Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis

. 2024 Feb ; 3 (1) : 100195. [epub] 20231122

Status PubMed-not-MEDLINE Jazyk angličtina Země Spojené státy americké Médium electronic-ecollection

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid38187863
Odkazy

PubMed 38187863
PubMed Central PMC10770725
DOI 10.1016/j.jacig.2023.100195
PII: S2772-8293(23)00120-0
Knihovny.cz E-zdroje

BACKGROUND: Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell-mediated diseases. OBJECTIVE: This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. METHODS: In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks' blinded treatment, followed by 38 weeks' open-label treatment and 12 weeks' drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. RESULTS: The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (-54.4% vs -34.2% for part 1 and -59.0% vs -41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. CONCLUSION: Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.

Zobrazit více v PubMed

Deckers I.A., McLean S., Linssen S., Mommers M., van Schayck C.P., Sheikh A. Investigating international time trends in the incidence and prevalence of atopic eczema, 1990-2010: a systematic review of epidemiological studies. PLoS One. 2012;7 PubMed PMC

Simpson E.L., Bieber T., Guttman-Yassky E., Beck L.A., Blauvelt A., Cork M.J., et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335–2348. PubMed

Guttman-Yassky E., Teixeira H.D., Simpson E.L., Papp K.A., Pangan A.L., Blauvelt A., et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397:2151–2168. PubMed

Leung D.Y., Guttman-Yassky E. Assessing the current treatment of atopic dermatitis: unmet needs. J Allergy Clin Immunol. 2017;139:S47–S48. PubMed

Stander S. Atopic dermatitis. N Engl J Med. 2021;384:1136–1143. PubMed

Deleanu D., Nedelea I. Biological therapies for atopic dermatitis: an update. Exp Ther Med. 2019;17:1061–1067. PubMed PMC

Blauvelt A., de Bruin-Weller M., Gooderham M., Cather J.C., Weisman J., Pariser D., et al. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017;389:2287–2303. PubMed

Thaci D., LS E., Deleuran M., Kataoka Y., Chen Z., Gadkari A., et al. Efficacy and safety of dupilumab monotherapy in adults with moderate-to-severe atopic dermatitis: a pooled analysis of two phase 3 randomized trials (LIBERTY AD SOLO 1 and LIBERTY AD SOLO 2) J Dermatol Sci. 2019;94:266–275. PubMed

Wollenberg A., Beck L.A., Blauvelt A., Simpson E.L., Chen Z., Chen Q., et al. Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS) Br J Dermatol. 2020;182:1120–1135. PubMed PMC

Blauvelt A., Teixeira H.D., Simpson E.L., Costanzo A., De Bruin-Weller M., Barbarot S., et al. Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-wevere atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2021;157:1047–1055. PubMed PMC

Rinvoq. Package insert. AbbVie Inc; North Chicago (Ill): April 2022.

Kabashima K., Matsumura T., Komazaki H., Kawashima M., Nemolizumab-JP01 Study Group Trial of nemolizumab and topical agents for atopic dermatitis with pruritus. N Engl J Med. 2020;383:141–150. PubMed

Wollenberg A., Blauvelt A., Guttman-Yassky E., Worm M., Lynde C., Lacour J.P., et al. Tralokinumab for moderate-to-severe atopic dermatitis: results from two 52-week, randomized, double-blind, multicentre, placebo-controlled phase III trials (ECZTRA 1 and ECZTRA 2) Br J Dermatol. 2021;184:437–449. PubMed PMC

Guttman-Yassky E., Blauvelt A., Eichenfield L.F., Paller A.S., Armstrong A.W., 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;156:411–420. PubMed PMC

Simpson E.L., Gooderham M., Wollenberg A., Weidinger S., Armstrong A., Soung J., et al. Efficacy and safety of lebrikizumab in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis: a randomized clinical trial (ADhere) JAMA Dermatol. 2023;159:182–191. PubMed PMC

Simpson E.L., Sinclair R., Forman S., Wollenberg A., Aschoff R., Cork M., et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020;396:255–266. PubMed

Silverberg J.I., Simpson E.L., Thyssen J.P., Gooderham M., Chan G., Feeney C., et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156:863–873. PubMed PMC

Simpson E.L., Forman S., Silverberg J.I., Zirwas M., Maverakis E., Han G., et al. Baricitinib in patients with moderate-to-severe atopic dermatitis: results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5) J Am Acad Dermatol. 2021;85:62–70. PubMed

Furue M., Furue M. OX40L-OX40 signaling in atopic dermatitis. J Clin Med. 2021;10:2578. PubMed PMC

Calderhead D.M., Buhlmann J.E., van den Eertwegh A.J., Claassen E., Noelle R.J., Fell H.P. Cloning of mouse Ox40: a T cell activation marker that may mediate T-B cell interactions. J Immunol. 1993;151:5261–5271. PubMed

Gramaglia I., Weinberg A.D., Lemon M., Croft M. Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol. 1998;161:6510–6517. PubMed

Akiba H., Oshima H., Takeda K., Atsuta M., Nakano H., Nakajima A., et al. CD28-independent costimulation of T cells by OX40 ligand and CD70 on activated B cells. J Immunol. 1999;162:7058–7066. PubMed

Kondelkova K., Vokurkova D., Krejsek J., Borska L., Fiala Z., Ctirad A. Regulatory T cells (TREG) and their roles in immune system with respect to immunopathological disorders. Acta Medica (Hradec Kralove) 2010;53:73–77. PubMed

Lathrop S.K., Huddleston C.A., Dullforce P.A., Montfort M.J., Weinberg A.D., Parker D.C. A signal through OX40 (CD134) allows anergic, autoreactive T cells to acquire effector cell functions. J Immunol. 2004;172:6735–6743. PubMed

Maxwell J.R., Yadav R., Rossi R.J., Ruby C.E., Weinberg A.D., Aguila H.L., et al. IL-18 bridges innate and adaptive immunity through IFN-gamma and the CD134 pathway. J Immunol. 2006;177:234–245. PubMed

Suarez-Farinas M., Dhingra N., Gittler J., Shemer A., Cardinale I., de Guzman Strong C., et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013;132:361–370. PubMed PMC

Noda S., Suarez-Farinas M., Ungar B., Kim S.J., de Guzman Strong C., Xu H., et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015;136:1254–1264. PubMed

Esaki H., Brunner P.M., Renert-Yuval Y., Czarnowicki T., Huynh T., Tran G., et al. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J Allergy Clin Immunol. 2016;138:1639–1651. PubMed

Nakano M., Fukumoto Y., Satoh K., Ito Y., Kagaya Y., Ishii N., et al. OX40 ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization. Cardiovasc Res. 2010;88:539–546. PubMed

Burgess J.K., Carlin S., Pack R.A., Arndt G.M., Au W.W., Johnson P.R., et al. Detection and characterization of OX40 ligand expression in human airway smooth muscle cells: a possible role in asthma? J Allergy Clin Immunol. 2004;113:683–689. PubMed

Gudi G., CA V., 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 Invest Dermatol. 2018;138(5 suppl):S185. doi: 10.1016/j.jid.2018.03.1107. DOI

Macoin J., Blein S., Monney T., Lissilaa R., Sancheti P., Reddy V., et al. GBR 830: an OX40 antagonist antibody with a favorable toxicity profile in non-human primates. J Invest Dermatol. 2018;138(5 suppl):S186. doi: 10.1016/j.jid.2018.03.1112. DOI

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;99:82–89. PubMed

Guttman-Yassky E., Pavel A.B., Zhou L., Estrada Y.D., Zhang N., Xu H., et al. GBR 830, an anti-OX40, improves skin gene-signatures and clinical scores in atopic dermatitis. J Allergy Clin Immunol. 2019;144:482–493.e7. PubMed

US Food and Drug Administration . 2018. E6(R2) good clinical practice: integrated addendum to ICH E6(R1). Guidance for industry. Rockville (MD): US Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Control; Center for Biologics Evaluation and Research.

World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–2194. PubMed

Eichenfield L.F., Tom W.L., Chamlin S.L., Feldman S.R., Hanifin J.M., Simpson E.L., et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70:338–351. PubMed PMC

Worm M., Simpson E.L., Thaci D., Bissonnette R., Lacour J.P., Beissert S., et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156:131–143. PubMed PMC

Guttman-Yassky E., Simpson E.L., 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. Lancet. 2023;401:204–214. PubMed

Furue M. Regulation of skin barrier function via competition between AHR axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis. J Clin Med. 2020;9:3741. PubMed PMC

Liu Y.J. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell–mediated allergic inflammation. J Allergy Clin Immunol. 2007;120:238–244. PubMed

Nakahara T., Kido-Nakahara M., Tsuji G., Furue M. Basics and recent advances in the pathophysiology of atopic dermatitis. J Dermatol. 2021;48:130–139. PubMed

Wang Y.H., Liu Y.J. Thymic stromal lymphopoietin, OX40-ligand, and interleukin-25 in allergic responses. Clin Exp Allergy. 2009;39:798–806. PubMed PMC

Weidinger S. 2021. A phase 2a study of KY1005, a novel non-depleting anti-OX40 ligand (OX40L) mAb in patients with moderate to severe AD. Paper presented at: 35th Congress of the European Academy of Dermatology and Venereology (EADV); September 29-Ocober 2. virtual meeting. Abstract 2729.

Kaufman B.P., Guttman-Yassky E., Alexis A.F. Atopic dermatitis in diverse racial and ethnic groups—variations in epidemiology, genetics, clinical presentation and treatment. Exp Dermatol. 2018;27:340–357. PubMed

Najít záznam

Citační ukazatele

Nahrávání dat ...

Možnosti archivace

Nahrávání dat ...