Research ArticleAutoimmune Disease

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

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Science Translational Medicine  06 Oct 2010:
Vol. 2, Issue 52, pp. 52ra72
DOI: 10.1126/scitranslmed.3001107
  • Fig. 1

    Clinical response to AIN457 in patients with chronic plaque psoriasis. Patients were treated with a single intravenous infusion of AIN457 (3 mg/kg) between week 0 and week 12. Panel 1: mean reduction in PASI; panels 2 to 4: proportion of patients with PASI50, PASI75, and PASI90, respectively. Error bars, SE. Arrow: visit at which drug or placebo was administered. (Lower panels) Clinical improvement in psoriasis in a patient treated with a single intravenous infusion of AIN457 (3 mg/kg).

  • Fig. 2

    Immunohistochemistry of skin biopsies: Representative immuno-costaining of CD3 and IL-17. (A to D) Lesional skin demonstrating colocalization of IL-17A and CD3 at baseline (week 0) and week 4 after a single dose of AIN457 (3 mg/kg) (B and D) or placebo (A and C). Cells were stained with antibodies to CD3 (Ventana) and IL-17 (R&D Systems). (E) Isotype controls: IgG mouse (red), IgG goat (brown), rabbit isotype control (Ventana), and IgG goat (Cedarlane). Yellow arrows: agglomerations of IL-17+ CD3+ cells. Magnification, ×10; scale bars, 100.8 μm. (F) Comparison of dermal CD3+/IL-17+ cell counts between week 0 and week 4. Error bars, SE. T cell counts were done manually by a pathologist. Percent of dermal CD3+/IL-17+ pixels was calculated with Aperio ImageScope software.

  • Fig. 3

    Gene expression changes in skin of patients with psoriasis treated with AIN457. Subjects were given a single dose of AIN457 (3 mg/kg) (n = 3) or placebo (n = 5) at week 4; data are expressed as compared to baseline (week 0). (A) Real-time RT-PCR analysis showing mean fold change (±SE) at week 4 relative to baseline mRNA expression normalized to human control gene [glucuronidase β (GUSB)]. *P < 0.05; **P < 0.01. (B) Affymetrix HG-U133 Plus 2.0 chip analysis showing mean fold change (±SE) at week 4 relative to baseline mRNA expression and ANOVA. *P < 0.05; **P < 0.01; ***P < 0.001.

  • Fig. 4

    ACR20, DAS28, and CRP changes for a two-dose infusion regimen of AIN457 (10 mg/kg) versus placebo. (A) The proportion of ACR20 responders (±SE) is presented for each treatment group at each visit. (B and C) Appropriate baseline-adjusted means (±SE) from the statistical models of DAS28 (B) and CRP (C) are presented for each treatment group at each visit.

  • Fig. 5

    Vitreous haze (posterior segment uveitis) or anterior chamber cells (anterior uveitis) at week 8 versus week 0. Posterior segment uveitis includes patients with intermediate, posterior, and pan uveitis. One patient with anterior uveitis discontinued at week 2 because of worsening uveitis, and thus, week 8 data were not available for this. Each line represents one individual patient.

  • Table 1

    Baseline demographics and disease characteristics for the three proof-of-concept trials. BMI, body mass index; CV, coefficient of variation; ND, not determined; VAS, visual analog scale; PGA, patient global assessment; CRP, C-reactive protein; DAS28, 28-joint Disease Activity Score; DMARD, disease-modifying antirheumatic drug; IGA, investigator global assessment; PASI, psoriasis area-and-severity index; SD, standard deviation.

    PsoriasisRheumatoid arthritisUveitis
    AIN457 (3 mg/kg)PlaceboAIN457 (10 mg/kg)PlaceboAIN457 (10 mg/kg)
    n = 18n = 18n = 26n = 26n = 16
    Age (years) (mean ± SD)50.7 ± 8.7350.9 ± 12.0449.9 ± 8.5349.8 ± 15.1942.6 ± 14.88
    Male, n (%)11 (61)13 (72)7 (27)6 (23)4 (25)
    Caucasians, n (%)17 (94)17 (94)23 (88)22 (85)7 (44)
    BMI (kg/m2) (mean ± SD)32.97 ± 7.4433.79 ± 10.5428.48 ± 6.6628.13 ± 5.58ND
    PASI (mean ± SD)18.5 ± 8.718.3 ± 8.1
    IGA score, n (%)
      2 (mild)0 (0)1
      3 (moderate)13 (72)11 (61)
      4 (severe)5 (28)5 (28)
      5 (very severe)0 (0)1 (6)
    Rheumatoid factor positive (≥10), n (%)1416 (62)
    Disease duration (years), median (range)3.9 (1–20)2.9 (1–37)
    DAS28 (mean ± SD)6.48 ± 5.737.44 ± 8.85
    CRP (mg/L), geometric mean (CV%)6.25 (113.2)10.11 (150.0)
    Previous DMARD, n (%)
      123 (88%)24 (92%)
      23 (12%)2
    PGA on 100-mm VAS (mean ± SD)67.3 ± 15.8462.1 ± 19.09
    IGA on 100-mm VAS (mean ± SD)62.3 ± 17.8565.0 ± 19.20
  • Table 2

    Adverse events. (A) Number and percent of patients in each treatment group who (i) had any AE, (ii) had an SAE, (iii) died, or (iv) discontinued the study because of an AE. AEs were assigned to a primary body system using the Medical Dictionary for Regulatory Activities (MedDRA). In each treatment group, the number (%) of patients who experienced an AE in each primary body system was calculated. (B) Body systems in which >10% of patients in at least one of the active AIN457 groups experienced an AE. Individual AEs with an event rate of >10% in at least one of the active AIN457 groups are also presented underneath the related body system. Body systems and AEs (within relevant body system) are displayed in alphabetical order. A subject experiencing multiple AEs within a body system is counted only once in the respective body system category row.

    EventsPsoriasisRheumatoid arthritisUveitis
    AIN457 (3 mg/kg)PlaceboAIN457 (10 mg/kg)PlaceboAIN457 (10 mg/kg)
    n = 18n = 18n = 26n = 26n = 16
    (A) General, n (%)
      Any AE9 (50)8 (44)2117 (65)10 (63)
      Any SAE1 (6)01 (4)20
      Death00000
      Discontinuation of follow-up owing to AE0021 (4)0
    (B) Body system, n (%)
      Eye disorders01 (6)1 (4)04 (25)
          Eye pain00002 (13)
          Ocular hyperemia00003 (19)
          Vision blurred00002 (13)
      Gastrointestinal disorders1 (6)1 (6)3 (12)5 (19)6 (38)
          Abdominal pain, upper00003 (19)
          Vomiting001 (4)3 (12)2 (13)
      General disorders and administration site conditions3 (17)1 (6)6 (23)1 (4)2 (13)
          Fatigue2 (11)1 (6)21 (4)2 (13)
      Infections and infestations5 (28)3 (17)9 (35)9 (35)2 (13)
      Injury, poisoning, and procedural complications003 (12)20
      Investigations3 (17)3 (17)001 (6)
          Blood cholesterol increased2 (11)0000
          Blood glucose increased2 (11)1 (6)000
          Blood triglycerides increased2 (11)2 (11)001 (6)
      Metabolism and nutrition disorders2 (11)0220
      Musculoskeletal and connective tissue disorders01 (6)8 (31)4 (15)4 (25)
          Back pain003 (12)1 (4)2 (13)
          Muscle spasm00202 (13)
          Rheumatoid arthritis003 (12)20
      Nervous system disorders1 (6)1 (6)5 (19)6 (23)9 (56)
          Dizziness003 (12)3 (12)1 (6)
          Headache1 (6)1 (6)1 (4)29 (56)
          Sinus headache00002 (13)
      Respiratory, thoracic, and mediastinal disorders1 (6)04 (15)3 (12)1 (6)
      Skin and subcutaneous tissue disorders2 (11)04 (15)20
      Vascular disorders2 (11)1 (6)3 (12)21 (6)
          Hypertension2 (11)1 (6)200

Additional Files

  • Supplementary Material for:

    Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

    Wolfgang Hueber, Dhavalkumar D. Patel,* Thaddeus Dryja, Andrew M. Wright, Irina Koroleva, Gerard Bruin, Christian Antoni, Zoe Draelos, Michael H. Gold, the Psoriasis Study Group, Patrick Durez, Paul P. Tak, Juan J. Gomez-Reino, the Rheumatoid Arthritis Study Group, C. Stephen Foster, Rosa Y. Kim, C. Michael Samson, Naomi S. Falk, David S. Chu, David Callanan, Quan Dong Nguyen, the Uveitis Study Group, Kristine Rose, Asifa Haider, Franco Di Padova

    *To whom correspondence should be addressed. E-mail: office.patel{at}novartis.com

    Published 6 October 2010, Sci. Transl. Med.2, 52ra72 (2010)
    DOI: 10.1126/scitranslmed.3001107

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Patient disposition for the psoriasis study, the rheumatoid arthritis study, and the noninfectious uveitis study.
    • Investigators in the study listed by indication and site.

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