was analyzed from 151 subjects with suspected sleep disordered breathing who wore the chest monitor for a single night. The apnea-hypopnea index (AHI) and central AHI (cAHI) were calculated with the monitor’s automated algorithm using a 3% oxygen desaturation threshold. A cardiac technician reviewed ECG recordings to identify presence of clinically significant arrhythmias including multi-focal or high burden premature ventricular complexes (PVCs), atrial or ventricular bi/tri/quadrigeminy, ventricular tachycardia, atrial fibrillation, second- or third-degree atrioventricular block, and sinus pauses. Results At least one clinically significant arrhythmia was observed in 32% (48/151) of all subjects, 26% (9/35) of those with AHI&amp;lt; 5, 34% (39/116) of those with AHI≥5, and 79% (11/14) of those with cAHI≥5. Significant arrhythmias of supraventricular origin were observed in 9% of subjects with AHI≥5 and 36% with cAHI≥5 but were not observed in subjects with AHI&amp;lt; 5. Atrial fibrillation was observed in three subjects overall, all with AHI≥5 and one with cAHI≥5. Ventricular arrhythmias were observed in most subjects with significant arrhythmias. Medical histories demonstrated that only 21% of all detected arrhythmias had been previously diagnosed. Conclusion Patients with OSA and CSA experienced more nocturnal cardiac arrhythmias than those without. This work motivates additional investigation in larger populations to understand how simultaneous detection of sleep-disordered breathing and arrhythmias in the home environment could impact diagnosis, risk stratification, and outcomes. Support (if any) National Science Foundation; Georgia Research Alliance; Huxley Medical, Inc.

Much progress has been made in understanding how the brain combines signals from the two eyes. However, most of this work has involved achromatic (black and white) stimuli, and it is not clear if the same processes apply in color-sensitive pathways. In our first experiment, we measured contrast discrimination (“dipper”) functions for four key ocular configurations (monocular, binocular, half-binocular, and dichoptic), for achromatic, isoluminant L-M and isoluminant S-(L+M) sine-wave grating stimuli (L: long-, M: medium-, S: short-wavelength). We find a similar pattern of results across stimuli, implying equivalently strong interocular suppression within each pathway. Our second experiment measured dichoptic masking within and between pathways using the method of constant stimuli. Masking was strongest within-pathway and weakest between S-(L+M) and achromatic mechanisms. Finally, we repeated the dipper experiment using temporal luminance modulations, which produced slightly weaker interocular suppression than for spatially modulated stimuli. We interpret our results in the context of a contemporary two-stage model of binocular contrast gain control, implemented here using a hierarchical Bayesian framework. Posterior distributions of the weight of interocular suppression overlapped with a value of 1 for all dipper data sets, and the model captured well the pattern of thresholds from all three experiments.

Abstract Introduction Historically, atopic dermatitis (AD) was believed to affect primarily children. However, a recent meta-analysis of 17 studies reporting age of AD onset as &amp;gt;16 years found that the pooled proportion of adult-onset AD was 26.1%, and that AD onset can occur at all ages. Lebrikizumab (LEB) is a high-affinity monoclonal antibody which targets IL-13, the key cytokine implicated in AD. Objectives This analysis investigated the efficacy and safety of lebrikizumab in adults ≥60 years with moderate-to-severe AD. Methods Data for patients aged ≥60 years from two Phase 3 trials, ADvocate1 and ADvocate2, were pooled. A total of 98 patients ≥ 60 years participated in the ADvocate trials (N=28 placebo (PBO), N=70 LEB). Patients were treated with lebrikizumab 250mg every 2 weeks or PBO, for 16 Weeks. Baseline demographics and characteristics were recorded. Efficacy was assessed in the pooled modified intent to treat population at Week 16 with Investigator’s Global Assessment (IGA) (0,1) with ≥2-point improvement, ≥75% improvement in Eczema Area and Severity Index (EASI 75), EASI percentage change from baseline (CFB), and Pruritus Numeric Rating Scale (NRS) ≥4-point improvement. Categorical outcomes were evaluated by Cochran Mantel Haenszel tests to compare treatment groups. Continuous outcomes were analyzed using the analysis of covariance model. Data collected after use of rescue medication or discontinuation due to lack of efficacy were imputed with non-responder imputation (NRI) for categorical endpoints, or baseline values for continuous endpoints. Data collected after discontinuation for other reasons were set to missing and missing data were imputed with multiple imputation. Safety was also assessed in the integrated modified safety population. Results The baseline mean age was 67.2 years (standard deviation [SD] 6.7, range 60-93) in LEB- treated patients and 69 years ([6.2], range 60-85) in PBO. The LEB-treated population was 62.9% male (n=44/70) vs PBO 46.4% (n=13/28). Race was comparable between groups. At baseline 67.1% LEB (n=47/70) and 57.1% PBO (n=16/28) patients had IGA 3, while 32.9% LEB (n=23/70) and 42.9% PBO (n=12/28) had IGA 4. Other baseline characteristics were comparable: EASI: LEB 26.1, [10.6] vs PBO 27.1, [8.1]; BSA: LEB 38.3, [19.8] vs. PBO 40.9, [18.1]; and Pruritus NRS: LEB 7.5, [2.0] vs PBO 7.4, [1.7]. At Week 16, IGA (0,1) was achieved by 34.5% LEB-treated patients vs 11% PBO (P=0.022). EASI 75 was achieved by 48.9% and 16.3% of LEB- and PBO-treated patients, respectively (P=0.004). Pruritus NRS with ≥4-point improvement was reported by 45.5% and 12.2% of LEB vs PBO, respectively (P=0.004). The mean percent CFB EASI was LEB -58.5% (SE 8.5) and PBO -29.4% (SE 11.1) (P=0.002). Safety results in the older adult population were consistent with the overall modified safety population. Conclusions At Week 16, efficacy and patient reported outcome endpoints were met in the older adult population. These results indicate that lebrikizumab is an effective treatment for moderate-to-severe AD in the adult population ≥60 years of age and has a consistent safety profile.

ABSTRACT This paper represents the first study to focus on quantifying racial/ethnic group differences in older adults’ involvement with adult protective services (APS). Across 3 independent county programs, the rate of APS reports was about twice as high for Black older adults compared to White older adults. These differences were greater for clients who were older and male but remained similar across allegation type. The percent of reports validated was slightly but consistently lower for Black clients than for White clients, and a lower percentage of Black clients’ cases were closed due to investigation or service refusal. Findings for Hispanic clients differed by county, so it was impossible to generalize about their APS experience. Researchers should distinguish racial/ethnic group differences that persist across multiple programs from those that are program-specific. Further studies with larger data sets are needed to guide APS practice and ensure equity for all clients served.

The control of the inflammatory response induced by the implantation of foreign biomaterials is fundamental in determining tissue healing. It has been shown that the activation of specific macrophage pathways upon contact with a biomaterial can lead either to a chronic inflammation preventing a physiological tissue repair or to an improved tissue healing. In the case of bone repair, calcium phosphate cements with good osteoconductivity properties have been successfully applied in bone defect filling and repair, but poor handling properties, insufficient viscous flow and unmatched degradation rate are still problems that remain unsolved. In this study, a strontium-doped hydroxyapatite (HA) gel was modified by integrating branched poly(epsilon-lysine) dendrons with third-generation branches exposing phosphoserine (SrHA/G3-K PS). The interaction of this material with macrophages was investigated in vitro, focusing on the secretion and gene expression of specific pro-inflammatory cytokines. Our results showed that the addition of strontium and G3-K PS to HA sol-gel could down-regulate the gene expression of inflammatory factors such as IL-1β, TNF-α and MCP-1, while increasing the gene expression of IL-6, a cytokine known for its osteogenic effect. These results were further confirmed by ELISA test of the respective protein concentrations. When exposed to supernatants of macrophage culture in the presence of strontium and G3-K PS, osteoblast viability was promoted with elevated osteogenic gene markers, in terms of OPG, ALP, OCN and COL-I. In vivo implantation experiments using an osteoporotic rat model with bone defect further confirmed that the addition of G3-K PS to HA could dramatically promote new bone regeneration. Although the introduction of strontium improved the degradation properties of the injectable materials, no positive effect on promoting in vivo bone regeneration was observed.