Randomised study evaluating the pharmacodynamics of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease

Ryo Kubota, David G Birch, Jeff K Gregory, John M Koester, Ryo Kubota, David G Birch, Jeff K Gregory, John M Koester

Abstract

Background/aims: Stargardt disease is a rare, inherited, degenerative disease of the retina that is the most common type of hereditary macular dystrophy. Currently, no approved treatments for the disease exist. The purpose of this study was to characterise the pharmacodynamics of emixustat, an orally available small molecule that targets the retinal pigment epithelium-specific 65 kDa protein (RPE65), in subjects with macular atrophy secondary to Stargardt disease.

Methods: In this multicentre study conducted at six study sites in the USA, 23 subjects with macular atrophy secondary to Stargardt disease were randomised to one of three doses of daily emixustat (2.5 mg, 5 mg or 10 mg) and treated for 1 month. The primary outcome was the suppression of the rod b-wave recovery rate on electroretinography after photobleaching, which is an indirect measure of RPE65 inhibition.

Results: Subjects who received 10 mg emixustat showed near-complete suppression of the rod b-wave amplitude recovery rate postphotobleaching (mean=91.86%, median=96.69%), whereas those who received 5 mg showed moderate suppression (mean=52.2%, median=68.0%). No effect was observed for subjects who received 2.5 mg emixustat (mean=-3.31%, median=-12.23%). The adverse event profile was consistent with prior studies in other patient populations and consisted primarily of ocular adverse events likely related to RPE65 inhibition.

Conclusion: This study demonstrated dose-dependent suppression of rod b-wave amplitude recovery postphotobleaching, confirming emixustat's biological activity in patients with Stargardt disease. These findings informed dose selection for a 24-month phase 3 trial (SeaSTAR Study) that is now comparing emixustat to placebo in the treatment of Stargardt disease-associated macular atrophy.

Trial registration: ClinicalTrials.gov NCT03033108.

Keywords: clinical trial; drugs; electrophysiology; macula; retina.

Conflict of interest statement

Competing interests: RK, JKG and JMK are employees of Kubota Vision. RK has pending and issued patents related to emixustat hydrochloride. DGB received grants from Kubota Vision during the conduct of the study.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Disposition of study subjects.
Figure 2
Figure 2
Mean±SE of the mean rod b-wave amplitudes prior to photobleaching and then over a 30 min period postbleaching at (A) baseline, prior to emixustat treatment and (B) after 1 month of daily treatment with emixustat.

References

    1. Tanna P, Strauss RW, Fujinami K, et al. . Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol 2017;101:25–30. 10.1136/bjophthalmol-2016-308823
    1. Briggs CE, Rucinski D, Rosenfeld PJ, et al. . Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration. Invest Ophthalmol Vis Sci 2001;42:2229–36.
    1. Rivera A, White K, Stöhr H, et al. . A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet 2000;67:800–13. 10.1086/303090
    1. Zernant J, Xie YA, Ayuso C, et al. . Analysis of the ABCA4 genomic locus in Stargardt disease. Hum Mol Genet 2014;23:6797–806. 10.1093/hmg/ddu396
    1. Braun TA, Mullins RF, Wagner AH, et al. . Non-exomic and synonymous variants in ABCA4 are an important cause of Stargardt disease. Hum Mol Genet 2013;22:5136–45. 10.1093/hmg/ddt367
    1. Molday RS, Zhong M, Quazi F. The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration. Biochim Biophys Acta 2009;1791:573–83. 10.1016/j.bbalip.2009.02.004
    1. Cideciyan AV, Swider M, Aleman TS, et al. . Abca4 disease progression and a proposed strategy for gene therapy. Hum Mol Genet 2009;18:931–41. 10.1093/hmg/ddn421
    1. Strauss RW, Kong X, Bittencourt MG, et al. . Scotopic microperimetric assessment of rod function in Stargardt disease (smart) study: design and baseline characteristics (report No. 1). Ophthalmic Res 2019;61:36–43. 10.1159/000488711
    1. Kubota R, Gregory J, Henry S, et al. . Pharmacotherapy for metabolic and cellular stress in degenerative retinal diseases. Drug Discov Today 2020;25:30455–6. 10.1016/j.drudis.2019.11.013
    1. Bavik C, Henry SH, Zhang Y, et al. . Visual cycle modulation as an approach toward preservation of retinal integrity. PLoS One 2015;10:e0124940. 10.1371/journal.pone.0124940
    1. Brown KT, Wiesel TN. Localization of origins of electroretinogram components by intraretinal recording in the intact cat eye. J Physiol 1961;158:257–80. 10.1113/jphysiol.1961.sp006768
    1. Bonting SL, Caravaggio LL, Gouras P. The rhodopsin cycle in the developing vertebrate retina. Exp Eye Res 1961;1:14–24. 10.1016/S0014-4835(61)80004-3
    1. Lee KA, Nawrot M, Garwin GG, et al. . Relationships among visual cycle retinoids, rhodopsin phosphorylation, and phototransduction in mouse eyes during light and dark adaptation. Biochemistry 2010;49:2454–63. 10.1021/bi1001085
    1. Dugel PU, Novack RL, Csaky KG, et al. . Phase II, randomized, placebo-controlled, 90-day study of EMIXUSTAT hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Retina 2015;35:1173–83. 10.1097/IAE.0000000000000606
    1. Rosenfeld PJ, Dugel PU, Holz FG, et al. . Emixustat hydrochloride for geographic atrophy secondary to age-related macular degeneration. Ophthalmology 2018;125:1556–67. 10.1016/j.ophtha.2018.03.059
    1. Kuehlewein L, Hariri AH, Ho A, et al. . Comparison of manual and semiautomated fundus autofluorescence analysis of macular atrophy in Stargardt disease phenotype. Retina 2016;36:1216–21. 10.1097/IAE.0000000000000870
    1. Cideciyan AV, Swider M, Aleman TS, et al. . Reduced-illuminance autofluorescence imaging in ABCA4-associated retinal degenerations. J Opt Soc Am A Opt Image Sci Vis 2007;24:1457–67. 10.1364/JOSAA.24.001457
    1. Strauss RW, Muñoz B, Ho A, et al. . Progression of Stargardt disease as determined by fundus autofluorescence in the retrospective progression of Stargardt disease study (ProgStar report No. 9). JAMA Ophthalmol 2017;135:1232–41. 10.1001/jamaophthalmol.2017.4152
    1. Strauss RW, Muñoz B, Jha A, et al. . Comparison of short-wavelength reduced-illuminance and conventional autofluorescence imaging in Stargardt macular dystrophy. Am J Ophthalmol 2016;168:269–78. 10.1016/j.ajo.2016.06.003
    1. Lois N, Holder GE, Bunce C, et al. . Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus. Arch Ophthalmol 2001;119:359–69. 10.1001/archopht.119.3.359
    1. Birch DG, Hood DC, Locke KG, et al. . Quantitative electroretinogram measures of phototransduction in cone and rod photoreceptors: normal aging, progression with disease, and test-retest variability. Arch Ophthalmol 2002;120:1045–51. 10.1001/archopht.120.8.1045
    1. Grover S, Fishman GA, Birch DG, et al. . Variability of full-field electroretinogram responses in subjects without diffuse photoreceptor cell disease. Ophthalmology 2003;110:1159–63. 10.1016/S0161-6420(03)00253-7
    1. Mata NL, Radu RA, Clemmons RC, et al. . Isomerization and oxidation of vitamin A in cone-dominant retinas: a novel pathway for visual-pigment regeneration in daylight. Neuron 2002;36:69–80. 10.1016/s0896-6273(02)00912-1
    1. Sato S, Kefalov VJ. cis Retinol oxidation regulates photoreceptor access to the retina visual cycle and cone pigment regeneration. J Physiol 2016;594:6753–65. 10.1113/JP272831
    1. Kubota R, Boman NL, David R, et al. . Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator. Retina 2012;32:183–8. 10.1097/IAE.0b013e318217369e
    1. Kubota R, Al-Fayoumi S, Mallikaarjun S, et al. . Phase 1, dose-ranging study of EMIXUSTAT hydrochloride (ACU-4429), a novel visual cycle modulator, in healthy volunteers. Retina 2014;34:603–9. 10.1097/01.iae.0000434565.80060.f8
    1. Strauss RW, Ho A, Muñoz B, et al. . The natural history of the progression of atrophy secondary to Stargardt disease (ProgStar) studies: design and baseline characteristics: ProgStar report No. 1. Ophthalmology 2016;123:817–28.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere