Emerging Biologic Therapies for the Treatment of Atopic Dermatitis.


Journal

Drugs
ISSN: 1179-1950
Titre abrégé: Drugs
Pays: New Zealand
ID NLM: 7600076

Informations de publication

Date de publication:
04 Oct 2024
Historique:
accepted: 09 09 2024
medline: 4 10 2024
pubmed: 4 10 2024
entrez: 4 10 2024
Statut: aheadofprint

Résumé

Atopic dermatitis (AD) is a prevalent inflammatory skin disease having a significant impact on patients' quality of life. Conventional treatments, including topical therapies and systemic immunosuppressants, often have limited efficacy and long-term safety concerns. Emerging biologic therapies target specific immune pathways implicated in AD pathogenesis, offering new therapeutic options in a disease known for its complex immune pathomechanisms. This review focuses on novel biologics under investigation, particularly those targeting specific immune pathways such as interleukin-4 (IL-4), IL-13, IL-22, IL-31, thymic stromal lymphopoietin (TSLP), and OX40-OX40L axis. Interleukin-4 and IL-13 inhibitors aim to reduce Th2-driven inflammation, while IL-22 inhibitors focus on restoring skin barrier function. Interleukin-31 inhibitors help alleviate pruritus, a major symptom in AD. OX40-OX40L pathway inhibitors can selectively suppress the activity of pathogenic T cells, without inducing significant immunosuppression. Bispecific antibodies targeting both IL-4 and IL-31 pathways are emerging as potential dual-action treatment for AD. Thymic stromal lymphopoietin inhibitors offer a novel strategy to control inflammation. While many of these therapies offer promising safety and efficacy profiles, long-term studies and real-world data are essential to confirm their lasting impact. This review highlights the potential of these emerging systemic therapies to continue transforming AD management and improve patient outcomes.

Identifiants

pubmed: 39365406
doi: 10.1007/s40265-024-02095-4
pii: 10.1007/s40265-024-02095-4
doi:

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024. The Author(s).

Références

Wollenberg A, Christen-Zäch S, Taieb A, Paul C, Thyssen JP, De Bruin-Weller M, et al. ETFAD/EADV Eczema task force 2020 position paper on diagnosis and treatment of atopic dermatitis in adults and children. Acad Dermatol Venereol. 2020;34:2717–44.
doi: 10.1111/jdv.16892
Weidinger S, Beck LA, Bieber T, Kabashima K, Irvine AD. Atopic dermatitis. Nat Rev Dis Primers. 2018;4:1.
pubmed: 29930242 doi: 10.1038/s41572-018-0001-z
Müller S, Maintz L, Bieber T. Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs. Allergy. 2024. https://doi.org/10.1111/all.16009 .
doi: 10.1111/all.16009 pubmed: 39099205
Wu JJ, Lafeuille M-H, Emond B, Fakih I, Duh MS, Cappelleri JC, et al. Real-world effectiveness of newly initiated systemic therapy for atopic dermatitis in the united states: a claims database analysis. Adv Ther. 2022;39:4157–68.
pubmed: 35821555 pmcid: 9402759 doi: 10.1007/s12325-022-02197-z
Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: clinical implications. Allergy Asthma Proc. 2019;40:84–92.
pubmed: 30819278 pmcid: 6399565 doi: 10.2500/aap.2019.40.4202
Drislane C, Irvine AD. The role of filaggrin in atopic dermatitis and allergic disease. Ann Allergy Asthma Immunol. 2020;124:36–43.
pubmed: 31622670 doi: 10.1016/j.anai.2019.10.008
Fujii M. The pathogenic and therapeutic implications of ceramide abnormalities in atopic dermatitis. Cells. 2021;10:2386.
pubmed: 34572035 pmcid: 8468445 doi: 10.3390/cells10092386
Strid J, Hourihane J, Kimber I, Callard R, Strobel S. Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response. Eur J Immunol. 2004;34:2100–9.
pubmed: 15259007 doi: 10.1002/eji.200425196
Brandt EB, Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2011. https://doi.org/10.4172/2155-9899.1000110 .
doi: 10.4172/2155-9899.1000110 pubmed: 21994899 pmcid: 3189506
Gallegos-Alcalá P, Jiménez M, Cervantes-García D, Salinas E. The keratinocyte as a crucial cell in the predisposition, onset, progression, therapy and study of the atopic dermatitis. IJMS. 2021;22:10661.
pubmed: 34639001 pmcid: 8509070 doi: 10.3390/ijms221910661
Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. THE IL-4 RECEPTOR: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701–38.
pubmed: 10358772 doi: 10.1146/annurev.immunol.17.1.701
Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol. 2018;9:888.
pubmed: 29930549 pmcid: 6001902 doi: 10.3389/fimmu.2018.00888
Badloe FMS, De Vriese S, Coolens K, Schmidt-Weber CB, Ring J, Gutermuth J, et al. IgE autoantibodies and autoreactive T cells and their role in children and adults with atopic dermatitis. Clin Transl Allergy. 2020;10:34.
pubmed: 32774842 pmcid: 7398196 doi: 10.1186/s13601-020-00338-7
Saleem MD, Oussedik E, D’Amber V, Feldman SR. Interleukin-31 pathway and its role in atopic dermatitis: a systematic review. J Dermatol Treat. 2017;28:591–9.
doi: 10.1080/09546634.2017.1290205
Fujita H. The role of IL-22 and Th22 cells in human skin diseases. J Dermatol Sci. 2013;72:3–8.
pubmed: 23746568 doi: 10.1016/j.jdermsci.2013.04.028
Facheris P, Jeffery J, Del Duca E, Guttman-Yassky E. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment. Cell Mol Immunol. 2023;20:448–74.
pubmed: 36928371 pmcid: 10203371 doi: 10.1038/s41423-023-00992-4
Pan Y, Du D, Wang L, Wang X, He G, Jiang X. The role of T helper 22 cells in dermatological disorders. Front Immunol. 2022;13: 911546.
pubmed: 35911703 pmcid: 9331286 doi: 10.3389/fimmu.2022.911546
Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev. 2009;229:173–91.
pubmed: 19426222 pmcid: 2729757 doi: 10.1111/j.1600-065X.2009.00766.x
Furue M, Furue M. OX40L–OX40 signaling in atopic dermatitis. JCM. 2021;10:2578.
pubmed: 34208041 pmcid: 8230615 doi: 10.3390/jcm10122578
Croft M, Esfandiari E, Chong C, Hsu H, Kabashima K, Kricorian G, et al. OX40 in the pathogenesis of atopic dermatitis—a new therapeutic target. Am J Clin Dermatol. 2024. https://doi.org/10.1007/s40257-023-00838-9 .
doi: 10.1007/s40257-023-00838-9 pubmed: 38340153 pmcid: 11070392
Zhang L, Ding Y, Wang Q, Pan W, Wei Z, Smith PA, et al. Preclinical immunological characterization of rademikibart (CBP-201), a next-generation human monoclonal antibody targeting IL-4Rα, for the treatment of Th2 inflammatory diseases. Sci Rep. 2023;13:12411.
pubmed: 37524768 pmcid: 10390583 doi: 10.1038/s41598-023-39311-2
Wang J, White J, Sansone KJ, Spelman L, Sinclair R, Yang X, et al. Rademikibart (CBP -201), a next-generation monoclonal antibody targeting human IL-4Rα : two phase I randomized trials, in healthy individuals and patients with atopic dermatitis. Clin Transl Sci. 2023;16:2614–27.
pubmed: 37849431 pmcid: 10719461 doi: 10.1111/cts.13656
Silverberg JI, Strober B, Feinstein B, Xu J, Guttman-Yassky E, Simpson EL, et al. Efficacy and safety of rademikibart (CBP-201), a next-generation mAb targeting IL-4Rα, in adults with moderate to severe atopic dermatitis: a phase 2 randomized trial (CBP-201-WW001). J Allergy Clin Immunol. 2024;153:1040–9 (e12).
pubmed: 38157942 doi: 10.1016/j.jaci.2023.11.924
Zhang J, Li P, Guo J, Yun J, Yun J, Wei Z, et al. CBP-201, a next-generation IL-4Rα antibody, achieved all primary and secondary efficacy endpoints in the treatment of adults with moderate-to-severe atopic dermatitis (AD): a randomized, double-blind, pivotal trial in China (CBP-201-CN002). 2023 Annual Meeting of the American Academy of Dermatology (AAD 2023); New Orleans, LA, USA; March 17–21, 2023.
Zhao Y, Zhang J, Yang B, Li J, Ding Y, Wu L, et al. Efficacy and safety of CM310 in moderate-to-severe atopic dermatitis: a multicenter, randomized, double-blind, placebo-controlled phase 2b trial. Chin Med J. 2024;137:130–9.
doi: 10.1097/CM9.0000000000002747
Wynne CJ, Cole A, Lemech C, Wang G, Zhang Y, Chen B, et al. Safety, pharmacokinetics and preliminary efficacy of IL4-Rα monoclonal antibody AK120 in both healthy and atopic dermatitis subjects: a phase I, randomized, two-part, double-blind, placebo-controlled, dose-escalation, first-in-human clinical study. Dermatol Ther (Heidelb). 2023;13:2357–73.
pubmed: 37668898 pmcid: 10539271 doi: 10.1007/s13555-023-01010-1
Cevikbas F, Ward A, Firth C, Veverka K. Eblasakimab, a novel IL-13 receptor alpha 1 monoclonal antibody, blocks STAT6 phosphorylation with low dose in human volunteers. Clin Immunol. 2023;253: 109677.
pubmed: 37315681 doi: 10.1016/j.clim.2023.109677
Veverka KA, Thng STG, Silverberg JI, Armstrong AW, Menezes J, Kaoukhov A, et al. Safety and efficacy of eblasakimab, an interleukin 13 receptor α1 monoclonal antibody, in adults with moderate-to-severe atopic dermatitis: a phase 1b, multiple-ascending dose study. J Am Acad Dermatol. 2024;90:504–11.
pubmed: 37866456 doi: 10.1016/j.jaad.2023.10.026
Simpson E, Gooderham M, Kircik LH, Schlesinger T, Del Rosso J, Murrell D, et al. Topline results from TREK-AD: a randomized, double-blind, placebo-controlled, Phase 2b study of eblasakimab in adult patients with moderate-to-severe atopic dermatitis. 2023 European Academy of Dermatology and Venereology Congress (32
ASLAN Pharmaceuticals. ASLAN pharmaceuticals to present additional data from interim analysis of TREK-DX phase 2 study of Eblasakimab in Dupilumab-experienced atopic dermatitis patients during virtual KOL event. 2024. https://ir.aslanpharma.com/news-releases/news-release-details/aslan-pharmaceuticals-present-additional-data-interim-analysis . Accessed May 31, 2024.
Thaçi D, Laquer V, Lynde C, Reich A, Soong W, Worm M, et al. Efficacy and safety of IL-22RA1 inhibition in patients with moderate-to-severe atopic dermatitis: results from a Phase 2a monotherapy trial. 2023 European Academy of Dermatology and Venereology Congress (32
Gooderham M, Reich A, Laquer V, Lynde C, Soong W, Worm M, et al. Individual patient responses to IL-22RA1 inhibition in a Phase 2a monotherapy trial for moderate-to-severe atopic dermatitis. 82nd Annual Meeting of the American Academy of Dermatology (AAD); San Diego, California, USA; March 08-12, 2024.
Keam SJ. Nemolizumab: first approval. Drugs. 2022;82:1143–50.
pubmed: 35834124 doi: 10.1007/s40265-022-01741-z
Galderma. Galderma receives U.S. FDA approval for Nemluvio® (nemolizumab) for adult patients living with prurigo nodularis Galderma. https://www.galderma.com/news/galderma-receives-us-fda-approval-nemluvior-nemolizumab-adult-patients-living-prurigo . Accessed August 18, 2024.
Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wollenberg A, et al. Anti–interleukin-31 receptor a antibody for atopic dermatitis. N Engl J Med. 2017;376:826–35.
pubmed: 28249150 doi: 10.1056/NEJMoa1606490
Kabashima K, Furue M, Hanifin JM, Pulka G, Wollenberg A, Galus R, et al. Nemolizumab in patients with moderate-to-severe atopic dermatitis: randomized, phase II, long-term extension study. J Allergy Clin Immunol. 2018;142:1121–30 (e7).
pubmed: 29753033 doi: 10.1016/j.jaci.2018.03.018
Silverberg JI, Pinter A, Pulka G, Poulin Y, Bouaziz J-D, Wollenberg A, et al. Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus. J Allergy Clin Immunol. 2020;145:173–82.
pubmed: 31449914 doi: 10.1016/j.jaci.2019.08.013
Sidbury R, Alpizar S, Laquer V, Dhawan S, Abramovits W, Loprete L, et al. Pharmacokinetics, safety, efficacy, and biomarker profiles during nemolizumab treatment of atopic dermatitis in adolescents. Dermatol Ther (Heidelb). 2022;12:631–42.
pubmed: 35088348 pmcid: 8941010 doi: 10.1007/s13555-021-00678-7
Kabashima K, Matsumura T, Komazaki H, Kawashima M. Trial of nemolizumab and topical agents for atopic dermatitis with pruritus. N Engl J Med. 2020;383:141–50.
pubmed: 32640132 doi: 10.1056/NEJMoa1917006
Kabashima K, Matsumura T, Komazaki H, Kawashima M, for the 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*. Br J Dermatol. 2022;186:642–51.
Igarashi A, Katsunuma T, Matsumura T, Komazaki H, for the Nemolizumab-JP04 Study Group, Takahashi H, et al. Efficacy and safety of nemolizumab in paediatric patients aged 6–12 years with atopic dermatitis with moderate-to-severe pruritus: results from a phase III, randomized, double-blind, placebo-controlled, multicentre study. British Journal of Dermatology. 2023;190:20–8.
Silverberg JI, Wollenberg A, Reich A, Thaçi D, Legat FJ, Papp KA, 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. The Lancet. 2024;404:445–60.
doi: 10.1016/S0140-6736(24)01203-0
Guttman-Yassky E, Pavel AB, Zhou L, Estrada YD, Zhang N, Xu H, et al. GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;144:482–93 (e7).
pubmed: 30738171 doi: 10.1016/j.jaci.2018.11.053
Nakagawa H, Iizuka H, Nemoto O, Shimabe M, Furukawa Y, Kikuta N, et al. Safety, tolerability and efficacy of repeated intravenous infusions of KHK4083, a fully human anti-OX40 monoclonal antibody, in Japanese patients with moderate to severe atopic dermatitis. J Dermatol Sci. 2020;99:82–9.
pubmed: 32651105 doi: 10.1016/j.jdermsci.2020.06.005
Weidinger S, Bieber T, Cork MJ, Reich A, Wilson R, Quaratino S, et al. Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial. Br J Dermatol. 2023;189:531–9.
pubmed: 37463508 doi: 10.1093/bjd/ljad240
Tkachev V, Furlan SN, Watkins B, Hunt DJ, Zheng HB, Panoskaltsis-Mortari A, et al. Combined OX40L and mTOR blockade controls effector T cell activation while preserving T
pubmed: 28931653 pmcid: 5681253 doi: 10.1126/scitranslmed.aan3085
Saghari M, Gal P, Gilbert S, Yateman M, Porter-Brown B, Brennan N, et al. OX40L inhibition suppresses KLH-driven immune responses in healthy volunteers: a randomized controlled trial demonstrating proof-of-pharmacology for KY1005. Clin Pharma Therapeutics. 2022;111:1121–32.
doi: 10.1002/cpt.2539
Weidinger S, Blauvelt A, Papp K, Reich A, Lee C-H, Worm M, et al. 523 - Efficacy and safety of amlitelimab (an anti-OX40 ligand antibody) in patients with moderate-to-severe atopic dermatitis: 24-week results from a phase 2b trial (STREAM-AD). Br J Dermatol. 2024;190:ii24–6.
doi: 10.1093/bjd/ljad498.028
Guttman-Yassky E, Simpson EL, Reich K, Kabashima K, Igawa K, Suzuki T, et al. An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study. The Lancet. 2023;401:204–14.
doi: 10.1016/S0140-6736(22)02037-2
Gudi G, A VC, Gn S, Von Gunten C, Back J, Fang H, et al. Clinical pharmacokinetics and immunogenicity of GBR 830, a first-in-class humanized monoclonal antibody inhibiting OX40 to treat atopic dermatitis. J Investig Dermatol. 2018;138:S185.
doi: 10.1016/j.jid.2018.03.1107
Rewerska B, Sher LD, Alpizar S, Pauser S, Pulka G, Mozaffarian N, et al. Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2024;3: 100195.
Ichnos Sciences Enters Licensing Agreement For OX40 Antagonist Monoclonal Antibody Portfolio With Astria Therapeutics. https://iginnovate.com/2024/01/16/ichnos-sciences-enters-licensing-agreement-for-ox40-antagonist-monoclonal-antibody-portfolio-with-astria-therapeutics/ . Accessed May 23, 2024.
Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.
pubmed: 31175342 doi: 10.1038/s41573-019-0028-1
Tietz J, Gunde T, Warmuth S, Weinert C, Brock M, Simonin A, et al. A bispecific, tetravalent antibody targeting inflammatory and pruritogenic pathways in atopic dermatitis. JID Innov. 2024;4: 100258.
pubmed: 38375189 pmcid: 10875227 doi: 10.1016/j.xjidi.2024.100258
Deng F, Qiu Y, Zhang X, Guo N, Hu J, Yang W, et al. GB12-09, a bispecific antibody targeting IL4Rα and IL31Rα for atopic dermatitis therapy. Antibody Therapeutics. 2024;7:77–87.
pubmed: 38371956 pmcid: 10873276 doi: 10.1093/abt/tbad032
Luo J, Zhu Z, Zhai Y, Zeng J, Li L, Wang D, et al. The role of TSLP in atopic dermatitis: from pathogenetic molecule to therapeutical target. Tsuji F, editor. Mediators of Inflammation. 2023;2023:1–8.
Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, et al. Tezepelumab, an anti–thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial. J Am Acad Dermatol. 2019;80:1013–21.
pubmed: 30550828 doi: 10.1016/j.jaad.2018.11.059
Parish JL, Appel JE, Silverberg JI, Zhang C, Teng S-W, Zhang J, et al. Clinical efficacy, safety, and pharmacokinetic profile of bosakitug (BSI-045B), an anti-Thymic Stromal Lymphopoietin (TSLP) mAb in a phase 2 study of moderate and severe atopic dermatitis subjects. Revolutionizing Atopic Dermatitis conference 2024; Chicago, Illinois, USA; June 8-10, 2024.
Maudinet A, Law-Koune S, Duretz C, Lasek A, Modiano P, Tran THC. Ocular surface diseases induced by dupilumab in severe atopic dermatitis. Ophthalmol Ther. 2019;8:485–90.
pubmed: 31230264 pmcid: 6692787 doi: 10.1007/s40123-019-0191-9
Guttman-Yassky E, Blauvelt A, Eichenfield LF, Paller AS, Armstrong AW, Drew J, et al. Efficacy and safety of lebrikizumab, a high-affinity interleukin 13 inhibitor, in adults with moderate to severe atopic dermatitis: a phase 2b randomized clinical trial. JAMA Dermatol. 2020;156:411.
pubmed: 32101256 pmcid: 7142380 doi: 10.1001/jamadermatol.2020.0079
Ferreira S, Torres T. Conjunctivitis in patients with atopic dermatitis treated with dupilumab. DIC. 2020;9:1–8.

Auteurs

José Miguel Alvarenga (JM)

Department of Dermatology, Unidade Local de Saúde de Santo António, Porto, Portugal.

Thomas Bieber (T)

Department of Dermatology, University Hospital of Zürich, Zürich, Switzerland.
University of Bonn, Bonn, Germany.
Christine Kühne-Center for Allergy Research and Education, Medicine Campus Davos, Davos, Switzerland.

Tiago Torres (T)

Department of Dermatology, Unidade Local de Saúde de Santo António, Porto, Portugal. torres.tiago@outlook.com.
Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal. torres.tiago@outlook.com.

Classifications MeSH