An Era of Therapeutic Evolution and Revolution: Insights into Studies on Dupilumab, Tralokinumab, Lebrikizumab, Nemolizumab, Eblasakimab, and OX40/OX40L Agents (Rocatinlimab and Amlitelimab) in Moderate-to-Severe Atopic Dermatitis

Abstract

Atopic dermatitis (AD), a prevalent chronic inflammatory skin condition, presents with diverse phenotypes and endotypes. Traditional treatments have included topical corticosteroids, phototherapy, calcineurin inhibitors, and systemic immunosuppressants, the latter often necessitating frequent lab monitoring due to concerns about adverse effects. Recently, the AD treatment landscape has evolved significantly, marked by the introduction of innovative therapies. This advancement is driven by the identification of biomarkers predictive of therapeutic responses and the integration of bench research, leading to improved disease stratification and treatment selection. Emerging therapies, particularly monoclonal antibodies and targeted treatments, have shown exceptional efficacy in managing moderate-to-severe AD. This chapter focuses on clinical trials evaluating the effectiveness of these novel biologic agents other than JAK inhibitors.

1. Introduction

Atopic dermatitis (AD) is one the most common chronic inflammatory skin diseases, with a variety of phenotypes and endotypes. In recent decades, treatments have been based on topical corticosteroids, phototherapy, calcineurin inhibitors, and systemic immunosuppressants. However, with systemic immunosuppressant therapy, many patients require frequent laboratory monitoring and some are undertreated for concerns regarding adverse effects [1]. In the last decade, the therapeutic pipeline of AD has been enriched. As a consequence, there has been an emergence of novel and promising therapeutic perspectives. The identification of biomarkers that can have therapeutic responses as well as the integration of bench studies are the key to this translational revolution. This novel approach led to a better disease stratification and a better therapeutic selection.

New agents have been developed, including monoclonal antibodies and narrow targeting therapies, which proved to outstanding efficacy against moderate-to-severe AD. The objective of this chapter is to shed light on clinical trials assessing the efficacy of the major novel emerging biologics.

We will focus on dupilumab, an anti-IL4 and IL13 antibody, tralokinumab, an anti-IL-13 antibody, lebrikizumab that binds specifically to soluble IL-13, neomizumab, an anti-IL-31 antibody, eblazakimab, an IL-13R-alpha-1 monoclonal antibody, and agents targeting OX40/OX40L.

2. Biologics

A summary of biologics is presented in Table 1.

Drug	Mode of action	Current phase of clinical trial and approvals	Dose and frequency	Baseline laboratory workup	Follow-up workup	Side effects	Contraindications or precautions
Monoclonal antibodies
Dupilumab	Fully human monoclonal antibody that binds to the alpha subunit of the IL-4 receptor and inhibits downstream signaling of IL-4 and IL-13	FDA approved for moderate-to-severe AD in: adults and children ≥12 y.o (2017) children 6–12 y.o (2021) children 6 months-6 y.o (2022) FDA approved for patients ≥6 months old	≥18 y.o: initial loading dose: 600 mg SC injection followed by 300 mg Q2W.; 6–18[y.o: ≥60 kg: 600 mg loading; dose then 300 mg Q2W; 30–60[kg: 400 mg loading dose then 200 mg Q2W; 15–30[kg: 600 mg loading dose then 300 mg Q4W; 6 months-6[y.o: 15–30[kg; NO loading.; 300 mg Q4W; 5–15[kg: NO loading.; 200 mg Q4W	None	None	injection site reaction ocular surface disease (11–26%): conjunctivitis and, infrequently, keratitis, eye dryness, burning or stinging, pruritus, blepharitis, and blurred vision Seronegative arthritis and enthesitis/enthesopathy: psoriasis and inflammatory arthritis and enthesitis, associated, paradoxical emergence of T helper type 17 (Th17) diseases (spondyloarthropathy-pattern arthritis, psoriasiform skin disease, and occasional anterior uveitis.) Exacerbation or new onset of head and neck dermatitis (4–10%) antibody development against the drug eosinophilia herpes simplex virus infection (ex: oral herpes) upper respiratory tract, skin infection	Pregnancy: limited data. Risk-benefit balance Lactation: limited data. Risk-benefit balance renal insufficiency: no adjustment for mild-to-moderate renal impairment. No data if severe. hepatic insufficiency: no data Parasitic (helminth infections): Patients with known helminth infections were excluded from clinical studies. It is unknown if dupilumab might influence immune response against helminth infections. Treat patients with pre-existing helminth infections before initiating dupilumab. If patients become infected while on dupilumab and do not respond to antihelminth treatment, discontinue dupilumab until infection resolves. Vaccinations: Consider completing all age-appropriate vaccinations. Avoid live vaccines. Unknown if efficacy or safety of vaccine will be altered with dupilumab
Tralokinumab	Fully human monoclonal anti-IL-13 antibody	FDA approved for moderate-to-severe AD in: Adults ≥18 y.o (2021)	initial loading dose: 600 mg SC injection followed by 300 mg Q2W, or Q4W may be considered in patients <100 kg who achieve clear or almost clear skin after 16 weeks of treatment	None	None	viral upper respiratory tract infection (15%) ocular surface disease (5.6%) injection-site reactions (3/5%) eosinophilia atopic dermatitis exacerbation	Same as dupilumab
Lebrikizumab	Monoclonal antibody that binds specifically to soluble IL-13	Not yet FDA approved	initial loading dose: 500 mg SC injection followed by 250 mg Q2W			atopic dermatitis exacerbation (9%) ocular surface disease (8%) nasopharyngitis (8%); Herpes infection eosinophilia
Nemolizumab	Humanized monoclonal antibody against the receptor of IL-31, a cytokine known to be associated with pruritus via IL-31 receptor activation	Not yet FDA approved	Yet to be determined.			atopic dermatitis exacerbation respiratory tract infections peripheral edema elevated CPK injection site reactions headache GI symptoms

Table 1.

Summary of biologics in atopic dermatitis.

2.1 Dupilumab

Despite the presence of a multitude of newly emerging drugs, the approval of dupilumab, is the major breakthrough in managing moderate to severe AD in the last decade. Dupilumab has been evaluated in many randomized clinical trials, prospective cohort studies, and meta-analyses.

2.1.1 Meta-analysis

A network meta-analysis [2] demonstrated with a high degree of certainty that dupilumab is the most effective treatment in achieving EASI-75 (risk ratio 3.04, 95% CI 2.51–3.69) and improving the POEM score (mean difference 7.3, 95% CI 6.61–8.00) during short-term follow-up when compared with placebo. This meta-analysis was performed on 74 randomized trials with >8000 participants. Moreover, in achieving EASI-75 and the score of POEM, dupilumab ranked first compared to other investigational and noninvestigational biologics. However, due to a lack of head-to-head studies, ranking of nonivestigational drugs with respect to dupilumab is not possible.

2.1.2 SOLO1 and SOLO2 studies

SOLO1 (671 patients) and SOLO2 (708 patients) are two identically-designed randomized, placebo-controlled, phase 3 trials in adults with moderate-to-severe atopic dermatitis, inadequately controlled by topical treatment [3]. Patients were randomly assigned for 16 weeks to receives: either 300 mg dupilumab weekly or placebo weekly or 300 mg of dupilumab every other week alternating with placebo. The primary outcome of the studies was the proportion of patients with a score of 0 (clear) or 1 (almost clear) on the Investigator’s Global Assessment (IGA) and a reduction of 2 points or more in IGA from baseline at the end of the study.

In SOLO 1, the primary outcome occurred in 85 patients (38%) on dupilumab every 2 weeks, in 83 on dupilumab weekly (37%), vs. 10% (n = 23) on placebo (p < 0.001 for each vs. placebo).

In SOLO 2, the primary outcome occurred in 84 patients (36%) on dupilumab every other week, in 36% (n = 87) receiving dupilumab weekly, vs. 8% (n = 20) receiving placebo (p < 0.001 for both comparisons).

In SOLO1 and SOLO2, EASI-75 was achieved in significantly more patients receiving each regimen of dupilumab than in those receiving placebo (p < 0.001 for all comparisons). In addition, dupilumab was also associated with a reduction in itch, anxiety or depression, and improvement in quality of life.

2.1.3 LIBERTY AD CHRONOS study

LIBERTY AD CHRONOS is a randomized, double-blind, trial that aimed to study long-term efficacy and safety of dupilumab [4]. Patients were randomly assigned to receive dupilumab 300 mg once weekly or dupilumab 300 mg every 2 weeks or placebo for 52 weeks. A concurrent treatment with topical steroids was given to all patients. The two coprimary endpoints were the proportion of patients with both an IGA score of 0 or 1 or at least 2 point reduction and the proportion of patients achieving EASI-75 at the end of the study. At the end, more patients in the dupilumab groups achieved both: the IGA endpoint and EASI-75 vs. placebo (40 versus 13%, and 65 versus 22%, respectively).

2.1.4 Other studies

An open-label, extension study [5] examined 1491 patients enrolled in previous studies given 300 mg of dupilumab every week for up to 76 weeks at data cutoff. While the primary outcome was safety, efficacy was also evaluated. Among 1491 enrolled, 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials, with no new safety signals. Among the common adverse events, we note: nasopharyngitis, conjunctivitis, and cutaneous reactions at the site of injection. Sustained improvement was seen up to 76 weeks, with >60% achieving EASI-90 scores at 56 and 76 weeks.

2.2 Tralokinumab

2.2.1 ECZTRA 1 and ECZTRA 2 studies

ECZTRA 1 and ECZTRA 2 are 2 identical randomized trials, in which 1596 adult patients with moderate-to-severe AD were randomized to receive either subcutaneous tralokinumab 300 mg every 2 weeks or placebo [6]. Primary endpoints were a score of 0 or 1 in IGA and EASI 75 at the 16th week. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at the end of the 16th week were rerandomized to receive either tralokinumab Q2W or tralokinumab every 4 weeks or placebo, for another 36 weeks. An IGA score of 0/1 was achieved by 16% in tralokinumab vs. 7% placebo in ECZTRA 1 and 22% in tralokinumab vs. 11% in placebo in ECZTRA 2. EASI-75 was achieved by 25 vs. 13% and 33 vs. 11% in these 2 studies, respectively. Tralokinumab was also more effective than placebo in reducing the SCORAD score, improving pruritus, and improving quality of life. The majority of tralokinumab responders at week 16 maintained response at week 52 with continued treatment.

2.2.2 ECZTRA 3 study

ECZTRA 3 is a trial in which 380 patients were assigned to receive either tralokinumab 300 mg every 2 weeks or placebo in combination with a topical corticosteroid applied as needed [7]. At 16 weeks, the IGA score 0/1 was 39 vs. 26% and EASI-75 was 56 vs. 36% for tralokinumab vs. placebo, respectively. Similar results were observed with concomitant topical corticosteroid use in adults previously treated with cyclosporine (ECZTRA 7 study).

In a meta-analysis of >16,000 participants (60 clinical trials), tralokinumab was found to be slightly less effective than dupilumab in reducing EASI at the same dose at week 16 [8].

2.3 Lebrikizumab

2.3.1 ADhere study

ADhere study is a 16-week randomized, double-blinded, placebo-controlled, and multicentre study on moderate-to-severe AD patients [9]. 211 adults and adolescents were assigned to receive lebrikizumab (loading dose of 500 mg at baseline and week 2, followed by 250 mg every 2 weeks) in combination with low- to mid-potency topical corticosteroids vs. placebo. The proportion of those in the drug group achieving an IGA score of 0/1 at week 16 was higher (41% vs. 22%).

2.3.2 ADvocate1 and ADvocate2 studies

ADvocate1 and ADvocate2 are identical trials in which 851 adults and adolescents with moderate-to-severe AD were assigned to receive either lebrikizumab (loading dose of 500 mg at baseline followed by 250 mg every other week) or placebo [10]. More patients in the lebrikizumab groups achieved an IGA score of 0/1 at week 16 (43 vs. 13% and 33 vs. 11%).

In an extension study of the ADvocate1 and ADvocate2 studies, 71% in the group lebrikizumab every 2 weeks, 77% in the group lebrikizumab every 4 weeks, and 48% in the placebo group achieved an IGA score of 0/1 at week 52 [11].

2.4 Nemolizumab

• A phase 2, randomized, double-blind, and 12-week study [12] was conducted assigning patients to receive either nemolizumab (0.1, 0.5 mg, or 2 mg/kg) or placebo every 4 weeks or nemolizumab 2 mg/kg every 8 weeks. The primary end point was the improvement in the score on the pruritus visual-analogue. Secondary end points were EASI and BSA of AD. Pruritus was reduced by 44%, 60%, and 63% in the nemolizumab 0.1, 0.5, and 2 mg groups, respectively, compared to the placebo group with 21%. The BSA of AD decreased by 8, 20, and 19% in nemolizumab groups, vs. 16% in the placebo group.

• A Japanese randomized trial [13] including 215 patients ≥13 y.o with AD and moderate to severe pruritus were assigned to receive either nemolizumab 60 mg or placebo every 4 weeks for 16 weeks plus topical therapy. At week 16, the least squares mean of the pruritus visual analogue scale score was reduced by 43% in the treated group vs. 21% in the placebo.

Although studies are promising regarding the use of neomizumab in moderate-to-severe atopic dermatitis, more studies are needed to evaluate its safety and long-term efficacy.

2.5 Eblasakimab

Eblasakimab is an IL-13R-alpha-1 monoclonal antibody currently being evaluated in a phase 2b randomized clinical trial. Early data presented at the American Academy of Dermatology 2022 showed significant efficacy after 8 weeks of treatment in a small sample size of patients that were assigned to receive eblasakimab 200 mg, 400 mg, or 600 mg vs. placebo. A significant EASI reduction was noted: 61% with 600 mg, 63% with 400 mg group, and 50% with 200 mg. EASI 50 was achieved in 77%, 71%, and 50% of patients in the respective eblasakimab groups vs. 38% in the placebo group. EASI 75 was achieved in 50%, 57%, and 50% with eblasakimab groups, vs. 13% in the placebo group. Moreover, the peak pruritus NRS decreased by 37% with eblasakimab 600 mg, vs. 16% with placebo [14].

2.6 Agents targeting OX40/OX40L

Agents binding to OX40, a costimulatory receptor on activated T cells (telazorlimab and rocatinlimab) or to the OX40 ligand (amlitelimab) have been evaluated in phase 2 studies in adults. Rocatinlimab, was evaluated in a study phase 2b that was placebo-controlled. At week 16, groups receiving rocatinlimab achieved a reduction in the EASI greater than the placebo (−48.3% to −61.1%). There was a sustained response up to 20 weeks after the treatment was stopped. Amlitelimab was studied in a phase 2a clinical trial, at week 16, amlitelimab groups reached the EASI mean percentage − 69.9% and − 80.1% versus the placebo (−49.4%). Both treatments were shown to be safe and well tolerated [15, 16]

3. Conclusion

New biologics have been developed in the treatment of moderate-to-severe AD and have displayed outstanding efficacy [17].

Recent studies have elucidated the mechanism of AD by characterizing various phenotypes and endotypes. Emerging topical and systemic narrow-targeting treatments have been developed according to these findings.

Emerging topical and systemic targeted agents, which have displayed safety and efficacy, are being developed on the basis of expanding knowledge of the pathophysiology of this disease. On the other hand, upcoming clinical trials will provide data for additional options in AD treatments. These new therapies might raise problems like long-term socioeconomic burden associated with biologics. We are currently at the dawn of a new era in the treatment of AD.