Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials.

Ophthalmology. 2013 Apr;120(4):777-87.

Dick AD, Tugal-Tutkun I, Foster S, Zierhut M, Melissa Liew SH, Bezlyak V, Androudi S.

School of Clinical Sciences and School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom. a.dick@bristol.ac.uk

Abstract

PURPOSE: To determine the efficacy and safety of different doses of secukinumab, a fully human monoclonal antibody for targeted interleukin-17A blockade, in patients with noninfectious uveitis.

DESIGN: Three multicenter, randomized, double-masked, placebo-controlled, dose-ranging phase III studies: SHIELD, INSURE, and ENDURE.

PARTICIPANTS: A total of 118 patients with Behçet’s uveitis (SHIELD study); 31 patients with active, noninfectious, non-Behçet’s uveitis (INSURE study); and 125 patients with quiescent, noninfectious, non-Behçet’s uveitis (ENDURE study) were enrolled.

METHODS: After an initial subcutaneous (s.c.) loading phase in each treatment arm, patients received s.c. maintenance therapy with secukinumab 300 mg every 2 weeks (q2w), secukinumab 300 mg monthly (q4w), or placebo in the SHIELD study; secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the INSURE study; or secukinumab 300 mg q2w, secukinumab 300 mg q4w, secukinumab 150 mg q4w, or placebo in the ENDURE study.

MAIN OUTCOME MEASURES: Reduction of uveitis recurrence or vitreous haze score during withdrawal of concomitant immunosuppressive medication (ISM). Other end points included best-corrected visual acuity, ISM use (expressed as a standardized ISM score), and safety outcomes.

RESULTS: After completion or early termination of each trial, there were no statistically significant differences in uveitis recurrence between the secukinumab treatment groups and placebo groups in any study. Secukinumab was associated with a significant reduction in mean total post-baseline ISM score (P = 0.019; 300 mg q4w vs. placebo) in the SHIELD study. Likewise, secukinumab was associated with a greater median reduction in ISM score versus placebo in the INSURE study, although no statistical analysis of the difference was conducted because of the small sample size. Overall, there was no loss in visual acuity reported in any treatment group during follow-up in all 3 studies. According to descriptive safety statistics, the frequencies of ocular and nonocular adverse events seemed to be slightly higher among secukinumab groups versus placebo across the 3 studies.

CONCLUSIONS: The primary efficacy end points of the 3 studies were not met. The secondary efficacy data from these studies suggest a beneficial effect of secukinumab in reducing the use of concomitant ISM.

Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc.

PMID: 23290985

 

Supplement:

Noninfectious uveitis, an immune-mediated intraocular inflammatory disease of heterogenous etiology, is responsible for a substantial proportion of new cases of visual impairment and blindness each year. Inflammation may occur in a portion or the entirety of the uveal tract, a layer of tissue located between the outer layer (cornea and sclera) and the inner layer (the retina) of the eye.  (Figure) The uvea is divided into the iris, the ciliary body, and the choroid.

Andrew Dick-1

Systemic glucocorticoid therapy is widely used in the treatment of noninfectious uveitis, but the risks of long-term use of these agents are well known (1). Nonsteroidal immunosuppressive drugs are effective and enable reduction of steroid dosage, but pose their own safety and tolerability issues, such as hepatotoxicity (associated with azathioprine and methotexate), bone marrow suppression (azathioprine and cyclophosphamide), cytopenias (methotrexate), gastrointestinal disturbances (azathioprine, mycophenolate mofetil), and nephrotoxicity (cyclosporine and tacrolimus) (2).

In recent years, biologic therapies have been evaluated for the treatment of noninfectious uveitis on the premise that they provide a more targeted approach to treatment than broad immunosuppressants. The cytokine interleukin (IL)-17A, which is the characteristic product of T-helper 17 cells and is believed to play a role in host defense against extracellular pathogens, has been recognized as a key mediator of immune-mediated inflammatory disease, including noninfectious uveitis, and is therefore a promising target for this condition (3). IL-17A signaling drives inflammation by inducing the release of chemokines, growth factors, and cytokines from target cells. We therefore conducted clinical trials of the effects of secukinumab, a fully human monoclonal antibody to IL-17A, in patients with non-infectious uveitis. Given the heterogeneous etiology and variable course of this disease, we performed 3 studies of secukinumab in distinct patient groups with noninfectious uveitis, including respectively:

  • SHIELD Study: Patients with Behçet’s disease, a systemic inflammatory disorder associated with noninfectious uveitis
  • INSURE Study: Patients with noninfectious uveitis not attributable to Behçet’s disease and currently experiencing intraocular inflammation (active disease)
  • ENDURE Study: Patients with noninfectious uveitis not attributable to Behçet’s disease and not currently experiencing intraocular inflammation (quiescent disease)

The primary endpoint of the studies was reduction in uveitis exacerbations or vitreous haze during withdrawal of concomitant immunosuppressive medication. Secukinumab doses were administered for 24-28 weeks by subcutaneous injection and included 150 mg every 4 weeks, 300 mg every 4 weeks, and 300 mg every 2 weeks.

The primary endpoint of the SHIELD study was not met; the rate of ocular exacerbations did not significantly differ between secukinumab and placebo over 24 weeks of treatment. Given the results of the SHIELD study, the INSURE study was terminated early. The ENDURE study was also terminated early, after an interim data analysis did not show significant effects of secukinumab on any primary or secondary endpoint.

Although the primary endpoints of these trials were not met, the results suggest some intriguing conclusions about the potential of IL-17A inhibition in the treatment of noninfectious uveitis. The SHIELD study did show significant reductions in the usage of immunosuppressant medication in patients receiving secukinumab. This finding, in conjunction with the possibility that the high amount of concomitant immunosuppressive therapy at baseline diminished treatment differences in the rate of ocular exacerbations (primary endpoint), imply that secukinumab did exert therapeutic activity in the SHIELD study. Additionally, the patients enrolled in the SHIELD study had an aggressive form of uveitis (ie, need for immunosuppressive therapy and ≥2 exacerbations in the previous 6 months). The effects of secukinumab in other subgroups of patients with noninfectious uveitis may be different.

The pathogenesis of autoimmune inflammation has not been fully elucidated, and it is possible that cytokine expression may vary between individual patients. Such variations may have implications for the secukinumab dose and treatment duration needed to therapeutically modify IL-17A activity. This conclusion is supported by the positive results of a previous, proof-of-concept study of secukinumab in active noninfectious uveitis, in which patients received a higher (10 mg/kg) intravenous dose than the subcutaneous doses used in the present study (4).

References

1.            Lee RW, Dick AD. Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation. Eye (Lond). 2012;26:17-28.

2.            Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, Nussenblatt RB, Stiehm ER, Tessler H, Van Gelder RN, Whitcup SM, Yocum D. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513.

3.            Amadi-Obi A, Yu CR, Liu X, Mahdi RM, Clarke GL, Nussenblatt RB, Gery I, Lee YS, Egwuagu CE. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat Med. 2007;13:711-8.

4.            Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, Antoni C, Draelos Z, Gold MH; Psoriasis Study Group, Durez P, Tak PP, Gomez-Reino JJ; Rheumatoid Arthritis Study Group, Foster CS, Kim RY, Samson CM, Falk NS, Chu DS, Callanan D, Nguyen QD; Uveitis Study Group, Rose K, Haider A, Di Padova F. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2:52ra72.

 

Acknowledgements

Novartis participated in the design of each study, conducting each study, data collection, data management, data analysis, interpretation of the data, and preparation and review of the manuscript.

 

Contact:

Andrew D. Dick, MD

Bristol Eye Hospital

Lower Maudlin St.

Bristol BS1 2LX

United Kingdom

a.dick@bristol.ac.uk.

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