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Introduction/Background Targeting and binding OX40 ligand (OX40L) expressed on antigen-presenting cells may inhibit the persistent immune response that drives atopic dermatitis (AD) pathophysiology. Amlitelimab (SAR445229; KY1005) is a potential first-in-class, fully human, non-depleting anti-OX40L monoclonal antibody that blocks OX40L-OX40 interactions and has shown efficacy and an acceptable safety profile in a Phase 2a trial in adults with moderate-to-severe AD. Here, we present 24-week efficacy and safety results (Part 1) from an ongoing dose-ranging Phase 2b trial. The study remains blinded to individual patient data (Part 2 ongoing). Objectives: To evaluate the efficacy and safety of amlitelimab in adults with moderate-to-severe AD. Methods: STREAM-AD (NCT05131477) is a 52-week, randomised, double-blinded, placebo-controlled Phase 2b monotherapy trial. This study is designed with 2 parts (double-blind throughout): a 24-week treatment period (Part 1, completed and presented here) and a 36-week maintenance/withdrawal period (Part 2, ongoing). Adults (18 to <75 years; n=390) with moderate-to-severe AD were randomised 1:1:1:1:1 to receive subcutaneous amlitelimab Q4W (250 mg with 500 mg loading dose [LD], n=77; 250 mg without LD, n=78; 125 mg without LD, n=77; or 62.5 mg without LD, n=79) or placebo Q4W (n=79). The primary endpoint was percentage change in Eczema Area and Severity Index (EASI) from baseline at Week 16. Key secondary endpoints included percentage change in EASI at Week 24 and percentage of patients with at least 75% reduction from baseline in EASI (EASI-75), percentage of patients with Investigator Global Assessment response of 0 (clear) or 1 (almost clear) and a reduction from baseline of ≥2 points (IGA 0/1), and proportion of patients with a weekly average reduction of Peak Pruritus Numerical Rating Scale (PP-NRS) ≥4 points from baseline. The primary efficacy analysis included all randomised patients who completed Week 24 or discontinued treatment or study prior to Week 24 visit (n=390), whereas the safety analysis included all treated patients (n=388). Results: Treatment with amlitelimab resulted in statistically significant improvements in percentage change in EASI from baseline to Week 16 compared to placebo for all four doses studied. The 250 mg with LD group had the numerically highest response versus placebo at Week 16, with a least-squares mean change from baseline of -32.1% (95% CI: -43.9, -20.3; P<0.0001); the remaining groups without LD had the following responses versus placebo: 250 mg, -27.3 (95% CI: -39.1, -15.6; P<0.0001); 125 mg, -22.2 (95% CI: -34.0, -10.4; P=0.0002); and 62.5 mg, -30.2 (95% CI: -41.9, -18.5; P<0.0001). There were also clinically meaningful improvements in all key secondary efficacy outcome measures, with all amlitelimab dose groups demonstrating nominally significant (P<0.05) efficacy versus placebo for EASI-75, IGA 0/1, and PP-NRS =4, except 250 mg (no LD) in IGA 0/1 at Week 16 (P=0.0562). Continued improvements were generally observed through Week 24 in primary and key secondary efficacy outcomes. Amlitelimab was well tolerated across all dose groups, with no safety concerns identified. Conclusions: In this dose-ranging Phase 2b trial of amlitelimab in adults with moderate-to-severe AD, amlitelimab demonstrated clinically meaningful efficacy over 24 weeks with an acceptable safety profile across all four dose groups. [ABSTRACT FROM AUTHOR]

Background Amlitelimab is a fully-human, non-depleting, anti-OX40 ligand (OX40L) monoclonal antibody that binds to OX40L on antigen-presenting cells. Amlitelimab blocks the interaction of OX40L with OX40 on activated T-cells, inhibiting T-cell dependent inflammation without depleting T-cells. Objective To evaluate the efficacy and safety of amlitelimab (Part 1), and explore the maintenance of clinical response over a 28-Week period (Part 2) in patients with moderate-to-severe AD. Methods STREAM-AD (NCT05131477), was a randomized, double-blind, placebo-controlled Phase 2b trial, that included a 24-Week, double-blind, treatment period (Part 1), a 28-Week maintenance/withdrawal period (Part 2), and a 16-Week safety follow-up. In Part 1, adult participants were randomized 1:1:1:1:1 to subcutaneous amlitelimab Q4W (250mg with 500mg loading dose [+ LD], n=77; 250mg, n=78; 125mg, n=77; 62.5mg, n=79) or placebo Q4W (n=79). In Part 2, Clinical responders (defined as those achieving EASI-75 and/or IGA 0/1 at Week-24) in Part 1, were rerandomized 3:1 to withdraw or continue pre-Week 24 Q4W dose (250mg + LD, n=34 [withdrawal]/n=13 [continuing]; 250mg, n=28/n=12; 125mg, n=33/n=12; 62.5mg, n=35/n=7; placebo responders continuing placebo, n=16), and were followed to Week-52 to evaluate maintenance of clinical response. Primary efficacy endpoint was percent change in EASI from baseline at Week-16. Key secondary endpoints were proportion of patients achieving IGA 0/1, EASI-75, PP-RNS≥4. The statistical analysis was performed using two methods: 1) imputing the endpoint as nonresponder after rescue medication use (NRI); and 2) including all measurements regardless of rescue use (treatment policy). Results Out of 390 participants enrolled in Part 1, 190 entered Part 2. In Part 1, all four doses of amlitelimab demonstrated statistically significant improvements in percent change in EASI from baseline to Week-16 vs placebo; the highest response was seen with 250mg + LD group. Clinically meaningful improvements in key secondary endpoints were observed at Week-16, with continued improvements through Week-24. In Part 2, maintenance of EASI-75 and/or IGA 0/1 response at Week-52 was observed in 59%, 63%, 55%, and 66% of clinical responders withdrawn from 250mg + LD, 250mg, 125mg, and 62.5mg, respectively (NRI). Using treatment policy, 77%, 82%, 67%, and 74% maintained response off-drug, respectively. Those continuing amlitelimab treatment had numerically higher maintenance response rates. AD-related biomarkers were reduced during Part 1 and remained decreased over Part 2. Amlitelimab was well tolerated across all dose groups, with no new safety concerns identified during the 52-Weeks. Conclusion Clinically meaningful efficacy with amlitelimab was demonstrated over 52-Weeks, with an acceptable safety profile. Clinical responses were maintained in most patients 28-Weeks after treatment discontinuation. [ABSTRACT FROM AUTHOR]

Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting 2–7% of adults globally, with 30% experiencing moderate-to-severe disease. Although several treatments for moderate-to-severe AD are available, the efficacy of many treatments has not been compared in head-to-head trials. Objectives Using a network meta-analysis (NMA), we evaluated the relative efficacy between lebrikizumab, an emerging biologic, and approved targeted systemic treatments for AD. Methods Double-blind, randomized, placebo-controlled clinical trials (systemic monotherapy-only) for moderate-to-severe AD in adults (≥18 years) and adolescents (≥12 years to ≤18 years) published before April 2023 were identified in a systematic literature review. Data were extracted for short-term (12–16 weeks) efficacy outcomes (Investigator's Global Assessment [IGA] 0/1 with ≥2-point improvement from baseline and the Eczema Area and Severity Index [EASI]) and patient-reported outcomes (Pruritus Numeric Rating Scale [NRS] with ≥4-point improvement from baseline). Bayesian NMAs were performed using random-effects models, with baseline-risk adjustment. Key estimates from the NMAs included pairwise differences between all treatments and absolute response rates for each treatment. Results Twenty-two clinical trials were included. For % achieving IGA 0/1, at 12–16 weeks, the estimated response rates (posterior median and 95% credible interval) for each of the treatments were: upadacitinib 30 mg 55.8% (43.7–64.2%), upadacitinib 15 mg 41.3% (30.1–50.0%), abrocitinib 200 mg 39.0% (29.8–47.8%), dupilumab 300 mg 31.8% (23.1–38.7%), lebrikizumab 250 mg 31.4% (24.1–39.2%), abrocitinib 100 mg 24.5% (17.5–32.0%), tralokinumab 300 mg 17.3% (12.8–22.2%), baricitinib 4 mg 16.7% (9.8–25.5%), baricitinib 2 mg 15.5% (9.6–22.0%), and placebo 6.0% (4.3–7.3%). Similar trends were observed for the EASI and pruritus NRS responses at 12–16 weeks. Conclusions This 16-week NMA shows that lebrikizumab had a similar response rate to dupilumab, the most widely used targeted systemic therapy for AD, and may represent a valuable treatment option for moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Introduction Atopic dermatitis (AD) is a common, chronic inflammatory disease requiring long-term, continuous therapy, yet in real life, patients may need to temporarily interrupt therapy. Objectives To indirectly compare long-term outcomes with lebrikizumab, tralokinumab, and dupilumab, we present an exploratory efficacy index, which accounts for on-drug and off-drug combined outcomes at Week 52. Methods The data set consisted of patients who, after 16 weeks, responded to treatment, defined as achieving either an IGA 0,1 or EASI 75 score, and who were randomized to receive maintenance dosages of lebrikizumab 250 mg Q4W (ADvocate1; ADvocate2), tralokinumab 300 mg Q2W (ECZTRA1; ECZTRA 2), and dupilumab 300 mg QW, Q2W (SOLO-CONTINUE) or were randomized to withdraw these treatments up to Week 52. The efficacy index is based on a weighted combination of response rates at Week 52, using non-responder imputation results, for IGA 0,1 or EASI 75, for patients who were either in the treatment continuation or the withdrawal arm. Here, we report the efficacy index, in which the weight places equal emphasis on continuing or stopping treatment, and we compare the efficacy index of tralokinumab and dupilumab with lebrikizumab. Results The efficacy index (95% CI) for lebrikizumab, tralokinumab, and dupilumab, respectively, was 53% (45%-61%), 45% (37%-53%), and 34% (28%-40%) with IGA 0,1; 63% (55%-71%), 42% (35%-49%), and 51% (45%-57%) with EASI 75. With IGA 0,1, lebrikizumab was statistically different from dupilumab; with EASI 75, lebrikizumab was statistically different from dupilumab and tralokinumab. Conclusions This novel efficacy index, which accounts for the importance of continuing or stopping therapy after Week 16, may be a useful tool to indirectly compare long-term treatment outcomes. Lebrikizumab's higher efficacy index may translate to improved long-term management of AD. [ABSTRACT FROM AUTHOR]