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

Retina

Volumn 35, Issue 6, 2015, Pages 1173-1183

  Dugel, Pravin U ^a   Novack, Roger L ^b   Csaky, Karl G ^c   Richmond, Preston P ^d   Birch, David G ^e   Kubota, Ryo ^f  

^a RETINAL CONSULTANTS OF ARIZONA   (United States)

^b RETINA VITREOUS ASSOCIATES MEDICAL GROUP   (United States)

^c TEXAS RETINA ASSOCIATES   (United States)

^d Central Florida Retina   (United States)

^e RETINA FOUNDATION OF THE SOUTHWEST   (United States)

^f Acucela Inc   (United States)

Author keywords

ACU 4429; age related macular degeneration; emixustat hydrochloride; geographic atrophy; Phase II; safety; visual cycle modulator

Indexed keywords

EMIXUSTAT; PLACEBO; CIS TRANS ISOMERASE; DIPHENYL ETHER DERIVATIVE; ENZYME INHIBITOR; PROPANOLAMINE DERIVATIVE; RETINOID ISOMEROHYDROLASE;

ADULT; ADVERSE OUTCOME; AGE RELATED MACULAR DEGENERATION; AGED; ARTICLE; BLEACHING; BLURRED VISION; CLINICAL ASSESSMENT; CLINICAL EVALUATION; COLOR VISION; CONTROLLED STUDY; DARK ADAPTATION; DISEASE ASSOCIATION; DISEASE SEVERITY; DIZZINESS; DRUG EFFECT; DRUG INDUCED HEADACHE; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; ELECTRORETINOGRAPHY; FEMALE; GEOGRAPHIC ATROPHY; HUMAN; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NAUSEA; NIGHT BLINDNESS; PATIENT COMPLIANCE; PHARMACODYNAMICS; PHASE 2 CLINICAL TRIAL; PHOTOPHOBIA; PHOTORECEPTOR; RANDOMIZED CONTROLLED TRIAL; RETINA ROD; SENSITIVITY ANALYSIS; SPRAIN; URINARY TRACT INFECTION; VISUAL ACUITY; VISUAL FIELD DEFECT; VISUAL IMPAIRMENT; VITREOUS BODY DETACHMENT; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; MIDDLE AGED; ORAL DRUG ADMINISTRATION; PATHOPHYSIOLOGY; PHYSIOLOGY; VERY ELDERLY;

ADMINISTRATION, ORAL; AGED; AGED, 80 AND OVER; CIS-TRANS-ISOMERASES; DARK ADAPTATION; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; ELECTRORETINOGRAPHY; ENZYME INHIBITORS; FEMALE; GEOGRAPHIC ATROPHY; HUMANS; MALE; MIDDLE AGED; PHENYL ETHERS; PROPANOLAMINES; RETINAL ROD PHOTORECEPTOR CELLS; VISUAL ACUITY;

EID: 84930433977     PISSN: 0275004X     EISSN: 15392864     Source Type: Journal    
DOI: 10.1097/IAE.0000000000000606     Document Type: Article

References (35)

1. de Jong PT. Age-related macular degeneration. N Engl J Med 2006;355:1474-1485.
2. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med 2008;358:2606-2617.
3. Klein R, Chou CF, Klein BE, et al. Prevalence of age-related macular degeneration in the US population. Arch Ophthalmol 2011;129:75-80.
4. Resnikoff S, Pascolini D, Etya'ale D, et al. Global data on visual impairment in the year 2002. Bull World Health Organ 2004;82:844-851.
5. Pascolini D, Mariotti SPM. Global estimates of visual impairment: 2010. Br J Ophthalmol 2012;96:614-618.
6. Seddon J, Sobrin L. Epidemiology and risk factors for agerelated macular degeneration. In: Ryan S, ed. Retina. 5th ed. St. Louis, MO: Mosby; 2013:1134-1144.
7. Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564-572.
8. Rein DB, Wittenborn JS, Zhang X, et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol 2009;127:533-540.
9. Donoso LA, Kim D, Frost A, et al. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2006;51:137-152.
10. Kanda A, Abecasis G, Swaroop A. Inflammation in the pathogenesis of age-related macular degeneration. Br J Ophthalmol 2008;92:448-450.
11. Sparrow JR, Zhou J, Ben-Shabat S, et al. Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci 2002;43:1222-1227.
12. Lamb LE, Simon JD. A2E: a component of ocular lipofuscin. Photochem Photobiol 2004;79:127-136.
13. Finnemann SC, Leung LW, Rodriguez-Boulan E. The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium. Proc Natl Acad Sci U S A 2002;99:3842-3847.
14. Bermann M, Schutt F, Holz FG, Kopitz J. Does A2E, a retinoid component of lipofuscin and inhibitor of lysosomal degradative functions, directly affect the activity of lysosomal hydrolases? Exp Eye Res 2001;72:191-195.
15. Suter M, Remé C, Grimm C, et al. Age-related macular degeneration. The lipofusion component N-retinyl-N-retinylidene ethanolamine detaches proapoptotic proteins from mitochondria and induces apoptosis in mammalian retinal pigment epithelial cells. J Biol Chem 2000;275:39625-39630.
16. Schmitz-Valckenberg S, Bindewald-Wittich A, Dolar-Szczasny J, et al. Correlation between the area of increased autofluorescence surrounding geographic atrophy and disease progression in patients with AMD. Invest Ophthalmol Vis Sci 2006;47:2648-2654.
17. Schmitz-Valckenberg S, Bultmann S, Dreyhaupt J, et al. Fundus autofluorescence and fundus perimetry in the junctional zone of geographic atrophy in patients with age-related macular degeneration. Invest Ophthalmol Vis Sci 2004;45:4470-4476.
18. Schmitz-Valckenberg S, Fleckenstein M, Helb HM, et al. In vivo imaging of foveal sparing in geographic atrophy secondary to age-related macular degeneration. Invest Ophthalmol Vis Sci 2009;50:3915-3921.
19. Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol 2007;143:463-472.
20. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, et al. Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol 2009;54:96-117.
21. Radu RA, Mata NL, Nusinowitz S, et al. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. Proc Natl Acad Sci U S A 2003;100:4742-4747.
22. Golczak M, Kuksa V, Maeda T, et al. Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle. Proc Natl Acad Sci U S A 2005;102:8162-8167.
23. Maeda A, Maeda T, Golczak M, et al. Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protection from light damage in mice. Mol Pharmacol 2006;70: 1220-1229.
24. Golczak M, Maeda A, Bereta G, et al. Metabolic basis of visual cycle inhibition by retinoid and nonretinoid compounds in the vertebrate retina. J Biol Chem 2008;283:9543-9554.
25. Brown KT, Wiesel TN. Localization of origins of electroretinogram components by intraretinal recording in the intact cat eye. J Physiol 1961;158:257-280.
26. Bonting SL, Caravaggio LL, Gouras P. The rhodopsin cycle in the developing vertebrate retina. I. Relation of rhodopsin content, electroretinogram and rod structure in the rat. Exp Eye Res 1961;1:14-24.
27. Kubota R, Boman NL, David R, et al. Safety and effect on rod function of emixustat, a novel small-molecule visual cycle modulator. Retina 2012;32:183-188.
28. Kubota R, Al-Fayoumi S, Mallikaarjun S, et al. Phase 1, doseranging study of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers. Retina 2014;34: 603-609.
29. Marmor MF, Fulton AB, Holder GE, et al. ISCEV standard for full-field clinical electroretinography (2008 update). Doc Ophthalmol 2009;118:69-77.
30. Ferris FL III, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol 1982;94: 91-96.
31. Klein ML, Ferris FL III, Francis PJ, et al. Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 2010;117:1554-1559.
32. Lindblad AS, Lloyd PC, Clemons TE, et al; Age-related Eye Disease Study Research Group. Change in area of geographic atrophy in the age-related eye disease study: AREDS report number 26. Arch Ophthalmol 2009;127:1168-1174.
33. Choudhry N, Giani A, Miller JW. Fundus autofluorescence in geographic atrophy: a review. Semin Ophthalmol 2010;25: 206-213.
34. Eldred GE, Lasky MR. Retinal age pigments generated by selfassembling lysosomotropic detergents. Nature 1993;361: 724-726.
35. Sparrow JR, Wu Y, Kim CY, Zhou J. Phospholipid meets alltrans-retinal: the making of RPE bisretinoids. J Lipid Res 2010;51:247-261.