Elsevier

Ophthalmology

Volume 120, Issue 7, July 2013, Pages 1403-1408
Ophthalmology

Original article
Penetration of a Topically Administered Anti–Tumor Necrosis Factor Alpha Antibody Fragment into the Anterior Chamber of the Human Eye

https://doi.org/10.1016/j.ophtha.2012.12.015Get rights and content

Objective

To determine whether topically applied ESBA105, a single-chain antibody fragment against tumor necrosis factor (TNF)-α, could efficiently penetrate into the anterior chamber of the human eye.

Design

Multicenter, interventional cohort study.

Participants

Otherwise healthy patients undergoing cataract surgery (cohorts I–III) or combined cataract surgery and vitrectomy (cohort IV).

Methods

ESBA105 (n = 57) or placebo (n = 22) was preoperatively applied as eye drops to 1 eye in patients scheduled for cataract surgery (n = 73) or combined cataract surgery and vitrectomy (n = 6). ESBA105 was administered on the day of surgery at 1-hour intervals (last dose 1 hour preoperatively) as 1.6 mg in 4 drops for cohort I (n = 15) and as 3.2 mg in 8 drops for cohorts II (n = 15) and IV (n = 6). Cohort III (n = 43) was randomized 1:1 in double-masked fashion to receive either ESBA105 6.4 mg or placebo over 4 days using 4 drops per day at 4-hour intervals (last dose 12 hours preoperatively). Aqueous humor (all cohorts), vitreous humor (cohort IV only), and blood samples (all cohorts) were collected for measurement of ESBA105.

Main Outcome Measures

ESBA105 intraocular concentration.

Results

Both 4 times daily over 4 days dosing (cohort III) and 8 times daily dosing (cohorts II and IV) resulted in reliably high ESBA105 concentrations in aqueous humor. Mean molar excess of intraocular ESBA105 over its target (intraocular TNF-α) was calculated as 96-fold (cohort III) to 359-fold (cohorts II and IV). Results from the cohorts receiving 4 and 8 hourly drops per 1 day (cohorts I, II, and IV) indicated that dose-dependent intraocular concentrations of ESBA105 were achieved within hours of dosing. After 8 times daily dosing, 5 of 6 vitreous samples (cohort IV) had undetectable ESBA105 levels. ESBA105 was detected in 17 of 55 preoperative serum samples but no longer detectable in serum 1 day after surgery (0 of 19 samples). In cohort III, treatment-emergent adverse events were identical between ESBA105 and placebo groups (2 cases each of eye irritation).

Conclusions

These results demonstrate that the topically applied single-chain antibody fragment ESBA105 penetrated into the anterior chamber of the human eye at therapeutic levels.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Study Design

This interventional cohort study examined the intraocular penetration, biodistribution, safety, and apparent penetration coefficient (as primary outcomes of the study) of ESBA105 applied topically to 1 eye of otherwise healthy patients recruited from 2 eye clinics in Switzerland who were to undergo cataract surgery (cohorts I–III) or combined cataract surgery and vitrectomy owing to epiretinal fibroplasias (cohort IV). Cohorts I, II, and IV used an open-label, single-arm design, but patients in

Patient Disposition and Demographics

In total, 139 patients throughout Switzerland consented to be included in the study, which was initiated on December 9, 2008, and was completed on June 18, 2010. After screening examination, 60 patients were excluded owing to positive tuberculosis test (n = 43), previously unknown health problems (n = 7), withdrawal of consent (n = 7), or other reasons (n = 3). Overall participant flow is shown in Figure 1 (available online at http://aaojournal.org), and demographics are shown in Table 1. For

Discussion

The therapeutic efficacy of an intraocularly injected antibody fragment—ranibizumab, which is approved for the treatment of wet age-related macular degeneration, diabetic macular edema, and macular edema after retinal vein occlusion—has already been demonstrated, but this study is the first to our knowledge demonstrating therapeutic intraocular levels of an antibody fragment in humans after topical administration. Two different ESBA105 topical dosing regimens—8 hourly preoperative doses on the

Acknowledgments

The authors thank Alfons Schwarz as the Clinical Trial Manager for overseeing this study, and Mrs Edith Manuel, the study nurse at the Luzerner Kantonsspital. Jennifer Klem, PhD, provided medical writing assistance in drafting the manuscript, which was funded by Alcon Laboratories, Inc.

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    Manuscript no. 2012-1307.

    Financial Disclosure(s): The authors have made the following disclosures:

    Dominik Escher: Employee, Stock Options—ESBATech.

    Peter Lichtlen: Employee, Stock Options—ESBATech.

    Annette Schmidt: Employee, Stock Options—ESBATech.

    Supported by ESBATech, an Alcon Biomedical Research Unit (a member of the Novartis corporate group) located in Zurich, Switzerland. The sponsor participated in the design of the study, conducting the study, data collection, data management, data analysis, interpretation of the data, and preparation, review, and approval of the manuscript.

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