Portal de Periódicos da CAPES

Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial

2012; Elsevier BV; Volume: 132; Issue: 10 Linguagem: Inglês

10.1038/jid.2012.163

1523-1747

Kim Papp, Cathy Reid, Peter Foley, Rod Sinclair, David H. Salinger, Gary W. Williams, Hua Dong, James G. Krueger, Chris B. Russell, Roland Martinꝉ,

IL-33, ST2, and ILC Pathways

adverse events IL-17 receptor intravenously messenger RNA subcutaneously TO THE EDITOR IL-17 has emerged as a central factor in the pathogenesis of inflammatory and autoimmune diseases, including psoriasis (Di Cesare et al., 2009Di Cesare A. Di Meglio P. Nestle F.O. The IL-23/Th17 axis in the immunopathogenesis of psoriasis.J Invest Dermatol. 2009; 129: 1339-1350Abstract Full Text Full Text PDF PubMed Scopus (831) Google Scholar; Nograles and Krueger, 2011Nograles K.E. Krueger J.G. Anti-cytokine therapies for psoriasis.Exp Cell Res. 2011; 317: 1293-1300Crossref PubMed Scopus (43) Google Scholar). Both IL-17A and IL-17F are expressed at elevated levels in psoriatic skin (Johansen et al., 2009Johansen C. Usher P.A. Kjellerup R.B. et al.Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.Br J Dermatol. 2009; 160: 319-324Crossref PubMed Scopus (257) Google Scholar) and bind as homodimers or heterodimers to the IL-17 receptor (IL-17R), a heterodimer of IL-17RA and IL-17RC subunits (Iwakura et al., 2011Iwakura Y. Ishigame H. Saijo S. et al.Functional specialization of interleukin-17 family members.Immunity. 2011; 34: 149-162Abstract Full Text Full Text PDF PubMed Scopus (978) Google Scholar). IL-17RA is highly expressed on keratinocytes and in psoriasis lesions (Nograles et al., 2008Nograles K.E. Zaba L.C. Guttman-Yassky E. et al.Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.Br J Dermatol. 2008; 159: 1092-1102PubMed Google Scholar; Johansen et al., 2009Johansen C. Usher P.A. Kjellerup R.B. et al.Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.Br J Dermatol. 2009; 160: 319-324Crossref PubMed Scopus (257) Google Scholar). Early improvement in psoriasis after starting anti-tumor necrosis factor therapy is highly correlated with reductions in IL-17 and its signaling pathway (Zaba et al., 2009Zaba L.C. Suarez-Farinas M. Fuentes-Duculan J. et al.Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.J Allergy Clin Immunol. 2009; 124 (e395): 1022-1030Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar). A recent study with an anti-IL-17A mAb demonstrated partial histological and clinical improvement in psoriasis (Hueber et al., 2010Hueber W. Patel D.D. Dryja T. et al.Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis.Sci Transl Med. 2010; 2: 52ra72Crossref PubMed Scopus (739) Google Scholar), and suggested that IL-17 may be a co-conspirator along with other cytokines in psoriasis pathogenesis. IL-17RA is a heteromeric partner for other IL-17 coreceptors when binding various ligands (Gaffen, 2009Gaffen S.L. Structure and signalling in the IL-17 receptor family.Nat Rev Immunol. 2009; 9: 556-567Crossref PubMed Scopus (1063) Google Scholar, Gaffen, 2011Gaffen S.L. Recent advances in the IL-17 cytokine family.Curr Opin Immunol. 2011; 23: 613-619Crossref PubMed Scopus (227) Google Scholar) and thus blockade of IL-17RA offers the opportunity to prevent stimulatory signals by multiple IL-17 family ligands through the receptor complex using an IL-17RA-specific antagonist. AMG 827 is a human, IgG2 mAb that binds with high affinity (Kd=239pM) to human IL-17RA and prevents binding and biological activity of IL-17A, IL-17A/F, IL-17F, and IL-25. Twenty-five psoriasis subjects received a single dose of either AMG 827 (n=20; 4 at 140mg subcutaneously (SC), 8 each at 350mg SC and 700mg intravenously (IV)) or placebo (n=5) and followed for 85 days. Psoriasis Area and Severity Index (PASI) score ≥10 and affected BSA ≥10% were required to enroll. Most subjects were men (76%), median age (range) was 43 (19–55) years, and mean (standard deviation) baseline PASI score was 14.1 (3.7) (Supplementary Table S1 online). Skin biopsies were obtained from all subjects pretreatment (lesional and nonlesional) and twice after dosing (lesional only on weeks 2 and 6 except for four AMG 827 subjects (350mg) who had lesional biopsies on weeks 1 and 2). Dose selection for psoriasis subjects was based on previous safety and pharmacokinetic experience of AMG 827 in healthy volunteers and utilized an adaptive design to enable a broad range of exposures and responses to AMG 827 (see Supplemental materials online). Download .pdf (.37 MB) Help with pdf files Supplementary Information A single dose of AMG 827 at 350mg administered SC or 700mg IV resulted in rapid, dose-dependent improvement in PASI scores (Figure 1), static Physician Global Assessment (Supplementary Figure S1 online), and clinical appearance (Supplementary Figure S2 online) within 2 weeks after dosing. All 8 subjects receiving AMG 827 700mg IV achieved 50% improvement in PASI (PASI 50) by day 29, 7 (88%) had PASI 75 by day 43, and 3 (38%) reached PASI 90 by day 43. In the AMG 827 350mg SC cohort, 6 of 8 (75%) and 3 of 8 (38%) subjects achieved PASI 50 and PASI 75, respectively. PASI 50 was achieved by 2 of 4 subjects in the 140mg SC AMG 827 cohort and none of the placebo subjects. Significant reductions in epidermal thickening, keratin 16 (KRT16) levels, and Ki67-expressing cells were observed in subjects receiving AMG 827 at 350mg SC (P<0.05) and 700mg IV (P<0.001) (Figure 2a, Supplementary Figure S2 online), and these changes were noted on day 8 (350mg SC cohort only) or day 15 (140mg SC and 700mg IV cohorts). KRT16 protein expression in suprabasal keratinocytes was reduced to the range seen in nonlesional skin by day 43 in 7 of 8 subjects receiving 700mg IV (Figure 2b and data not shown). Following treatment with AMG 827, rapid and significant improvements were noted in lesional skin messenger RNA (mRNA) levels for a number of IL-17-modulated keratinocyte-derived factors, including DEFB4, cathelicidin (CAMP), KRT16, CCL18, and CCL20 (Figure 2c). mRNAs for cytokines that are not known to be directly regulated by IL-17R, including IL-22 and both subunits of IL-23 (IL-23A (not shown) and IL-12B), were also reduced in skin within 2 weeks of treatment with AMG 827. The mRNA levels of IL-17A (Figure 2c), as well as IL-17C and IL-17F (not shown), were reduced to nonlesional levels over 6 weeks. Safety profiles among the subjects who received AMG 827 and placebo were similar (Supplementary Table S2 online). In this small sample, no deaths, serious adverse events (AEs), dose-limiting toxicities, or withdrawals owing to AEs were reported. Treatment-emergent AEs were all mild or moderate in severity and were similar between AMG 827 and placebo cohorts with the exception of Koebner phenomena at the biopsy site, which was noted in three subjects who received AMG 827. Two subjects (one each in 350mg SC and 700mg IV groups) tested positive for anti-AMG 827 antibodies (non-neutralizing) on day 85 only. The AMG 827 serum concentration versus time profiles exhibited nonlinear pharmacokinetics. Pharmacokinetic parameters and concentration–time profiles for the 700mg IV dose in psoriasis subjects appeared to be comparable to those seen in healthy volunteers (Supplementary Table S3 online). These results demonstrate that symptoms of psoriasis may emanate from IL-17R activation, possibly through multiple IL-17 ligands. Key clinical and histological features of psoriasis were rapidly eliminated in the majority of subjects receiving AMG 827, most notably in the higher-dose cohorts. IL-17 effects on keratinocytes are well known (Nograles et al., 2008Nograles K.E. Zaba L.C. Guttman-Yassky E. et al.Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.Br J Dermatol. 2008; 159: 1092-1102PubMed Google Scholar); however, additional cell types, including various leukocyte populations present in psoriatic lesions, express IL-17R, hence the beneficial effects of AMG 827 may result from decreased inflammation from multiple synergistic cellular sources (Chiricozzi et al., 2011Chiricozzi A. Guttman-Yassky E. Suarez-Farinas M. et al.Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis.J Invest Dermatol. 2011; 131: 677-687Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar). To our knowledge, this study demonstrating that blockade of signaling through IL-17R induces a complete response of psoriasis as indicated by the PASI 75 response in the majority of subjects and a complete reversal of regenerative epidermal hyperplasia is previously unreported. This first-in-human clinical study of AMG 827 indicated that single doses up to 700mg IV had an acceptable safety profile in this small sample, and provides evidence that factors signaling through IL-17RA, including IL-17A and IL-17F, are proximal and central drivers of psoriasis immunopathogenesis. The promising results seen with AMG 827 warrant further study of this biologic in clinical trials, including a larger phase II study that has been completed (Papp et al., 2011Papp K. Leonardi C. Menter A. et al.Efficacy and safety of AMG 827 in subjects with moderate to severe plaque psoriasis: results of a phase 2, randomized, double-blind, placebo-controlled study.World Congress of Dermatology, Seoul, South Korea. 2011: 24-29Google Scholar). The study protocol was approved by the institutional review board or ethics committee at each study site and all subjects provided written consent before initiation of study-specific procedure. This study was registered under the US NIH ClinicalTrials.gov identifier NCT00867100 and was conducted in compliance with the Declaration of Helsinki. This study was funded by Amgen. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid