Results from a Prospective, Open-Label, Phase 4 Pilot Study of Repository Corticotropin Injection for Moderate and Severe Dry Eye Disease

Melissa Toyos, Rolando Toyos, Barbara Jodoin, Ryan Bunch, Melissa Toyos, Rolando Toyos, Barbara Jodoin, Ryan Bunch

Abstract

Introduction: There is a substantial unmet need for effective therapies to treat patients with refractory dry eye disease (DED). The goal of this open-label pilot study was to investigate the efficacy and safety of repository corticotropin injection (RCI; Acthar® Gel; Mallinckrodt Pharmaceuticals) in subjects with DED, most of whom did not experience adequate response to standard-of-care therapies.

Methods: Adults with moderate or severe-acute DED received 80 U of subcutaneous RCI twice weekly for 12 weeks. Primary efficacy outcomes were improvements in corneal fluorescein staining of superficial punctate keratitis (SPK) lesions and Symptom Assessment in Dry Eye (SANDE) scores. Secondary outcomes included changes in Schirmer's test scores, conjunctival lissamine green staining, erythema, intraocular pressure (IOP), and best corrected visual acuity (BCVA). Adverse events (AEs) were assessed continuously throughout the study.

Results: Fifteen subjects received at least 1 dose of RCI, and 12 subjects completed the study. Compared to baseline (day 1), significantly fewer fluorescein-stained SPK lesions were detected at day 14 (p = 0.0250) and day 84 (p = 0.0240) after RCI treatment. Mean SANDE scores progressively declined from 62.0 at baseline to 46.9 at day 84. Erythema (p = 0.0046), conjunctival lissamine green staining of SPK lesions (p = 0.0317), and IOP (p = 0.0052) were all significantly improved after 12 weeks of RCI therapy. Schirmer's test scores and BCVA showed no significant changes throughout the study. No ocular AEs or deaths occurred, and no new safety signals were identified for RCI.

Conclusions: These results suggest that RCI may be a safe and effective treatment for moderate and severe DED.

Trial registration: ClinicalTrials.gov identifier: NCT03287635.

Keywords: Acthar Gel; Clinical trial; DED; Ocular inflammation; RCI.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
CONSORT diagram showing patient disposition. AE Adverse event, RCI repository corticotropin injection
Fig. 2
Fig. 2
Primary efficacy endpoint analyses of fluorescein staining of SPK lesions (a) and SANDE scores (b) after treatment with RCI. All data are presented as the mean ± 95% confidence intervals. Fluorescein SPK staining was not performed at day 7. RCI Repository corticotropin injection, SANDE Symptom Assessment in Dry Eye, SPK superficial punctate keratitis
Fig. 3
Fig. 3
Erythema score (a), number of lissamine-stained SPK lesions (b), and IOP (c) after RCI treatment. All data are presented as the mean ± 95% confidence intervals. Erythema and lissamine SPK staining were not assessed at day 7. IOP Intraocular pressure, mm HG millimeters of mercury, RCI repository corticotropin injection, SPK superficial punctate keratitis
Fig. 4
Fig. 4
Schirmer’s test score (a) and BCVA (b) after treatment with RCI. All data are presented as the mean ± 95% confidence intervals. Schirmer’s score was not assessed at day 7. BCVA Best corrected visual acuity, logMAR logarithm of the minimum angle of resolution

References

    1. Simsek C, Dogru M, Kojima T, Tsubota K. Current management and treatment of dry eye disease. Turk J Ophthalmol. 2018;48(6):309–313. doi: 10.4274/tjo.69320.
    1. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf. 2017;15(3):334–365. doi: 10.1016/j.jtos.2017.05.003.
    1. Javadi MA, Feizi S. Dry eye syndrome. J Ophthalmic Vis Res. 2011;6(3):192–198.
    1. Farrand KF, Fridman M, Stillman IO, Schaumberg DA. Prevalence of diagnosed dry eye disease in the United States among adults aged 18 years and older. Am J Ophthalmol. 2017;182:90–98. doi: 10.1016/j.ajo.2017.06.033.
    1. Verjee MA, Brissette AR, Starr CE. Dry eye disease: early recognition with guidance on management and treatment for primary care family physicians. Ophthalmol Ther. 2020;9(4):877–888. doi: 10.1007/s40123-020-00308-z.
    1. Ru Y, Huang Y, Liu H, et al. alpha-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways. Sci Rep. 2015;5:18619. doi: 10.1038/srep18619.
    1. Mallinckrodt Pharmaceuticals. Acthar gel. Package insert. 2021. . Accessed 20 May 2020
    1. Fleischmann R, Furst DE, Connolly-Strong E, Liu J, Zhu J, Brasington R. Repository corticotropin injection for active rheumatoid arthritis despite aggressive treatment: a randomized controlled withdrawal trial. Rheumatol Ther. 2020;7(2):327–344. doi: 10.1007/s40744-020-00199-3.
    1. Furie RA, Mitrane M, Zhao E, Becker PM. Repository corticotropin injection in patients with persistently active SLE requiring corticosteroids: post hoc analysis of results from a two-part, 52-week pilot study. Lupus Sci Med. 2017;4(1):e000240. doi: 10.1136/lupus-2017-000240.
    1. Askanase AD, Zhao E, Zhu J, Bilyk R, Furie RA. Repository corticotropin injection for persistently active systemic lupus erythematosus: results from a phase 4, multicenter, randomized, double-blind, placebo-controlled trial. Rheumatol Ther. 2020;7(4):893–908. doi: 10.1007/s40744-020-00236-1.
    1. Huang YJ, Galen K, Zweifel B, Brooks LR, Wright AD. Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists. J Recept Signal Transduct Res. 2020;20:1–9. doi: 10.1080/10799893.2020.1859533.
    1. Benko AL, McAloose CA, Becker PM, et al. Repository corticotrophin injection exerts direct acute effects on human B cell gene expression distinct from the actions of glucocorticoids. Clin Exp Immunol. 2018;192(1):68–81. doi: 10.1111/cei.13089.
    1. Olsen NJ, Decker DA, Higgins P, et al. Direct effects of HP Acthar Gel on human B lymphocyte activation in vitro. Arthritis Res Ther. 2015;17:300. doi: 10.1186/s13075-015-0823-y.
    1. Cusick MF, Libbey JE, Oh L, Jordan S, Fujinami RS. Acthar gel treatment suppresses acute exacerbations in a murine model of relapsing-remitting multiple sclerosis. Autoimmunity. 2015;48(4):222–230. doi: 10.3109/08916934.2014.984836.
    1. Tauber J, Schechter BA, Bacharach J, et al. A phase II/III, randomized, double-masked, vehicle-controlled, dose-ranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease. Clin Ophthalmol. 2018;12:1921–1929. doi: 10.2147/OPTH.S175065.
    1. Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II diagnostic methodology report. Ocul Surf. 2017;15(3):539–574. doi: 10.1016/j.jtos.2017.05.001.
    1. Murphy PJ, Lau JS, Sim MM, Woods RL. How red is a white eye? Clinical grading of normal conjunctival hyperaemia. Eye. 2007;21(5):633–638. doi: 10.1038/sj.eye.6702295.
    1. Stevens S, Gilbert C, Astbury N. How to measure intraocular pressure: applanation tonometry. Commun Eye Health. 2012;25(79–80):60.
    1. Huang YJ, Galen K, Zweifel B, Brooks LR, Wright AD. Distinct binding and signaling activity of Acthar Gel compared to other melanocortin receptor agonists. J Recept Signal Transduct Res. 2021;41(5):425–433. doi: 10.1080/10799893.2020.1818094.
    1. Poola N, Due B, Wright D, Brooks LR, Zaman F. Pharmacokinetics and pharmacodynamics of repository corticotropin injection compared with synthetic ACTH1–24 depot and methylprednisolone in healthy subjects. Clin Pharmacol Drug Dev. 2022;11(4):502-15.
    1. Wang X, Pham L, Poola N, Brooks LR, Due B. Comparison of steroidogenic exposure following the administration of repository corticotropin injection with a synthetic ACTH1-24 depot and methylprednisolone in healthy subjects. Clin Pharmacol Drug Dev. 2021;10(7):777–788. doi: 10.1002/cpdd.894.

Source: PubMed

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