Search

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]

Background Given the chronic nature of psoriasis and the loss of response that can be observed with therapies over time, it is important to understand the long-term efficacy of new treatments. Objectives To evaluate maintenance of Week 16 responses with bimekizumab (BKZ) treatment through Year 3, in patients with moderate-to-severe plaque psoriasis. Methods Data were pooled from BKZ-treated patients in the 52-week (BE VIVID) and 56-week (BE READY and BE SURE) phase III studies, and their ongoing open-label extension (OLE), BE BRIGHT. Efficacy outcomes are reported through 3 years of BKZ treatment in patients with an efficacy response at Week 16. Missing data were imputed primarily using modified nonresponder imputation (mNRI), with nonresponder imputation and observed case data also reported. Results A total of 989 patients were randomized to BKZ at baseline in BE VIVID, BE READY and BE SURE. At Week 16, 693 patients achieved ≥ 90% reduction from baseline in Psoriasis Area and Severity Index (PASI 90), 503 achieved 100% reduction from baseline in PASI (PASI 100), 694 achieved absolute PASI ≤ 2 and 597 achieved body surface area (BSA) ≤ 1%, and continued into the OLE. Of these, 93.0% maintained PASI 90, 80.8% maintained PASI 100, 94.0% maintained PASI ≤ 2 and 90.3% maintained BSA ≤ 1% responses through to 3 years of BKZ treatment (mNRI). Among Week 16 PASI 90 responders, 96.8% and 72.5% also achieved Investigator's Global Assessment 0/1 and PASI 100 at Week 16, respectively, and 92.2% and 73.4% achieved these responses at Year 3 (mNRI). Among Week 16 PASI 100 responders, 76.3% also achieved Dermatology Life Quality Index (DLQI) 0/1 at Week 16, and DLQI 0/1 response increased with continuous BKZ treatment to 89.0% at Year 3 (mNRI). Conclusions High levels of clinical response were maintained through to 3 years of BKZ treatment in the vast majority of Week 16 responders. Long-term treatment with BKZ was efficacious, with important benefits for health-related quality of life, in patients with moderate-to-severe plaque psoriasis. [ABSTRACT FROM AUTHOR]

This descriptive analysis examines malignancy events reported among guselkumab-treated patients with prior malignancy (excluding NMSC) during VOYAGE 1 and VOYAGE 2 (NCT02207231; NCT02207244). More patients across a broader range of time following cancer remission and longer duration of follow-up are needed to better characterize the safety of guselkumab in patients with prior malignancy. Https://doi.org/10.1093/bjd/ljad081 Dear Editor, The pivotal 5-year VOYAGE 1 and 2 studies of guselkumab in moderate-to-severe psoriasis[1],[2] are among the first studies of biologics to include patients with a history of malignancy, including treated nonmelanoma skin cancer (NMSC) or cervical cancer I in situ i (without evidence of recurrence for >= 3 months) or other malignancy > 5 years before enrolment. [Extracted from the article]

Sleep disturbance is considered one of the most prevalent symptoms of atopic dermatitis (AD), and is associated with daytime sleepiness, anxiety and depression. In previous phase 3 trials, dupilumab treatment demonstrated signif - icant improvement in objective AD signs and severity of symptoms, including sleep disturbance and mental health symptoms. To investigate the effect of dupilumab for up to 24 weeks on sleep quality, daytime sleepiness, anxiety and depression, using data from the DUPISTAD (NCT04033367) study. The randomized, phase 4 DUPISTAD study, was divided into two 12-week periods: an initial double-blind pla - cebo-controlled period, and a subsequent 12-week open-la - bel extension (OLE) period. The 24-week study enrolled adult patients with moderate-to-severe AD (Eczema Area and Severity Index score ≥12, Peak Pruritus Numeric Rating Scale [NRS] score ≥3, Sleep Disturbance NRS average score ≥5) who showed an inadequate response to topical treat - ments. These patients were randomized 2 :1 to dupilumab 300 mg every 2 weeks (q2w) for both the double-blind and OLE periods or placebo for the initial double-blind period, followed by dupilumab 300 mg q2w for the OLE period. The use of concomitant topical corticosteroids was permitted as needed by both groups throughout the study. Endpoints included mean change from baseline to week 24 for Patient-Reported Outcome Measures Information System (PROMIS) Sleep T-score (standardized score ranging from 30 [best] to 80 [worst], with a mean of 50), Epworth Sleepiness Scale (ESS; scored 0–24; higher values indicate increased daytime sleepiness), and Hospital Anxiety and Depression Scale (HADS; scored 0–21; higher values indicate a worse outcome). Throughout the study, patients also completed a Sleep Diary, recording the NRS of restfulness upon waking up (scored 0–10; lower values indicate a worse outcome). Statistical comparisons were not performed on the data collected during the OLE observation period. A total of 188 patients were enrolled in the study: 127 received continuous dupilumab (dupilumab–dupilumab group) and 61 received placebo to week 12 and then dupilumab to week 24 (placebo–dupilumab group). Baseline demographics and disease characteristics were well balanced. Improvement from baseline in sleep quality, daytime sleepiness, anxiety and depression was observed at week 24 in both groups, as illustrated by the mean change from baseline in PROMIS Sleep T-scores (−12.5 in the dupilumab–dupilumab group and −11.7 in the placebo–dupilumab group), ESS scores (−4.6 in the dupilumab–dupilumab group and −3.7 in the placebo–dupilumab group), HADS anxiety scores (−3.8 in the dupilumab– dupilumab group and −4.4 in the placebo–dupilumab group), HADS depression scores (−4.4 in the dupilumab–dupilumab group and −3.4 in the placebo–dupilumab group), and the NRS of restfulness upon a waking-up item of the Sleep Diary (+3.3 in the dupilumab–dupilumab group and +3.4 in the placebo–dupilumab group). The improvement achieved by the placebo–dupilumab group converged with that of the dupilumab–dupilumab group during the OLE period, as shown by the mean change from week 12 to week 24 in PROMIS Sleep T-score (−3.8), ESS score (−1.9), HADS anxiety score (−1.6), HADS depression score (−0.9) and NRS of restfulness upon a waking-up item of the Sleep Diary (+1.5). The safety profile of dupilumab was consistent with the known safety profile. Dupilumab provided sustained improvement through 24 weeks in patient-reported measures of sleep, daytime sleepiness, anxiety, and depression in adult patients with moderate-to-severe AD. Patients who were switched from placebo to dupilumab at week 12 showed rapid improvement in these parameters after the switch, eventually matching the improvement achieved by patients who received dupilumab from baseline through week 24. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic disease characterized by sleep disturbance, associated with night-time itching and scratching, along with skin pain, resulting in daytime drowsiness, diminished daytime productivity and overall reduced quality of life (QoL) in patients with AD. To report the effect of up to 24 weeks of dupilumab treatment on the QoL of adult patients with moderate-to-severe AD, using data from the DUPISTAD (NCT04033367) study. Phase 4, a randomized DUPISTAD study, comprised two 12-week periods: an initial placebo-controlled double-blind period, and a subsequent 12-week open-label extension (OLE) period. Adult patients with moderate-to-severe AD (Eczema Area and Severity Index score ≥12, Peak Pruritus Numeric Rating Scale [NRS] score ≥3, Sleep Disturbance NRS average score ≥5), showing an inadequate response to topical treatments, were randomized 2:1 to dupilumab 300 mg every 2 weeks (q2w) for both the double-blind and OLE periods or placebo for the initial double-blind period, followed by dupilumab 300 mg q2w for the OLE period. The use of concomitant topical corticosteroids was permitted during the entire course of the study. Endpoints, including Patient-Oriented Eczema Measure (POEM; scored 0–28, with higher values indicating a worse outcome), Dermatology Life Quality Index (DLQI; scored 0–30, with higher values indicating a poorer QoL), Skin Pain and Sensitivity NRS (scored 0–10, where 0=no pain/normal sensitivity and 10=worst possible pain/ extremely sensitive) were assessed from baseline to week 24. The enrolled patients also completed a Work Productivity and Activity Impairment Questionnaire (WPAI-AD), including an NRS rating of the AD-Affected Ability to do Regular Daily Activities other than a Job (scored 0–10, where 0=‘no effect’ and 10=‘prevented me from doing my daily activities’). Formal statistical comparisons were not performed on the data resulting from the OLE period. The DUPISTAD study enrolled a total of 188 patients: 127 patients received dupilumab throughout (dupilumab–dupilumab group), and 61 patients received a placebo and then switched to dupilumab (placebo–dupilumab group). Baseline demographics and disease characteristics were well balanced. Improvement from baseline in AD-related patient-reported QoL indicators and AD symptoms was observed at week 24 in both groups, as illustrated by the mean change from baseline in POEM total scores (−14.6 in the dupilumab–dupilumab group and −15.9 in the placebo–dupilumab group), DLQI scores (−12.6 in the dupilumab–dupilumab group and −13.4 in the placebo–dupilumab group), Skin Pain NRS scores (−4.7 in the dupilumab–dupilumab group and −5.0 in the placebo–dupilumab group), Skin Sensitivity NRS scores (−4.6 in the dupilumab–dupilumab group and −5.0 in the placebo–dupilumab group), and the WPAI-AD NRS of Ability to do Regular Daily Activities scores (−4.2 in the dupilumab–dupilumab group and −3.8 in the placebo–dupilumab group). The placebo– dupilumab group experienced most of this improvement during the OLE period, as illustrated by the mean change from week 12 to week 24 in POEM total score (−11.5), DLQI score (−5.5), Skin Pain NRS score (−3.0), Skin Sensitivity NRS score (−3.0) and the WPAI-AD NRS of Ability to do Regular Daily Activities score (−2.0). The safety profile of dupilumab was consistent with the known safety profile. Dupilumab provided sustained improvements through 24 weeks in AD-related patient-reported measures of QoL and AD symptoms in adults with moderate-to-severe AD. Patients who were switched from placebo to dupilumab at week 12 showed rapid improvement in these parameters after the switch, eventually matching the improvement achieved by patients who received dupilumab from baseline through week 24. [ABSTRACT FROM AUTHOR]