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Revisiting Therapies for Atopic Dermatitis that Failed Clinical Trials

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Abstract

Multiple pathways contribute to the pathogenesis of atopic dermatitis (AD), and various targeted topical, biologic, and oral systemic agents have subsequently been developed. This review examines the mechanism of action and study designs of agents that have failed trials for AD to identify lessons that may shed light on reasons for their failure. Clinicaltrials.gov was searched for completed, placebo-controlled phase II and III studies assessing agents for AD that did not meet the primary endpoint, specifically reduction of AD severity. PubMed was then searched for further data on the agents identified with known mechanism of actions. Only phase II trials met inclusion criteria. Analyses of the mechanisms of action, study design, and patient demographics of the failed clinical trials for the following agents are presented: apremilast and roflumilast (PDE-4 inhibitors), fevipiprant and temapiprant (CRTH2 inhibitors), and tezepelumab and ustekinumab (monoclonal antibodies). Agents that did not meet their trial endpoints for AD may still hold therapeutic value in certain subpopulation groups or other diseases. Validating phase II trials based off subgroup analyses from previous trials may be warranted as our understanding of the pathophysiology of AD continues to grow.

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References

  1. Czarnowicki T, He H, Krueger JG, Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol. 2019;143:1.

    PubMed  Google Scholar 

  2. Guttman-Yassky E, Krueger JG. Atopic dermatitis and psoriasis: two different immune diseases or one spectrum? Curr Opin Immunol. 2017;48:68–73.

    CAS  PubMed  Google Scholar 

  3. Ogawa E, Sato Y, Minagawa A, Okuyama R. Pathogenesis of psoriasis and development of treatment. J Dermatol. 2018;45:264–72.

    CAS  PubMed  Google Scholar 

  4. Suarez-Farinas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C, Krueger JG, Guttman-Yassky E. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013;132:361–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Esaki H, Brunner PM, Renert-Yuval Y, Czarnowicki T, Huynh T, Tran G, Lyon S, Rodriguez G, Immaneni S, Johnson DB, Bauer B. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J Allergy Clin Immunol. 2016;138:1639–51.

    CAS  PubMed  Google Scholar 

  6. Noda S, Suarez-Farinas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, Peng X, Estrada YD, Nakajima S, Honda T, Shin JU. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015;136:1254–64.

    CAS  PubMed  Google Scholar 

  7. Li H, Zuo J, Tang W. Phosphodiesterase-4 inhibitors for the treatment of inflammatory diseases. Front Pharmacol. 2018;9:1048.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Butler JM, Chan SC, Stevens S, Hanifin JM. Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol. 1983;71:490–7.

    CAS  PubMed  Google Scholar 

  9. Cooper KD, Kang K, Chan SC, Hanifin JM. Phosphodiesterase inhibition by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis cells in vitro. J Investig Dermatol. 1985;84:477–82.

    CAS  PubMed  Google Scholar 

  10. Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17–26.

    PubMed  Google Scholar 

  11. Anacor Pharmaceuticals. EUCRISA™ (crisaborole) ointment, 2%, for topical use. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207695Orig1s000Lbl.pdf. Accessed 4 Sept 2019.

  12. Simpson EL, Imafuku S, Poulin Y, Ungar B, Zhou L, Malik K, Wen HC, Xu H, Estrada YD, Peng X, Chen M. A phase 2 randomized trial of apremilast in patients with atopic dermatitis. J Investig Dermatol. 2019;139:1063–72.

    CAS  PubMed  Google Scholar 

  13. Crowley J, Thaci D, Joly P, Peris K, Papp KA, Goncalves J, Day RM, Chen R, Shah K, Ferrándiz C, Cather JC. Long-term safety and tolerability of apremilast in patients with psoriasis: pooled safety analysis for ≥ 156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77:310–7.

    CAS  PubMed  Google Scholar 

  14. Mease PJ, Gladman DD, Gomez-Reino JJ, Hall S, Kavanaugh A, Lespessailles E, Schett G, Paris M, Teng L, Wollenhaupt J. Consistent safety profile with up to 4 years of apremilast treatment: analysis of data from 1493 subjects with psoriatic arthritis in 3 large, phase III, long-term studies [abstract]. Arthritis Rheumatol. 2017;69:604.

    Google Scholar 

  15. Yu S, Li Y, Zhou Y, Follansbee T, Hwang ST. Immune mediators and therapies for pruritus in atopic dermatitis and psoriasis. J Cutan Immunol Allergy. 2019;2:4–14.

    Google Scholar 

  16. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, Ramon M, Bergman R, Krueger JG, Guttman-Yassky E. IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009;123:1244–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Martel BC, Litman T, Hald A, Norsgaard H, Lovato P, Dyring-Andersen B, Skov L, Thestrup-Pedersen K, Skov S, Skak K, Poulsen LK. Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis. Exp Dermatol. 2016;25:453–9.

    CAS  PubMed  Google Scholar 

  18. Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Investig Dermatol. 2008;128:2625–30.

    CAS  PubMed  Google Scholar 

  19. Czarnowicki T, Gonzalez J, Shemer A, Malajian D, Xu H, Zheng X, Khattri S, Gilleaudeau P, Sullivan-Whalen M, Suárez-Fariñas M, Krueger JG. Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population. J Allergy Clin Immunol. 2015;136:104–15.

    CAS  PubMed  Google Scholar 

  20. Gottlieb AB, Matheson RT, Menter A, Leonardi CL, Day RM, Hu C, Schafer PH, Krueger JG. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol. 2013;12:888–97.

    CAS  PubMed  Google Scholar 

  21. Kitzen JM, Pergolizzi JV Jr, Taylor R Jr, Raffa RB. Crisaborole and apremilast: PDE4 inhibitors with similar mechanism of action, different indications for management of inflammatory skin conditions. Pharmacol Pharm. 2018;9:357.

    CAS  Google Scholar 

  22. Paller AS, Tom WL, Lebwohl MG, Blumenthal RL, Boguniewicz M, Call RS, Eichenfield LF, Forsha DW, Rees WC, Simpson EL, Spellman MC, Stein Gold LF, Zaenglein AL, Hughes MH, Zane LT, Hebert AA. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75:494–503.

    CAS  PubMed  Google Scholar 

  23. Lee HH, Patel KR, Rastogi S, Singam V, Vakharia PP, Chopra R, Silverberg JI. Placebo-responses in randomized controlled trials for systemic therapy in atopic dermatitis: a systematic review and meta-analysis. J Am Acad Dermatol. 2019. https://doi.org/10.1016/j.jaad.2019.05.102.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bissonnette R, Pavel AB, Diaz A, Werth JL, Zang C, Vranic I, Purohit VS, Zielinski MA, Vlahos B, Estrada YD, Proulx ES, Ports WC, Guttman-Yasky E. Crisaborole and atopic dermatitis skin biomarkers: an intrapatient randomized trial. J Allergy Clin Immunol. 2019;144:1274–89.

    CAS  PubMed  Google Scholar 

  25. Reich A, Riepe C, Anastasiadou Z, Mędrek K, Augustin M, Szepietowski JC, Ständer S. Itch assessment with visual analogue scale and numerical rating scale: determination of minimal clinically important difference in chronic itch. Acta Dermatovenereol. 2016;96:978–80.

    Google Scholar 

  26. Nygaard U, Deleuran M, Vestergaard C. Emerging treatment options in atopic dermatitis: topical therapies. Dermatology. 2017;233:333–43.

    PubMed  Google Scholar 

  27. Snape SD, Wigger-Alberti W, Goehring UM. A phase I randomized trial to assess the effect on skin infiltrate thickness and tolerability of topical phosphodiesterase inhibitors in the treatment of psoriasis vulgaris using a modified psoriasis plaque test. Br J Dermatol. 2016;175:479–86.

    CAS  PubMed  Google Scholar 

  28. Arcutis, Inc. Arcutis, Inc.’s ARQ-151 Development Program for Plaque Psoriasis. BioSpace. https://www.biospace.com/article/arcutis-inc-s-arq-151-development-program-for-plaque-psoriasis/. Published 2019. Accessed 20 Sept 2019.

  29. AD Breakthrough? Medimetriks’ MM36 Achieves Rapid Itch Relief, Safety in Phase 2 Study. https://practicaldermatology.com/news/ad-breakthrough-medimetriks-mm36-achieves-rapid-itch-relief-safety-in-phase-2-study. Practical Dermatology. Published 2017. Accessed 23 Sept 2019.

  30. Townley RG, Agrawal S. CRTH2 antagonists in the treatment of allergic responses involving TH2 cells, basophils, and eosinophils. Ann Allergy Asthma Immunol. 2012;109:365–74.

    CAS  PubMed  Google Scholar 

  31. Mathiesen JM, Christopoulos A, Ulven T, Royer JF, Campillo M, Heinemann A, Pardo L, Kostenis E. On the mechanism of interaction of potent surmountable and insurmountable antagonists with the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2006;69:1441–53.

    CAS  PubMed  Google Scholar 

  32. Kao CC, Parulekar AD. Spotlight on fevipiprant and its potential in the treatment of asthma: evidence to date. J Asthma Allergy. 2019;12:1–5.

    PubMed  PubMed Central  Google Scholar 

  33. Chang JE, Doherty TA, Baum R, Broide D. Prostaglandin D2 regulates human type 2 innate lymphoid cell chemotaxis. J Allergy Clin Immunol. 2014;133:899–901.

    CAS  PubMed  Google Scholar 

  34. Kupczyk M, Kuna P. Targeting the PGD2/CRTH2/DP1 signaling pathway in asthma and allergic disease: current status and future perspectives. Drugs. 2017;77:1281–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Straumann A, Hoesli S, Bussmann C, Stuck M, Perkins M, Collins LP, Payton M, Pettipher R, Hunter M, Steiner J, Simon HU. Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis. Allergy. 2013;68:375–85.

    CAS  PubMed  Google Scholar 

  36. Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol. 2017;139:S65–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Oldhoff JM, Darsow U, Werfel T, Katzer K, Wulf A, Laifaoui J, Hijnen DJ, Plötz S, Knol EF, Kapp A, Bruijnzeel-Koomen CA. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005;60:693–6.

    CAS  PubMed  Google Scholar 

  38. Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, van der Merwe R. 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.

    CAS  PubMed  Google Scholar 

  39. Fujisawa T, Fujisawa R, Kato Y, Nakayama T, Morita A, Katsumata H, Nishimori H, Iguchi K, Kamiya H, Gray PW, Chantry D. Presence of high contents of thymus and activation-regulated chemokine in platelets and elevated plasma levels of thymus and activation-regulated chemokine and macrophage-derived chemokine in patients with atopic dermatitis. J Allergy Clin Immunol. 2002;110:139–46.

    CAS  PubMed  Google Scholar 

  40. Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, Bautista DM. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155:285–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Paller AS, Kabashima K, Bieber T. Therapeutic pipeline for atopic dermatitis: end of the drought? J Allergy Clin Immunol. 2017;140:633–43.

    PubMed  Google Scholar 

  42. Kim J, Kim BE, Lee J, Han Y, Jun HY, Kim H, Choi J, Leung DY, Ahn K. Epidermal thymic stromal lymphopoietin predicts the development of atopic dermatitis during infancy. J Allergy Clin Immunol. 2016;137:1282–5.

    CAS  PubMed  Google Scholar 

  43. Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, van der Merwe R. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936–46.

    CAS  PubMed  Google Scholar 

  44. Benson JM, Peritt D, Scallon BJ, Heavner GA, Shealy DJ, Giles-Komar JM, Mascelli MA. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs. 2011;3:535–45.

    PubMed  PubMed Central  Google Scholar 

  45. Saeki H, Kabashima K, Tokura Y, Murata Y, Shiraishi A, Tamamura R, Randazzo B, Imanaka K. Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study. Br J Dermatol. 2017;177:419–27.

    CAS  PubMed  Google Scholar 

  46. Khattri S, Brunner PM, Garcet S, Finney R, Cohen SR, Oliva M, Dutt R, Fuentes-Duculan J, Zheng X, Li X, Bonifacio KM. Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol. 2017;26:28–35.

    CAS  PubMed  Google Scholar 

  47. Czarnowicki T, Malajian D, Shemer A, Fuentes-Duculan J, Gonzalez J, Suárez-Fariñas M, Krueger JG, Guttman-Yassky E. Skin-homing and systemic T-cell subsets show higher activation in atopic dermatitis versus psoriasis. J Allergy Clin Immunol. 2015;136:208–11.

    PubMed  Google Scholar 

  48. Savage LJ, Wittmann M, McGonagle D, Helliwell PS. Ustekinumab in the treatment of psoriasis and psoriatic arthritis. Rheumatol Ther. 2015;2:1–16.

    PubMed  PubMed Central  Google Scholar 

  49. Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, Ming JE, Ren H, Kao R, Simpson E, Ardeleanu M. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–9.

    PubMed  Google Scholar 

  50. Pocock SJ, Stone GW. The primary outcome fails—what next? N Engl J Med. 2016;375:861–70.

    PubMed  Google Scholar 

  51. Rosenfeld PJ, Feuer WJ. Lessons from recent phase III trial failures: don’t design phase III trials based on retrospective subgroup analyses from phase II trials. Ophthalmology. 2018;125:1488–91.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Gaurav Agnihotri

  2. Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Peter A. Lio

  3. Medical Dermatology Associates of Chicago, 363 W Erie Street, Suite 350, Chicago, IL, 60654, USA

    Peter A. Lio

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  1. Gaurav Agnihotri
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Correspondence to Peter A. Lio.

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Gaurav Agnihotri reports no conflicts of interest. Peter Lio has served as an investigator for AbbVie, Regeneron/Sanofi-Genzyme, and AOBiome. He has served as an advisor/consultant for AbbVie, AOBiome, Dermavant, Dermira, Eli Lilly, Exeltis, Galderma, IntraDerm, Johnson and Johnson, Kiniksa, L’Oreal, Menlo Therapeutics, Micreos, Pfizer, Pierre Fabre, Realm, Regeneron/Sanofi-Genzyme, Theraplex, UCB, and Unilever. He has served as a speaker for L’Oreal, Pfizer, TopMD, and Regeneron/Sanofi-Genzyme.

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Agnihotri, G., Lio, P.A. Revisiting Therapies for Atopic Dermatitis that Failed Clinical Trials. Clin Drug Investig 40, 421–431 (2020). https://doi.org/10.1007/s40261-020-00905-7

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