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


Interleukin-17A (IL-17A) is elaborated by the T helper 17 (TH17) subset of TH cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A–producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.


The homodimeric molecule interleukin-17A (IL-17A) is a pleiotropic cytokine that is key to the definition of the CD4+ T helper 17 (TH17) cell lineage (1, 2). IL-17A and IL-17F are two IL-17 family members that are secreted by TH17 cells and share the same receptors, IL-17 receptor A (IL-17RA) and IL-17 receptor C (IL-17RC) (3). IL-17RA and IL-17RC are ubiquitously expressed, including in keratinocytes, macrophages, fibroblasts, osteoblasts, and epithelial, endothelial, and dendritic cells (4), revealing the pleiotropic nature of IL-17A. Cell activation by IL-17A can cause release of proinflammatory cytokines and mediators of tissue destruction (57). IL-17A is mainly produced by TH17 cells, which derive from naïve CD4+ T cells after stimulation by transforming growth factor–β (TGF-β) and IL-6 (1, 2). Macrophages, astrocytes, Langerhans cells, and mast cells also contribute to IL-17A production (8, 9). Moreover, TH17 cells express the IL-23 receptor (IL-23R), and IL-23 is an important survival factor for TH17 cells and production of IL-17A (10, 11). A subset of TH17 cells also secretes IL-21, IL-22, IL-26, and interferon-γ (IFN-γ) (12).

IL-17A contributes to the pathogenesis of animal models of TH1-driven autoimmunity (1315). Recent insights into the TH17/IL-17 biology from these models have led to the hypothesis that the effects of TH17 cells and their signature cytokine IL-17A can more profoundly explain T cell–dependent pathobiology in these models, replacing the TH1 paradigm, in which TH1 cytokines are the paramount mediators of tissue damage, with an expanded TH1/TH17 paradigm (16).

Although the etiology of psoriasis, noninfections uveitis, and rheumatoid arthritis (RA) is unknown and clinical presentation of these diseases is diverse, activated (auto)reactive TH cells seem to initiate and drive organ-specific inflammatory processes in all of them (1719). Moreover, the recent discovery that polymorphisms in IL-23R can control susceptibility to psoriasis, psoriatic arthritis, inflammatory bowel disease, RA, and ankylosing spondylitis (20) emphasizes the importance of the TH17 pathway and IL-17A in these and related human immune-mediated diseases.

Psoriasis is a common skin disease characterized by excessive turnover of skin cells. Activated TH cells are recognized among the primary pathogenic modulators (21). IL-23 and its downstream TH17 cytokines are likely pathogenic in human psoriatic skin, because messenger RNA (mRNA) for the TH17 cytokines IL-17A, IL-17F, and IL-22 accumulates in cutaneous lesions (17). Indeed, inhibition of p40, the shared subunit of IL-23 and IL-12, is effective in the treatment of psoriasis (22).

RA is an autoimmune disease of synovial joints, characterized by recruitment and activation of immune cells such as autoreactive T and B cells, production of proinflammatory cytokines, and cartilage and bone destruction (23). Unlike psoriasis and uveitis, which are associated with human leukocyte antigen (HLA) class I and lack specific autoantibody responses, strong HLA class II association and specific autoantibodies are hallmarks of RA. Hence, it was postulated, contrary to the earlier TH1 paradigm of RA (18), that autoreactive B cells contribute to RA pathogenesis (24), as confirmed later by the effectiveness of B cell–targeting therapies in RA (25). Nevertheless, in support of T cell involvement, in vitro–expanded CD4+ T cells from RA patients contain more TH17 cells than do controls and produce more IL-17A, as measured in synovial fluid (SF) (23). To complicate matters, non-T cells such as mast cells are also involved in synovial production of IL-17A (9). Together, these recent data suggest that IL-17A is involved in the pathogenesis of RA.

Noninfectious uveitis is a form of intraocular inflammation that remains a major cause of visual loss. Uveitis is viewed as a prototypical organ-specific T cell–driven autoimmune disease of an immune-privileged site, with TH1 cells forming the pathogenic subset (19). Recent data from the experimental autoimmune uveitis (EAU) model show a distinct role for IL-23 in eliciting disease (26), fuelling the hypothesis that both IL-17A–producing TH17 cells and TH1 cells are culprits in tissue damage. Moreover, up-regulation of IL-23 and IL-17A occurs in patients with active uveitis suffering from Behçet’s or Vogt-Koyanagi-Harada (VKH) disease, as measured by mRNA in peripheral blood mononuclear cells (PBMCs), serum enzyme-linked immunosorbent assay (ELISA), or production of IL-17A in supernatants of PBMCs (27, 28).

Together, these data suggest that IL-17A may be a therapeutic target in T cell–driven inflammatory disorders. Here, we explored IL-17A blockade with AIN457, a highly specific, human immunoglobulin G1κ (IgG1κ) monoclonal antibody, to treat psoriasis, RA, and chronic noninfectious uveitis. The objective was to assess the safety and possible efficacy of AIN457 in these disorders.


Baseline characteristics and follow-up

We enrolled a total of 104 patients (60 AIN457- and 44 placebo-treated patients) in three clinical trials. All patients participated until the specified endpoints, except for three patients in the RA trial and one in the uveitis trial. Baseline characteristics were comparable between the active treatment and placebo arms in the psoriasis and RA trials; in the open-label uveitis trial, all patients received active treatment (Table 1).

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.

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In the psoriasis trial, after a single administration of AIN457 (3 mg/kg), disease severity (the mean PASI) was reduced relative to baseline by 58% and 4% in AIN457- and placebo-treated patients, respectively (P = 0.0001). Fifteen (83%) AIN457-treated patients showed significant reductions in the investigator global assessment (IGA) score categories at week 4 relative to baseline and to placebo-treated patients (11%) (P = 0.0004). The differences in PASI and IGA were maintained at week 12, with mean reductions in PASI relative to baseline of 63% for AIN457 and 9% for placebo, respectively (P = 0.0005) (Fig. 1, panel 1). All PASI response rates (PASI50, PASI75, and PASI90, defined as proportion of patients who achieved 50%, 75%, and 90% reductions in their PASI, respectively) were higher with AIN457 treatment than placebo at week 12 (Fig. 1, panels 2 to 4). Photographs of a representative patient before and after a single infusion of AIN457 (3 mg/kg) are shown in Fig. 1, which shows a reduction in typical disease features (redness, induration, and scaling).

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).

Immunostained micrographs at baseline (week 0) and week 4 of 14 placebo- and 16 AIN457-treated patients with psoriasis showed colocalization of IL-17A and CD3 (Fig. 2, A to E). AIN457 treatment resulted in a significant decrease in the area occupied by dermal IL-17A+ CD3+ T cells (P = 0.042) (in mean pixel counts) by week 4 (Fig. 2F). Skin samples from typical psoriasis plaques, assessed with reverse transcription polymerase chain reaction (RT-PCR) and microarray analysis of gene expression for a wide array of cytokines and chemokines implicated in autoimmunity, showed substantial changes, primarily down-regulation, in response to AIN457 treatment (Fig. 3). Notably, a relatively minor change in tumor necrosis factor–α (TNF-α) expression was observed, in line with reports that TNF-α expression in psoriatic skin lesions is primarily regulated posttranscriptionally (29).

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.

In the RA trial, the American College of Rheumatology 20% response (ACR20) rates were higher with AIN457 than with placebo at week 6 (46% versus 27%, P = 0.12; treatment difference was a priori considered statistically significant if P < 0.2) (Fig. 4A). The response to treatment was rapid: ACR20 responder rates reached 50% for AIN457 and 31% for placebo as early as week 4 (P = 0.13) and was maintained at week 16 (54% versus 31%; P = 0.08). The 28-joint disease activity scores (DAS28) and C-reactive protein (CRP) values decreased over time, with greater reductions for AIN457-treated patients than for placebo at week 6 (P = 0.16 and P = 0.0013, respectively) (Fig. 4, B and C). The treatment response to AIN457 measured by the area under the response-time curve (AUC) for ACR20, DAS28, and CRP was significantly higher for AIN457 than placebo (P = 0.011, P = 0.027, and P = 0.002, respectively).

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.

All patients in the uveitis trial had active uveitis at baseline, with an anterior chamber cell score of at least 1+ for anterior uveitis cases or a vitreous haze score of at least 1+ for posterior segment uveitis (intermediate, posterior, or panuveitis). Thirteen patients showed at least a one-step decrease in ocular inflammation at week 8 compared to baseline at week 0. Two patients had no change in ocular inflammation, and one patient (with anterior uveitis and unknown HLA-B27 status) had worsening of uveitis during the 2 weeks after the first dose and dropped out of the trial (Fig. 5). The response to treatment was rapid, with 50% of patients initially achieving an anterior chamber cell score of 0 to trace and a vitreous haze score of 0 to trace by week 2. Overall, 11 of the 16 patients had responded at week 8 (Fig. 5). Of five patients with anterior uveitis, three achieved quiescence while taking no topical or systemic corticosteroids. Of 11 patients with posterior segment uveitis, 8 were categorized as responders to treatment by meeting the following criteria: 3 patients had a 15-letter improvement in visual acuity, 4 patients had a two-step reduction or complete resolution of vitreous haze, and 4 patients were able to stop topical and systemic corticosteroids without worsening of uveitis.

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.


No deaths occurred and no safety events of concern were observed in the cohort of 104 patients participating in the three studies. No antibodies to AIN457 were detected. All observed infections were not serious, and their rates were similar in the AIN457 and placebo groups.

In the psoriasis trial, one serious adverse event (SAE) (worsening of preexisting congestive cardiac disease) occurred in the AIN457 group. Adverse events (AEs) were reported in nine AIN457- and eight placebo-treated patients. Two AEs were classified as severe, whereby one occurred in an AIN457-treated patient who experienced severe pruritus. All other reported AEs were mild or moderate. None of the patients discontinued treatment because of AEs or SAEs. Infections, reported in five AIN457- and three placebo-treated patients, were all rated mild and were mostly in the upper respiratory tract.

In the RA trial, one SAE (laryngeal abscess due to RA of the cricoarytenoid joint) occurred in an AIN457-treated patient after study termination. Two other SAEs (interstitial lung disease and brachial plexopathy), both requiring hospitalization, were reported in the placebo-treated group. The overall AE incidence rate was slightly higher in the AIN457 group compared to placebo (Table 2). A total of 18 patients, 9 in each group, had not-serious infections. Most frequently observed infections were nasopharyngitis and upper respiratory tract infections. Two patients treated with AIN457 and one with placebo discontinued the study because of worsening of arthritis.

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.

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In the uveitis trial, no SAEs were reported. Ten (63%) of the 16 participating patients experienced AEs, with the most frequent AEs being headache (56%), upper abdominal pain (19%), and conjunctival hyperemia (19%).


Here, we report our exploration of the therapeutic use of a monoclonal antibody to IL-17A for the treatment of three immune-mediated human diseases: psoriasis, RA, and chronic noninfectious uveitis. One or two doses of AIN457 significantly reduced the disease activity compared to the placebo-treated group (for psoriasis and RA) or had effects comparable to those of historical control subjects for chronic noninfectious uveitis treated with a biologic therapy (30).

In psoriasis patients, we noted faster (as early as week 2) and greater benefits with AIN457 treatment than with placebo at all time points up to week 12. Because PASI50 or greater response rates are generally considered a relevant difference, almost 75% of patients on AIN457 achieved a clinically meaningful reduction of disease activity. These clinical responses in patients treated with AIN457 were associated with reductions of histomorphological signs of acanthosis and epidermal hyperplasia, and changes in gene expression of markers of the IL-17A pathway. As shown by RT-PCR and array analysis, expression of IL-17A and IL-22 was markedly reduced after therapy with AIN457. Blockade of IL-17A had broad anti-inflammatory effects as shown by down-regulation of many mediators, including upstream cytokines such as IL-12B (the p40 subunit of IL-23 and IL-12) or downstream cytokines such as CCL20 [chemokine (C-C motif) ligand 20]. Moreover, our immunohistochemical data demonstrated large numbers of CD3+ T cells in the affected skin that colocalized with IL-17A, suggesting that T cells are the probable source of IL-17A. Additionally, T cell numbers were reduced after AIN457 therapy (Fig. 2F). Our observations suggest that IL-17A is pathogenic in psoriasis, and we hypothesize that IL-17A augments a feedback loop involving IL-23, possibly TNF, dendritic cells, and TH17 cells as main producers of IL-17A. In line with this hypothesis, therapies that block the activation or the differentiation of T cells, such as antibodies to p40, which target both IL-23 and IL-12 (17, 22), or to cyclosporine A (CsA) (31), are very effective against psoriasis.

In the RA trial, AIN457 had effects rapidly after the first infusion, and the improvements were maintained up to 13 weeks after the second infusion, indicating that AIN457 has the potential to rapidly suppress synovial inflammation and provide sustained benefit. One measure of disease severity (AUC of ACR20, DAS28, and CRP) showed significant differences between the AIN457- and placebo-treated groups, strengthening the notion that AIN457 may be efficacious in RA.

One concept of RA describes T cells as principle drivers of the autoimmune responses (18), and recently, their involvement in the production of IL-17A in RA has been proposed (23, 32, 33). Our findings suggest that IL-17A participates in RA pathogenesis because patients show relevant responses to inhibition of IL-17A. On the basis of earlier observations of elevated concentrations of IL-17A in SF (34) and recent reports of a correlation between SF TH17 cells and SF IL-17A (23), it is reasonable to infer that TH17 cells are among the main producers of IL-17A in RA. Mast cells were recently described to also produce IL-17A in synovial tissue (9); however, relative contributions of synovial cell types to IL-17A production need further investigation.

In the uveitis trial, patients with posterior segment uveitis had disease severity comparable to that of patients in an open-label trial of infliximab, an antibody to TNF-α (35). Most patients with uveitis involving the posterior segment responded to AIN457 with an improvement in visual acuity, a reduction in ocular inflammation, or the ability to stop corticosteroid therapy, with similar proportions of patients responding in these ways as did patients treated with infliximab. In these patients, there was a mean increase in visual acuity of more than two lines using Early Treatment of Diabetic Retinopathy Study (ETDRS) charts (see Materials and Methods) and a rapid reduction in vitreous haze that was sustained during the 8-week follow-up. Five patients with anterior uveitis had experienced one or more years of continuous or recurrent severe disease that was resistant to topical corticosteroids and that required repeated or systemic immunosuppression or periocular injections of corticosteroids. Although our study was short (2 months), without a placebo or other control group, and the primary objective of the study was to evaluate the safety of AIN457 in the treatment of uveitis, the reductions in ocular inflammation suggest that IL-17A inhibition may be beneficial in severe, chronic noninfectious uveitis requiring systemic immunosuppressive therapy.

The evolution of TH1 into a TH1/TH17 paradigm, first proposed for animal models of autoimmunity and later expanded to human diseases (16), finds further support in clinical results reported here. Our data suggest that IL-17A contributes to the pathogenesis of psoriasis, RA, and noninfectious uveitis, conditions in which TH1 cells are implicated in disease initiation and perpetuation (1719). We hypothesize that in psoriasis and uveitis, IL-17A may be produced mainly by TH17 cells, corroborated for psoriasis by our colocalization studies, and thus may be the pathogenic driver in these two diseases. This notion is supported by the responsiveness of psoriasis and uveitis to the T cell inhibitor CsA, which is able to effectively block production of IL-17A by TH17 cells (36). Unlike psoriasis and uveitis, RA is not unequivocally responsive to CsA (37). We observed comparatively lower response rates in RA, potentially attributable to a more complex interplay of pathogenic cells including T cell subsets (38), mast cells (9), and B cells (25).

A total of 60 patients in three proof-of-concept trials were exposed to AIN457 at doses ranging from 1 × 3 mg/kg to 2 × 10 mg/kg. The most frequent AEs observed in these studies were as expected for the respective diseases and populations and were consistent with previously reported effects of a fully human monoclonal antibody of the IgG1κ class (22). There was no clear-cut increase in AEs or SAEs after AIN457 compared with placebo treatment. Safety observations reported herein need to be confirmed in future trials with more diverse populations and ethnicities over longer observation periods for evaluation of long-term host defense risks in relation to therapeutic benefits.

Our proof-of-concept studies had limitations, including small patient numbers, use of preliminary dosing regimens that may require adjustment to provide optimal benefit (dose-ranging studies are ongoing), and the short follow-up periods that limit detection of infrequent or late-occurring adverse effects and demonstration of long-term benefits. In the RA trial, we cannot exclude that observed differences at the primary endpoint occurred at a 12% chance level. Therefore, our results need to be confirmed in larger trials. However, the observed difference between AIN457 and placebo effects at all time points and the significant result (P < 0.05) of the AUC analysis support the notion that AIN457 may have therapeutic effects in RA. Moreover, results reported recently from a small proof-of-concept study with a humanized monoclonal antibody to IL-17A (LY2439821) in patients with RA on background immunosuppressants demonstrated efficacy comparable to that observed in our trial (39).

In conclusion, our findings indicate that targeted inhibition of the proinflammatory cytokine IL-17A with AIN457 is a valid therapeutic approach and may be useful in the treatment of psoriasis, RA, and noninfectious uveitis. These positive results support development of AIN457 therapy for these and potentially other immune-mediated disorders where medical need continues to exist.

Materials and Methods

Three proof-of-concept studies were conducted in patients with psoriasis, RA, and chronic noninfectious uveitis (see fig. S1). All patients provided informed consent. Studies were approved by the institutional review boards at the participating centers and conducted in accordance with the principles of the Declaration of Helsinki.

Study design

The psoriasis study was a single-dose, double-blind, placebo-controlled, parallel-group study in which 36 patients were randomly assigned to receive a single infusion of either AIN457 (3 mg/kg) or saline (placebo) and monitored for 12 weeks.

The RA first-in-human study was designed in three parts to assess safety, tolerability, and pharmacokinetics of single or multiple doses of AIN457. In this report, we provide data from the cohort of patients randomly assigned to receive either two infusions of AIN457 (10 mg/kg) (the highest dose of the trial) or saline placebo. The interval of 3 weeks between the first and the second administration reflected the expected half-life of AIN457 (t1/2, 3 to 4 weeks). A total of 52 patients, 26 per group, were enrolled in this 16-week study.

The uveitis trial was an open-label study in which patients with active chronic noninfectious uveitis who required systemic immunosuppression were given two infusions of AIN457 (10 mg/kg): the first at baseline and the second 3 weeks later. Thus, responses were compared with those described in an open-label trial of infliximab, an antibody to TNF-α that is considered an effective therapy for refractory uveitis (35).

In all three trials, AIN457 was administered as a 2-hour intravenous infusion.


In the psoriasis trial, patients aged 18 to 69 years with active disease of at least 6 months of duration were eligible for inclusion if they had a coverage of at least 10% of body surface area with plaques, a score of 3 or more on the IGA scale, and a PASI of 12 or higher (4042). We excluded patients who received biological treatment for psoriasis within 2 months, systemic drugs for psoriasis and phototherapy within 1 month, and topical treatment for psoriasis within 2 weeks of randomization.

In the RA trial, patients aged 18 to 75 years with active disease were eligible for inclusion if they were taking a stable dose of methotrexate (≤25 mg per week) for at least 3 months and the condition had failed to respond to this therapy. We excluded patients who received biological treatment for RA within 2 or 3 months (respective to drug half-life), disease-modifying antirheumatic drugs (DMARDs) except for stable methotrexate within 1 month, intra-articular and systemic steroid injections for RA within 1 month, and investigational agents for RA within 3 months of randomization.

In the uveitis trial, patients with uveitis aged 18 to 75 years who had visual acuity of 20/40 or worse in at least one eye were eligible for inclusion. Sixteen patients were enrolled: four with HLA-B27–associated anterior uveitis, one with anterior uveitis with HLA-B27 status unknown, four with idiopathic panuveitis, three with sarcoidosis-associated uveitis (panuveitis, posterior uveitis, and intermediate uveitis), two with VKH disease, one with idiopathic posterior uveitis, and one with Behçet’s-associated panuveitis. The anterior uveitis patients had disease sufficiently severe and recurrent that a systemic immunosuppressive drug was indicated. Patients with posterior segment uveitis were either intolerant or refractory to systemic corticosteroids or at a stage in their disease course where a corticosteroid-sparing immunosuppressant therapy was required. Exclusion criteria included infections, uveitis of uncertain etiology, and treatment with any immunosuppressant therapy within 3 months before study start.

Endpoints and assessments

In the psoriasis study, the co-primary endpoints were PASI and IGA at week 4. Both parameters were assessed at screening, baseline, weekly until week 6, and then at weeks 8 and 12. Secondary endpoints included pharmacokinetic and pharmacodynamic assessments. Analyses of samples collected at baseline (week 0) and after treatment (week 4) included enumeration of dermal T cells (Fig. 2F) and immunohistology measures of psoriasis plaques (acanthosis, parakeratosis, epidermal thickening, and Ki-67 staining; detailed data for 18 placebo- and 18 AIN457-treated patients available upon request). Gene expression analysis was performed by quantitative RT-PCR for IL-12B (the shared p40 subunit of IL-23 and IL-12), IL-17A, IL-17F, IL-21, IL-22, IL-26, IFN-γ, CCL20, and TNFα, and by array analysis with HG-U133 Plus 2.0 chips for IL-1β, IL-6, IL-8, defensin β4 (DEFB4), and keratin 16 (KRT16). Statistical comparisons between baseline and week 4 measurements were done by Student’s t tests for quantitative RT-PCR and CD3/IL-17+ T cell enumerations, and analysis of variance (ANOVA) for array data.

In the RA study, the primary endpoint was the ACR20 response rate at week 6. The assessment of components of ACR20, ACR50, and ACR70 measures of disease improvement was performed at weeks 1, 3, 4, 5, 6, 8, 12, and 16. Patients were considered to be ACR20 responders per criteria defined previously (43) using CRP. The DAS28 score using the CRP was also calculated at each visit (43).

In the chronic noninfectious uveitis study, the primary objective was to assess the safety and tolerability of AIN457. The secondary efficacy objective was to determine the number of patients who responded to therapy at week 8 relative to baseline, with a responder defined with criteria similar to but somewhat more stringent than those reported in an open-label trial of infliximab. In particular, to be a responder, a patient had to have a study eye either with at least a two-step improvement in anterior chamber cells or vitreous haze score to be able to stop topical prednisolone or oral prednisone therapy being taken at baseline, or with three-line improvement in visual acuity (44, 45). Visual acuity was measured with the ETDRS method (46).

Safety assessments

Because the RA study was the first-in-human study, a data safety monitoring board was in place to assess potential early safety signals and guide transition to higher-dose levels. Safety was assessed by recording AEs and SAEs, physical examination, and regular monitoring of vital signs, body weight, hematology, blood chemistry, and urine tests. Clinical signs and symptoms of infection were assessed throughout the studies, and immunogenicity to AIN457 was measured.

Statistical analysis

Sample size calculations are described in table S1. Demographic and baseline characteristics were summarized by treatment group. Continuous variables were summarized by mean and SD. SEM was calculated where applicable. Categorical variables were summarized by absolute frequencies and percentages.

In the psoriasis study, the Wilcoxon’s rank-sum test was used to compare the mean change from baseline in PASI between active treatment and placebo at each visit. The proportion of patients who achieved 50%, 75%, and 90% reductions in their PASI (PASI50, PASI75, and PASI90, respectively) was summarized by treatment group. The change in IGA score (that is, the number of levels reduced from baseline) was treated as a categorical variable and, at each visit, compared globally across treatment groups with Pearson χ2 test.

In the RA trial, Fisher’s exact test was used at each time point to compare the ACR20 response rate in the two treatment groups. Similar analyses were performed to compare the ACR50 and ACR70 response rates. For analysis of DAS28, a linear mixed-effect model was fitted with treatment group, time point, treatment-by-time interaction, and baseline DAS28 as fixed effects. An unstructured correlation matrix was fitted to adjust for the correlation within patients; a similar analysis was performed on CRP concentrations. In addition, for the ACR20, DAS28, and CRP variables, the AUC for each subject was calculated. The mean AUC in each treatment group was compared with a t test (for ACR20) and analysis of covariance with baseline as a covariate (for DAS28 and CRP). Due to the skewed nature of the data, the CRP concentrations were log-transformed before the analysis.

In the uveitis trial, for continuous and ordered categorical variables, differences between baseline and week 8 were compared with analysis of covariance models.

Supplementary Material

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.


  • The investigators in the Psoriasis Study Group, the Rheumatoid Arthritis Study Group, and the Uveitis Study Group are listed in the Supplementary Material.

  • Citation: W. Hueber, D. D. Patel, T. Dryja, A. M. Wright, I. Koroleva, G. Bruin, C. Antoni, Z. Draelos, M. H. Gold, the Psoriasis Study Group, P. Durez, P. P. Tak, J. J. Gomez-Reino, the Rheumatoid Arthritis Study Group, C. S. Foster, R. Y. Kim, C. M. Samson, N. S. Falk, D. S. Chu, D. Callanan, Q. D. Nguyen, the Uveitis Study Group, K. Rose, A. Haider, F. Di Padova, Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010).

References and Notes

  1. Acknowledgments: We thank R. Bonheim for writing assistance and A. Venjara (BioScience Communications, New York, NY), Y. Saidi (Novartis Pharma AG, Basel, Switzerland), and P. Bhardwaj and V. Singh (Novartis Pharma, India) for editorial assistance. We also thank the following persons for their scientific contributions or operational assistance in conducting the trials: M. Londei (Novartis Institute for Functional Genomics Inc., San Diego, CA), M. Cooreman (Ikarus Holdings Inc.), C. Wanke (formerly Novartis), C. Rordorf and Augusta Van Steijn (Novartis Institutes for BioMedical Research, Basel, Switzerland), B. Flannery and S. Uziel-Fusi (Novartis Pharmaceuticals Corp., East Hanover, NJ), and N. Sfikas (Novartis Pharma AG, Basel, Switzerland). Funding: This study was sponsored by Novartis Pharma AG. Author contributions: All authors have contributed toward designing of protocol and/or conduct of study and/or data collection and/or analysis and interpretation of data and/or preparing the manuscript. Competing interests: All authors have completed the Unified Competing Interest forms (available on request from the corresponding author) and declare that Z.D., M.H.G., P.D., P.P.T., J.J.G.-R., R.Y.K., C.M.S., D.C., and Q.D.N. have support from Novartis for the submitted work; that W.H., D.D.P., T.D., A.M.W., I.K., G.B., C.A., K.R., A.H., and F.D.P. are employees of Novartis; that their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and that none of the authors have any nonfinancial interests that may be relevant to the submitted work. M.H.G. has been a paid consultant to Genentech, P.P.T. is a paid consultant to Novartis, and J.J.G.-R. is a member of the Novartis Advisory Board. Novartis is the owner of a patent on the drug AIN457. Accession numbers: NCT00669916 (psoriasis), NCT00669942 (rheumatoid arthritis), and NCT00685399 (uveitis).
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