Investigating Efficacy of Atopic Dermatitis Systemic Therapeutics After Discontinuation Part I: Biologics

J Clin Aesthet Dermatol. 2025;18(2):33–37.

by Naiem T. Issa, MD, PhD; Rama Abdin, BSc; Kabir Al-Tariq, BSc; Dana Jaalouk, BSc; Michael Kaiser, MD; James Del Rosso, DO; and Shawn Kwatra, MD

Dr. Issa is with Forefront Dermatology in Vienna, Virginia; the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at the University of Miami, Leonard M. Miller School of Medicine in Miami, Florida; and the Department of Dermatology at George Washington University School of Medicine and Health Sciences in Washington, District of Columbia. Ms. Abdin is with the Charles E. Schmidt College of Medicine at Florida Atlantic University in Boca Raton, Florida. Mr. Al-Tariq is with the University of Rochester in Rochester, New York. Ms. Jaalouk is with Florida State University in Tallahassee, Florida. Dr. Kaiser is with Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery at the University of Miami, Leonard M. Miller School of Medicine in Miami, Florida. Dr. Del Rosso is with the Dermatology Department at Touro University Nevada in Henderson, Nevada; JDR Dermatology Research in Las Vegas, Nevada; and Advanced Dermatology and Cosmetic Surgery in Maitland, Florida. Dr. Kwatra is with the University of Maryland School of Medicine in Baltimore, Maryland.

FUNDING: No funding was provided for this article.

DISCLOSURES: Dr. Issa has received funding from the following entities either as a speaker, consultant, advisor, or investigator: Abbvie, Almirall, Bristol Myers Squibb, Castle
Biosciences, Dermavant Sciences, DermTech, Galderma, Incyte, Journey, LEO Pharma, Lilly, National Eczema Association, Ortho Dermatologics, Pfizer, Regeneron, Sanofi, SUN
Pharmaceuticals Industry, Topix, UCB, Verrica Pharmaceuticals. Ms. Abdin, Mr. Al-Tariq, Ms. Jaalouk, and Mr. Kaiser have no conflicts of interest relevant to the content of this article. Dr. Kwatra is an advisory board member/consultant for AbbVie, Alphyn Biologics, Amgen, Arcutis Biotherapeutics, Dermavant Sciences Inc., E.R. Squibb and Sons, Galderma, Genzyme Corporation, Incyte Corporation, Janssen, Novartis, Pfizer,  Regeneron Pharmaceuticals, Sanofi-Aventis

ABSTRACT: Objective: The authors sought to review published literature on the efficacy of biologics as monotherapy for atopic dermatitis (AD) following discontinuation. Methods: A comprehensive search of PubMed/MEDLINE was conducted examining drug withdrawal in AD clinical trials where participants were treated with biologics. Trials were included if they exclusively involved participants with AD that reported the maintenance or achievement of Eczema Area and Severity Index (EASI)-75 and Investigator Global Assessment (IGA) scores of 0 or 1 after withdrawal of biologic therapy. Clinical trials involving multidrug regimens, including those investigating concomitant topical therapeutics, were excluded from our analysis. Results: Five clinical trial programs met our inclusion criteria, each investigating a different biologic: dupilumab, tralokinumab, lebrikizumab, amlitelimab, and rocatinlimab. Limitations: Limitations to this review include a small number of trials that met the inclusion criteria, variations in study design that hinder direct comparisons, and the absence of long-term follow up data. Conclusion: The variability in eligibility criteria, treatment durations, and withdrawal periods across trials presents a major challenge in assessing biologics for AD, complicating the comparison of their sustained responses in the absence of head-to-head studies. This heterogeneity, combined with factors such as disease duration and prior use of systemic medications before trial enrollment, hampers the identification of key pathways in AD pathogenesis and impedes efforts to better understand and characterize the disease.

Keywords: Biologic, discontinuation, withdrawal, systemic, atopic dermatitis, dupilumab, tralokinumab, lebrikizumab

Introduction

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by pruritus, lichenified plaques, and a compromised skin barrier, making patients more susceptible to infections and allergens.¹ It typically begins in infancy or childhood and follows a relapsing-remitting course, with significant impacts on quality of life.² The pathogenesis of AD is complex and multifactorial, involving genetic predisposition, immune dysregulation, and environmental triggers.² Central to the disease is the overactivation of immune pathways, particularly T-helper 2 (Th2) cells, which drive the production of
pro-inflammatory cytokines, such as interleukin (IL)-4, IL-13, and IL-31, through the Janus kinase (JAK)-STAT pathway.³ This contributes to the chronic inflammation and barrier dysfunction seen in AD. More recently, the OX-40 signaling axis has been implicated in the activation of effector T lymphocytes that are contributory to AD.⁴ OX40 is a costimulatory molecule that is highly expressed on activated effector T cells and plays a key role in T cell differentiation and the development of memory T cells, with increased expression observed in individuals with AD.⁴ Anti-OX40 antibodies work by inhibiting and decreasing the OX40-expressing pathogenic T cells that drive the inflammatory response in AD via blockade of OX40 itself or OX-40 ligand (OX-40L).⁴

The systemic treatment landscape for AD has evolved significantly over the past decade. This progress includes the introduction of biologics targeting cytokines and their receptors, as well as small-molecule JAK inhibitors that block pro-inflammatory intracellular signaling.⁵ Current biologics approved by the the United States (US) Food and Drug Administration (FDA) for AD are dupilumab, tralokinumab, and lebrikizumab. Dupilumab blocks IL-4Rα, thereby preventing IL-4 and IL-13 signaling through both the Type I (IL-4Rα/yc) and Type II receptor (IL-4Rα/IL-13Rα1) heterodimers. In contrast, tralokinumab and lebrikizumab bind to different epitopes on the IL-13 cytokine, blocking the dimerization of IL-4Rα subunit with IL-13Rα1 subunit to ultimately prevent IL-13 signaling.⁶ Notably, tralokinumab does not allow the binding of IL-13 to IL13Rα2 whereas lebrikizumab does allow binding. Emergent OX40-targeting biologics currently undergoing Phase 3 clinical trial investigations include amlitelimab and rocatinlimab, antibodies that block OX40 and OX40L, respectively.⁴ 

As the use of biologic therapies continues to rise and as advancements in these treatments progress, it is crucial to evaluate their long-term efficacy in AD treatment. A key factor in this evaluation is understanding the proportion of participants in clinical trials who continue to maintain a therapeutic response after therapy is withdrawn and whether this is related to the half-life/bioavailability of the biologic or a true bona fide disease-modifying biological effect.⁷ This information is vital for uncovering mechanisms and patient sub-types that may lend to a disease-modifying outcome. This study aims to survey the current biologic therapeutic landscape in AD with respect to traditional clinical trial success endpoints for subjects who initially achieved treatment success (defined as EASI-75 and/or IGA 0/1) and were then placed in a placebo withdrawal group for a pre-specified length of time. This study ultimately portrays a high-level view of “off-drug treatment success” while bringing forth current gaps in trial design as a whole for assessing such outcomes. 

Methods

A comprehensive search of PubMed/MEDLINE was conducted examining drug withdrawal in AD clinical trials where participants were treated with biologics as monotherapy. Trials were included if they exclusively involved participants with AD that reported the maintenance or achievement of Eczema Area and Severity Index (EASI)-75 and/or Investigator Global Assessment (IGA) scores of 0 or 1 after biologic therapy. Outcomes after the induction period were evaluated, with a specific focus on the results of the withdrawal group at the end of the study. We contacted trial investigators for studies that met our inclusion criteria but lacked readily available data for our outcome measures or when clarification was needed. Clinical trials involving multidrug regimens, including those investigating concomitant topical therapeutics, were excluded from our analysis.

Results 

Our search identified five clinical trial programs that met the eligibility criteria, each investigating a different biologic: dupilumab, tralokinumab, lebrikizumab, amlitelimab, and rocatinlimab (Table 1). Study designs are detailed in Figure 1. Pooled data of treatment successes after treatment withdrawal are shown in Figure 2.

Dupilumab. Dupilumab is a fully human monoclonal IgG4 antibody which competitively inhibits IL-4 and IL-13 signaling by binding to the α-subunit of the IL-4 receptor.⁸ It is FDA approved for the treatment of moderate-to-severe AD in patients aged six months and older. SOLO 1 and SOLO 2 were two parallel, randomized, placebo-controlled, Phase 3 trials investigating the treatment of moderate-to-severe AD in adults with dupilumab 300mg weekly or every other week for 16 weeks in adult patients over 18 years of age.⁹ SOLO-CONTINUE was a randomized, double-blind, Phase 3 clinical trial to evaluate maintenance of clinical response and long-term safety of dupilumab monotherapy at the original dosage, less frequent regimens, or drug withdrawal (placebo) for an additional 36 weeks in participants treated with dupilumab who achieved IGA 0/1 or EASI-75 at Week 16 in the prior SOLO studies.¹⁰ In the withdrawal group, 30.4 percent of participants maintained EASI-75 (Figure 1A) and 14.3 percent of participants maintained IGA 0/1 (Figure 1B). Participants were considered to be nonresponders from the time of rescue medication use, withdrawal from study, or missing data.

Tralokinumab. Tralokinumab is a fully human, high-affinity IgG4 monoclonal antibody that targets the IL-13 cytokine to inhibit the downstream effects of this signaling pathway.¹¹ Currently, tralokinumab is approved by the FDA for the treatment of moderate-to-severe AD in adults and children 12 years of age and older. 

ECZTRA 1 and ECZTRA 2 were both Phase 3 trials that evaluated the efficacy of tralokinumab monotherapy in adults with moderate-to-severe AD.¹¹ These were identically designed, 52-week, multicenter, international, randomized, double-blinded, placebo-controlled trials. Participants who responded to treatment with tralokinumab 300mg Q2W for 16 weeks, defined as achieving an IGA 0/1 and/or EASI-75 with tralokinumab at Week 16, were re-randomized to receive tralokinumab 300mg Q2W, tralokinumab 300mg Q4W, or placebo for a 36-week maintenance treatment period.¹¹ In a pooled analysis of these two trials, Simpson et al¹² revealed that at Week 52, 26.4 percent of participants in the withdrawal group maintained EASI-75 (Figure 1A) and 34 percent maintained IGA 0/1 (Figure 1B).¹² Of note, during the maintenance treatment period, participants who exhibited a predefined decline relative to their Week 16 response over a four-week period were transferred to open-label treatment with tralokinumab.¹² Participants who received rescue medication, had missing data or were transferred to open-label treatment were considered nonresponders.¹² 

Lebrikizumab. Lebrikizumab is a high-affinity monoclonal antibody that targets IL-13 via an epitope distinct to that of tralokinumab.¹³ It is approved in the US for moderate-to-severe AD in patients 12 years of age and older who are candidates for systemic therapy.¹⁴ ADvocate 1 and ADvocate 2 were Phase 3 trials designed as identical, randomized, double-blind, placebo-controlled studies to evaluate lebrikizumab monotherapy in participants aged 12 years and older with moderate-to-severe AD.¹⁵ Participants who responded to treatment with 250mg of lebrikizumab every two weeks (Q2W) for 16 weeks, defined as achieving EASI-75 or attaining IGA 0/1 with a two-point improvement and no use of rescue medication, were re-randomized to receive either 250mg of lebrikizumab Q2W, 250mg of lebrikizumab every four weeks (Q4W), or placebo Q2W (lebrikizumab withdrawal) for an additional 36 weeks.¹⁵ Blauvelt et al¹³ pooled the non-responder imputation (NRI) results from these two trials (shown in Table S4 from their manuscript) and found that at Week 52, 39.5 percent of participants in the withdrawal group continued to exhibit IGA 0/1 and a ≥2-point improvement from baseline (Figure 1B).¹³ Additionally, EASI-75 was maintained by 56.1 percent of participants in the withdrawal group (Figure 1A).¹³ Of note, participants who did not maintain an acceptable response of at least a 50-percent reduction in EASI from baseline were also assigned to an open-label escape arm to receive lebrikizumab. Participants who received topical or systemic rescue medication, discontinued treatment, or transferred to the escape arm were considered nonresponders.¹³ Multiple imputation was used to handle missing data (data not shown; NRI data only shown for consistency).

Amlitelimab. Amlitelimab is a fully human monoclonal antibody against the OX40 ligand (OX40L).¹⁶ It has shown promising results in the treatment of moderate-to-severe AD in adults; however, amlitelimab is not currently FDA approved for the treatment of AD.¹⁶ STREAM-AD was a Phase 2b study in which participants previously treated with amlitelimab of varying doses for 24 weeks who achieved IGA 0/1 and/or EASI-75 at Week 24 were re-randomized to placebo (withdrawn from treatment) for 28 weeks.¹⁷ Pooled analysis of responses across dosages revealed 61.6 percent of participants achieved an EASI 75 response at Week 52 (Figure 1A), and 57.0 percent achieved IGA 0/1 (Figure 1B).¹⁸ Participants who discontinued treatment due to lack of efficacy, missing data, rescue medication use during the withdrawal period, or other factors impacting the efficacy were considered nonresponders. At the first instance of <EASI-50, participants were withdrawn from the study. 

Rocatinlimab. Rocatinlimab is a non-fucosylated IgG1 monoclonal antibody targeting the OX40 receptor. It has demonstrated efficacy in improving key outcomes in patients with moderate-to-severe AD. However, it is not currently approved by the FDA for the treatment of AD.¹⁹ 

A Phase 2b, randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of subcutaneous rocatinlimab in moderate-to-severe AD.²⁰ Participants were randomized to receive one of the following: 150mg every four weeks, 600mg every four weeks, 300mg every two weeks, 600mg every two weeks, or placebo for 18 weeks. After this period, participants entered an active-treatment extension Phase from Weeks 18 to 36, with the final injection at Week 34. Participants who initially received rocatinlimab continued the same dosage, while those in the placebo group were switched to rocatinlimab 600mg every two weeks. At Week 36, all participants discontinued treatment and were followed for an additional 20 weeks.²⁰ Participants who used rescue treatment (mostly topical corticosteroids) during follow-up while maintaining EASI-75 were not considered as having relapsed. Participants who received rescue treatment during off-treatment follow-up were kept on study and observed until study end but additional efficacy assessments were not included. Data obtained after initiation of rescue treatment were considered missing data.

For this analysis, pooled data across all dosage groups were obtained at Week 36 (end of treatment phase) and Week 56 (end of withdrawal phase). The proportion of participants maintaining target endpoints at Week 56 was calculated by dividing the total number of subjects who were initially treated with rocatinlimab (placebo group excluded) and achieved the endpoint at Week 56 by the total number of subjects in the full analysis set (excluding placebo) at the start of the study (N=210). By Week 56, 34.2 percent (72/210) of participants maintained an EASI-75 response (Figure 1A), and 27.1 percent (57/210) maintained a validated IGA 0/1 with a reduction of two or more points from baseline (Figure 1B).

Discussion 

Atopic dermatitis is a chronic inflammatory skin condition that affects individuals of all ages and can significantly impact an individual’s quality of life.² Through advances in both drug development and our understanding of the disease, newer systemic treatments for AD, such as biologics, bolster efficacy by targeting specific immunologic mediators that are central to the pathophysiology of AD.²¹ Although the development of these novel medications shows promising results for patients during treatment, there is a lack of consistent data on outcomes after discontinuation. In the trials that do assess post-treatment outcomes through withdrawal phases, there is variability in the criteria used to determine participant eligibility for entering the withdrawal period and in the duration of follow-up. This inconsistency makes it difficult to draw clear conclusions about the long-term effects of these therapies once treatment is stopped.

In our study comparing the sustained efficacy of biologics, two distinct eligibility criteria were used across the five trials to determine whether participants could enter the withdrawal phase. The rocatinlimab trial did not require specific criteria before drug discontinuation; however, the other trials mandated that participants achieve either EASI-75 or IGA 0/1 at the end of the treatment period. The duration participants remained off the drug also varied among trials. In the dupilumab,¹⁰ tralokinumab,¹² and lebrikizumab¹³ trials, participants were reassessed 36 weeks after their final treatment (administered at Week 16), representing the longest withdrawal period in our analysis. In contrast, participants in the amlitelimab¹⁷ and rocatinlimab²⁰ trials were reassessed 28 and 20 weeks after their last treatment, respectively. Notably, amlitelimab and rocatinlimab treatment arms had longer durations of treatment (24 weeks and 36 weeks, respectively) prior to discontinuation compared to dupilumab, tralokinumab and lebrikizumab. Rocatinlimab withdrawal data was also pooled as all prior treatment arms entered the withdrawal arm, which complicates data interpretation. Furthermore, requirements for topical and systemic treatment washout periods differed across each study, and baseline demographics of those patients who were on prior biologics and immunomodulators prior to study enrollment were not controlled for. For both dupilumab and lebrikizumab, participants had to discontinue systemic agents and phototherapy four weeks prior to their baseline visit and had to stop treatment with topical agents one week prior to their baseline visit.^11,13 Similarly, for tralokinumab, systemic medications had to be stopped four weeks prior to the baseline visit; however, topical treatments had to be stopped two weeks prior to the baseline visit.¹² For rocatinlimab, participants were required to stop systemic and topical agents for AD one week before their baseline visit.²⁰ For amlitelimab, topical treatments were to be washed out at least two weeks prior to baseline, and between three weeks and three months prior for other systemic therapies.¹⁶ In addition, for the dupilumab outcomes, the once weekly dosing treatment group was included in addition to the once every two weeks treatment group prior to re-randomization.¹⁰ These aspects are critical as they could alter the disease phenotype and ultimately outcomes.

With respect to the OX-40 inhibitors amlitelimab and rocatinlimab, the data is extrapolated from Phase 2b trials which usually have lower numbers of participants per treatment arm compared to Phase 3 trials. Furthermore, the pooling of data across all dosages for these two trials limits the interpretation of their sustained efficacy. Despite their promising results, it should be noted that OX-40 inhibitors are a newer class of biologics for AD with Phase 3 trials pending completion for appropriate treatment withdrawal analytics. 

Limitations. A major limitation to this study is the small number of trials included in our analysis. This is likely due to biologics being a relatively new therapeutic option for treating AD. As a result, trial design has focused on demonstrating on-drug efficacy and safety rather than effectiveness after discontinuation. With recent advances in biologics achieving complete clearance of AD in some patients, the focus must shift to a new milestone. Instead of solely emphasizing biologic efficacy and disease treatment, future research should prioritize understanding the durability of these responses after treatment discontinuation, which may illuminate potential for disease modification. Furthermore, in order to better compare these outcomes across different biologics using network meta-analyses or match-adjusted indirect comparisons (MAIC), there needs to be standardized washout, eligibility, and withdrawal criteria employed by future trials that not only facilitates generalizability of the results but also lends itself to inter-class comparability. 

Conclusion

The variability in eligibility criteria, treatment durations, and withdrawal periods among trials highlights a key challenge in evaluating biologics for AD. Without head-to-head trials in subjects matched for demographics and baseline disease severity, comparing the sustained response of these drugs becomes difficult, especially when participants are in different stages of disease remission or have been on or off the drug for varying lengths of time. Disease duration and prior systemic medications prior to trial enrollment are also confounders. This limits the ability to identify crucial pathways in the pathogenesis of AD, thus impeding the ability to better characterize this disease. Therefore, future clinical trials should prioritize both cohesive trial design and focus on investigating sustained efficacy after drug discontinuation. This approach will both augment our understanding of AD and help clinicians offer better counseling to patients regarding the most suitable biologic for their condition.

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