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Dugel, Pravin U. MD*; Novack, Roger L. MD, PhD; Csaky, Karl G. MD, PhD; Richmond, Preston P. MD§; Birch, David G. PhD; Kubota, Ryo MD, PhD**

doi: 10.1097/IAE.0000000000000606
Original Study

Purpose: This study assessed the safety, tolerability, and pharmacodynamics of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in subjects with geographic atrophy associated with dry age-related macular degeneration.

Methods: Subjects were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. Recovery of rod photoreceptor sensitivity after a photobleach was measured by electroretinography. Safety evaluations included analysis of adverse events and ophthalmic examinations.

Results: Seventy-two subjects (54 emixustat and 18 placebo) were evaluated. Emixustat suppressed rod photoreceptor sensitivity in a dose-dependent manner. Suppression plateaued by Day 14 and was reversible within 7 days to 14 days after drug cessation. Most systemic adverse events were not considered treatment related. Dose-related ocular adverse events (chromatopsia, 57% emixustat vs. 17% placebo and delayed dark adaptation, 48% emixustat vs. 6% placebo) were mild to moderate in severity, and the majority resolved on study or within 7 days to 14 days after study drug cessation. Reversibility of these adverse events with long-term administration, however, is undetermined.

Conclusion: In this Phase II study, emixustat produced a dose-dependent reversible effect on rod function that is consistent with the proposed mechanism of action. These results support further testing of emixustat for the treatment of geographic atrophy associated with dry age-related macular degeneration.

Supplemental Digital Content is Available in the Text.Emixustat hydrochloride (ACU-4429) slowed visual cycle activity in a dose-dependent manner in subjects with geographic atrophy associated with dry age-related macular degeneration. Commonly occurring adverse events were ocular; all were mild to moderate in severity and typically resolved despite continued dosing or within 7 days to 14 days after study drug cessation.

*Retinal Consultants of Arizona, Phoenix, Arizona;

Retina-Vitreous Associates Medical Group, Beverly Hills, California;

Texas Retina Associates, Dallas, Texas;

§Central Florida Retina, Orlando, Florida;

Retina Foundation of the Southwest, Dallas, Texas; and

**Acucela Inc, Seattle, Washington.

Reprint requests: Pravin U. Dugel, MD, Retinal Consultants of Arizona, 1101 E. Missouri Avenue, Phoenix, AZ 85064-2430; e-mail:

Supported by Acucela Inc. The sponsor participated in design and conduct of the study; data collection, management, and analysis; interpretation of the data; and preparation, review, and approval of the manuscript.

P. U. Dugel, K. G. Csaky, and D. G. Birch are paid advisory board members and consultants of Acucela Inc. R. Kubota is the Chairman of the Board of Acucela Inc. He is a patent inventor on behalf of the company, has received reimbursement for travel expenses, and owns stock in the company. R. L. Novack has no conflicting interests to disclose.

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© 2015 by Ophthalmic Communications Society, Inc.