By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration has approved nemolizumab, the first monoclonal antibody specifically targeting the interleukin-31 (IL-31) pathway linked to pruritus and skin inflammation associated with atopic dermatitis (AD). Nemolizumab is a humanized monoclonal modified immunoglobulin G that is an IL-31 receptor alpha antagonist. Approved for moderate-to-severe atopic dermatitis, it was launched in Japan in 2022. Nemolizumab is distributed by Galderma Laboratories as Nemluvio.
Indications
Nemolizumab is indicated for the treatment of adults and pediatric patients 12 years of age and older with moderate-to-severe AD. It is used in combination with topical corticosteroids and/or calcineurin inhibitors when topical prescription therapies fail to control AD.1
Dosage
The recommended dosage for nemolizumab is 60 mg (two 30 mg injections subcutaneously) initially followed by 30 mg every four weeks.1 After 16 weeks, for patients who achieve clear or almost clear skin, a dosage of 30 mg every eight weeks is recommended. Nemolizumab should be used with topical corticosteroids and/or topical calcineurin inhibitors until the disease has sufficiently improved. All age-appropriate vaccinations should be completed prior to treatment. Nemolizumab is available as a single-dose, pre-filled, dual-chamber pen containing 30 mg of nemolizumab-lyophilized powder and water for injection as the diluent.
Potential Advantages
Nemolizumab is the first drug that specially targets the IL-31 pathway.
Potential Disadvantages
Hypersensitivity reactions, such as facial angioedema, have been reported.1 Vaccinations should not be given during therapy with nemolizumab. Adverse reactions include heachache (5%), injection site reaction (1.2%), arthralgia, urticaria, and myalgia (1%).
Comments
The efficacy and safety of nemolizumab were evaluated in two identical 48-week randomized, double-blind, placebo-controlled trials (Arcadia 1 and Arcadia 2).1,2 Study participants had moderate-to-severe AD based on an Investigator’s Global Assessment (IGA) score of 3 and 4, an Eczema Area and Severity Index (EASI) score of ≥ 16, a minimum body surface area (BSA) involvement of ≥ 10%, and a Peak Pruritus Numerical Rating Scale (PP-NRS) score of ≥ 4. In Arcadia 1, 620 participants were assigned to nemolizumab and 321 were assigned to placebo. In Arcadia 2, 522 and 265 participants were assigned to nemolizumab and placebo, respectively. Concomitant low- and/or medium-potency topical corticosteroid (TCS) and/or topical calcineurin inhibitor (TCI) were administered for at least 14 days prior to baseline and continued during the trials. Topical therapies could be tapered and/or discontinued at investigator discretion. At baseline, 51% of participants were male, 80% were white, the mean age ranged from 33.3 years to 35.2 years, 15% were between 12-17 years of age, 70% had moderate AD, 30% had severe disease, the mean EASI score was 27.5, and the mean weekly average PP-NRS score was 7.1. Sixty-three percent of participants had received other previous systemic treatment.
Coprimary efficacy endpoints were the proportion of participants with an IGA success clear (IGA = 0) or almost clear (IGA = 1) and a ≥ 2-point reduction from baseline and proportion of participants with ≥ 75% improvement in EASI score from baseline (EASI-75). A key secondary outcome was PP-NRS improvement of ≥ 4 from baseline. IGA successes were 36% and 38% vs. 25% and 26%, respectively, for nemolizumab + TCS/TCI vs. placebo + TCS/TCI in Arcadia 1 and 2. EASI-75 improvement rates were 44% and 42% vs. 29% and 30%, respectively. PP-NRS improvement rates were 33% and 36% vs. 15%, respectively. Responders at Week 16 were re-randomized to nemolizumab every four weeks, every eight weeks, or placebo and evaluated at Week 48. TCS/TCI were continued in each arm. IGA success rates were 63%, 64%, and 55%, respectively, while EASI-75 were 75%, 77%, and 65%, respectively. Continuous improvement in pruritus and signs of AD and quality of life have been reported for up to 68 weeks.3
Clinical Implications
Atopic dermatitis has a multifactorial pathogenesis involving a variety of inflammatory cytokines, including IL-4, IL-5, IL-13, IL-31, and IL-33.4 Pruritogens include IL-4, IL-13, and IL-31. While there are no comparative trials between nemolizumab and other similar agents, a systematic review and network meta-analysis of randomized trials found nemolizumab to be similar to dupilumab and high-dose abrocitinib (a Janus kinase inhibitor) with high-dose upadacitinib being the most effective vs. placebo in reducing itch severity.5 In terms of patient-reported and clinician-reported AD severity, high-dose upadacitinib was the most effective, whereas nemolizumab was not clearly different from placebo.
Janus kinase inhibitors affect multiple cytokines, including IL-4, IL-5, IL-13, IL-22, IL-31, and interferon alpha. Dupilumab affects IL-4 and IL-13. In a head-to-head comparison, upadactinib was superior to dupilumab in improving EASI-75 and Worst Pruritus Numerical Rating Scale scores.6 However, Janus kinase inhibitors, were the most harmful in terms of adverse events. Duplumab, levrikizumab, and tralokinumab were of intermediate effectiveness and demonstrated more favorable safety profiles.5 Nemolizumab, solely an IL-31 antagonist, does not appear to offer any clear clinical advantage over existing therapies. The cost of nemolizumab is $4,240 for a 30 mg dose.
References
- Galderma Laboratories. Nemlovio prescribing information. Revised December 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761391s000lbl.pdf
- Silverberg JI, Wollenberg A, Reich A, et al. Nemolizumab with concomitant topical therapy in adolescents and adults with moderate-to-severe atopic dermatitis (ARCADIA 1 and ARCADIA 2): Results from two replicate, double-blind, randomised controlled phase 3 trials. Lancet. 2024;404(104451):445-460.
- Kabashima K, Matsumura T, Komazaki H, Kawashima M; Nemolizumab JP01 andJP02 Study Group. Nemolizumab plus topical agents in patients with atopic dermatitis (AD) and moderate-to-severe pruritus provide improvement in pruritus and signs of AD for up to 68 weeks: Results from two phase III, long-term studies. Brit J Dermatol. 2022;186(4):642-661.
- Müller S, Maintz L, Bieber T. Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs. Allergy. 2024;79(6):1501-1515.
- Chu AWL, Wong AM, Rayner DG, et al. Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials. J Allergy Clin Immunol. 2023;152(6):1470-1492.
- Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and safety of upadacitinib vs. dupilumab in adults with moderate-to-severe atopic dermatitis: A randomized clinical trial. JAMA Dermatol. 2021;157(9):1047-1055.
The U.S. Food and Drug Administration has approved nemolizumab, the first monoclonal antibody specifically targeting the interleukin-31 pathway linked to pruritus and skin inflammation associated with atopic dermatitis.
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