Elsevier

Ophthalmology

Volume 122, Issue 5, May 2015, Pages 939-948
Ophthalmology

Original article
Efficacy and Safety of Intravenous Secukinumab in Noninfectious Uveitis Requiring Steroid-Sparing Immunosuppressive Therapy

Presented at: the Meeting of the Association for Research in Vision and Ophthalmology, May 5–9, 2013, Seattle, Washington.
https://doi.org/10.1016/j.ophtha.2014.12.033Get rights and content

Purpose

Secukinumab, a fully human anti–interleukin-17A monoclonal antibody, exhibited promising activity in a proof-of-concept study when administered in intravenous (IV) doses to patients with active, chronic, noninfectious uveitis. This study compared the efficacy and safety of different IV and subcutaneous (SC) doses of secukinumab in patients with noninfectious uveitis.

Design

Multicenter, randomized, double-masked, dose-ranging, phase 2 clinical trial.

Participants

Thirty-seven patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who required corticosteroid-sparing immunosuppressive therapy.

Methods

Patients were randomized to secukinumab 300 mg SC every 2 weeks for 4 doses, secukinumab 10 mg/kg IV every 2 weeks for 4 doses, or secukinumab 30 mg/kg IV every 4 weeks for 2 doses. Intravenous or SC saline was administered to maintain masking. Efficacy was assessed on day 57 (2–4 weeks after last dose).

Main Outcome Measures

Percentage of patients with treatment response, defined as (1) at least a 2-grade reduction in vitreous haze score or trace or absent vitreous haze in the study eye without an increase in corticosteroid dose and without uveitis worsening or (2) reduction in corticosteroid dosages to prespecified levels without uveitis worsening. Percentage of patients with remission, defined as anterior chamber cell and vitreous haze scores of 0 or 0.5+ in both eyes without corticosteroid therapy or uveitis worsening.

Results

Secukinumab 30 mg/kg IV and 10 mg/kg IV, compared with the 300 mg SC dose, produced higher responder rates (72.7% and 61.5% vs. 33.3%, respectively) and remission rates (27.3% and 38.5% vs. 16.7%, respectively). Statistical and clinical superiority for the 30 mg/kg IV dose compared with the 300 mg SC dose was established in a Bayesian probability model. Other measures, including time to response onset, change in visual acuity, and change in vitreous haze score, showed numeric trends favoring IV dosing. Secukinumab, administered in IV or SC formulations, appeared safe and was well tolerated.

Conclusions

Intravenous secukinumab was effective and well tolerated in noninfectious uveitis requiring systemic corticosteroid-sparing immunosuppressive therapy. Greater activity with IV dosing suggests that patients may not receive sufficient drug with SC administration. High-dose IV secukinumab may be necessary to deliver secukinumab in therapeutic concentrations.

Section snippets

Study Design

This double-masked, dose-ranging study was conducted at 10 sites in the United States and 4 sites in Germany. Eligible patients were stratified by uveitis severity (vitreous haze <2+ vs. ≥2+) and then randomly assigned (1:1:1) to receive secukinumab 300 mg SC every 2 weeks (days 1, 15, 29, and 43), secukinumab 10 mg/kg IV every 2 weeks, or secukinumab 30 mg/kg IV every 4 weeks (days 1 and 29). Intravenous or SC saline was administered as needed to maintain masking of treatment groups.

Patient Disposition and Demographics

Thirty-seven patients were randomly allocated to the 3 treatment groups (Fig 1). Of these, 33 patients (89.2%) completed the study and 4 patients discontinued early (10.8%), including 2 patients who withdrew consent, 1 patient who had an AE (uveitis flare), and 1 patient who had an unsatisfactory therapeutic effect. All randomized patients were included in the safety analysis, and all except 1 patient with no valid post-baseline efficacy assessment were included in the efficacy analyses. The

Discussion

The results of this small dose-ranging study in patients with active noninfectious uveitis demonstrate that IV administration of secukinumab produced statistically superior responder rates compared with SC dosing following 8 weeks of treatment. In addition, IV dosing showed numeric trends for greater remission rates, faster responses, greater reductions in vitreous haze, and protection from visual acuity loss compared with the SC dose. Pharmacokinetic analyses showed that IV administration

Acknowledgments

The authors thank the following Novartis employees who contributed greatly to completion of the study: Karen Holopigian (clinical operations), Karin Meiser (statistical support), and Petra Brinkmann (statistical programming/analysis support). Editorial support for the preparation of this manuscript was provided by BioScience Communications, New York, New York, and supported by Novartis Pharma AG. The authors thank Barry Weichman for assistance in drafting the manuscript and Andrew Horgan of

References (29)

  • O.M. Durrani et al.

    Degree, duration, and causes of visual loss in uveitis

    Br J Ophthalmol

    (2004)
  • N.R. Acharya et al.

    Incidence and prevalence of uveitis: results from the Pacific Ocular Inflammation Study

    JAMA Ophthalmol

    (2013)
  • R.W. Lee et al.

    Current concepts and future directions in the pathogenesis and treatment of non-infectious intraocular inflammation

    Eye (Lond)

    (2012)
  • J. Kruh et al.

    Corticosteroid-sparing agents: conventional systemic immunosuppressants

    Dev Ophthalmol

    (2012)
  • Cited by (132)

    • Behçet's disease uveitis

      2023, Revue de Medecine Interne
    • Autoimmune uveitis in childhood

      2022, Translational Autoimmunity: Autoimmune Diseases in Different Organs
    View all citing articles on Scopus

    Supplemental material is available at www.aaojournal.org.

    Financial Disclosure(s): The author(s) have made the following disclosure(s): E.L.: Grants – Novartis.

    S.Y.: Grants – Novartis, AbbVie; Advisory/consultancy services – Bausch & Lomb, Santen Inc, Clearside.

    C.S.F.: Grants – AbbVie, Alcon Laboratories, Allergan, Eyegate, Lux Biosciences, Novartis; Compensation from consultancy services – AbbVie, Alcon Laboratories, Allergan, Ista Pharmaceuticals, Lux Biosciences, Novartis, Bausch & Lomb; compensation from speaking services – Alcon Laboratories, Allergan, Inspire Pharmaceuticals, Ista Pharmaceuticals, Lux Biosciences; Ownership of stock and/or stock options – Eyegate.

    M.B.: Salary and stock – Novartis Institutes for BioMedical Research.

    C.L.G.: Employee – Novartis Institutes for BioMedical Research.

    Funded by Novartis Pharma AG, Basel, Switzerland. The study sponsor participated in the design and conduct of the study; the collection, management, analysis, and interpretation of data; and the preparation, review, and approval of the manuscript.

    List of AIN457A2208 Study Group available at www.aaojournal.org.

    View full text