Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration.
OBJECTIVE
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.


CONCLUSIONS
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.
*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.
Pravin U
PU
Dugel
Roger L
RL
Novack
Karl G
KG
Csaky
Preston P
PP
Richmond
David G
DG
Birch
Ryo
R
Kubota
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D003623:Dark Adaptation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004596:Electroretinography; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D057092:Geographic Atrophy / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010647:Phenyl Ethers / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D011412:Propanolamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology*; D014792:Visual Acuity / Q000502:physiology; D019745:cis-trans-Isomerases / Q000037:antagonists & inhibitors*; D000099178:Retinoid Isomerohydrolase
D004791:Enzyme Inhibitors; D010647:Phenyl Ethers; D011412:Propanolamines; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C000592692:emixustat