emixustat and Macular-Degeneration

Age-related macular degeneration (AMD) is a highly prevalent condition in an ever-increasing elderly population. Although insidious in the early stages, advanced AMD (neovascular and atrophic forms) can cause significant visual disability and economic burden on health systems worldwide. The most common form, geographic atrophy, has no effective treatment to date, whereas neovascular AMD can be treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Geographic atrophy has a slow disease progression and patients tend to have preserved central vision until the final stages. This tendency, coupled with the use of modern imaging modalities, provides a large window of opportunity to intervene with validated methods to assess treatment efficacy. As geographic atrophy is an increasingly common condition with no effective intervention, many treatments are under investigation, one of which is visual cycle modulators. These medications have been shown to reduce lipofuscin accumulation in pre-clinical studies that have led to several clinical trials, reviewed herein.. To assess the efficacy and safety of visual cycle modulators for the prevention and treatment of geographic atrophy secondary to AMD.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); MEDLINE Ovid; Embase Ovid; Web of Science Core Collection; Scopus; Association for Research in Vision and Ophthalmology (ARVO) website; ClinicalTrials.gov and the WHO ICTRP to 11 January 2020 with no language restrictions. We also searched using the reference lists of reviews and existing studies and the Cited Reference Search function in Web of Science to identify further relevant studies.. We included randomised controlled trials (RCTs) and quasi-randomised clinical studies (if available) that compared visual cycle modulators to placebo or no treatment (observation) in people diagnosed with AMD (early, intermediate or geographic atrophy).. Two authors independently assessed risk of bias in the included studies and extracted data. Both authors entered data into RevMan 5. We resolved discrepancies through discussion. We graded the certainty of the evidence using the GRADE approach.. There is limited evidence to support the use of visual cycle modulators (emixustat and fenretinide) for the treatment of established geographic atrophy due to AMD. The possible reduction in the incidence of CNV observed with fenretinide, and to a lesser extent, emixustat, requires formal assessment in focused studies.

Topics: Aged; Aged, 80 and over; Choroidal Neovascularization; Clinical Trials, Phase II as Topic; Disease Progression; Fenretinide; Geographic Atrophy; Humans; Incidence; Macular Degeneration; Phenyl Ethers; Placebos; Propanolamines; Randomized Controlled Trials as Topic; Visual Acuity; Watchful Waiting

Stargardt macular dystrophy (STGD1) is a hereditary retinal degeneration that lacks effective treatment options. Gene therapy, stem cell therapy, and pharmacotherapy with visual cycle modulators (VCMs) and complement inhibitors are discussed as potential treatments.. Investigational therapies for STGD1 aim to reduce toxic bisretinoids and lipofuscin in the retina and retinal pigment epithelium (RPE). These agents include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Avacincaptad pegol is a C5 complement inhibitor that may reduce inflammation-related RPE damage. Animal models of STGD1 show promising data for these treatments, though proof of efficacy in humans is lacking. Fenretinide and emixustat are VCMs for dry AMD and STGD1 that failed to halt geographic atrophy progression or improve vision in trials for AMD. A1120 prevents retinol transport into RPE and may spare side effects typically seen with VCMs (nyctalopia and chromatopsia). Stem cell transplantation suggests potential biologic plausibility in a phase I/II trial. Gene therapy aims to augment the mutated ABCA4 gene, though results of a phase I/II trial are pending.. Stem cell transplantation, ABCA4 gene therapy, VCMs, and complement inhibitors offer biologically plausible treatment mechanisms for treatment of STGD1. Further trials are warranted to assess efficacy and safety in humans.

Topics: Animals; ATP-Binding Cassette Transporters; Complement Inactivating Agents; Genetic Therapy; Humans; Lipofuscin; Macular Degeneration; Phenyl Ethers; Propanolamines; Stargardt Disease; Stem Cell Transplantation; Therapies, Investigational

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.. 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.. 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.. 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.

Topics: Atrophy; Electroretinography; Humans; Macular Degeneration; Phenyl Ethers; Propanolamines; Stargardt Disease

ACU-4429 is a first in class small-molecule visual cycle modulator that inhibits the isomerase complex and, in mouse models of retinal degeneration, prevents the accumulation of A2E. The purpose of this study was to assess the tolerability, pharmacokinetics, pharmacodynamics, and safety of a single, orally administered dose of ACU-4429 in healthy subjects.. Sequential cohorts were administered single doses ranging from 2 mg to 75 mg. Full-field electroretinograms were recorded before and after exposure to full-field bleaching light. Pharmacokinetics samples were taken at predetermined times. Safety assessments included adverse events, vital signs, clinical laboratory assays, electrocardiograms, and ophthalmologic examination.. After 45-minute dark adaptation, electroretinographic findings demonstrated a dose-related slowing of the rate of recovery that reached its maximum on Day 2 and returned to baseline by Day 7. Mean area under the concentration curve and peak plasma concentration increased proportionally with increasing doses. Median time to peak concentration was 4 hours postdose. Mean elimination mean half-life was 4 hours to 6 hours. Adverse events were mild and visual in nature (dyschromatopsia and alteration in dark adaptation), transient, and resolved within a few days. Adverse event frequency was dose dependent.. Oral administration of ACU-4429 produced a dose-dependent inhibition of the b-wave of the electroretinograms, was well tolerated up to 75 mg, and demonstrated linear pharmacokinetics across doses.

Topics: Administration, Oral; Aged; Area Under Curve; Dark Adaptation; Dose-Response Relationship, Drug; Double-Blind Method; Electroretinography; Enzyme Inhibitors; Female; Humans; Macular Degeneration; Male; Middle Aged; Phenyl Ethers; Propanolamines; Retinal Rod Photoreceptor Cells; Vision, Ocular

We discuss how an imperfect visual cycle results in the formation of vitamin A dimers, thought to be involved in the pathogenesis of various retinal diseases, and summarize how slowing vitamin A dimerization has been a therapeutic target of interest to prevent blindness. To elucidate the molecular mechanism of vitamin A dimerization, an alternative form of vitamin A, one that forms dimers more slowly yet maneuvers effortlessly through the visual cycle, was developed. Such a vitamin A, reinforced with deuterium (C20-D3-vitamin A), can be used as a non-disruptive tool to understand the contribution of vitamin A dimers to vision loss. Eventually, C20-D3-vitamin A could become a disease-modifying therapy to slow or stop vision loss associated with dry age-related macular degeneration (AMD), Stargardt disease and retinal diseases marked by such vitamin A dimers. Human clinical trials of C20-D3-vitamin A (ALK-001) are underway.

Topics: Blindness; Clinical Trials as Topic; Deuterium; Dimerization; Humans; Macular Degeneration; Models, Chemical; Molecular Conformation; Molecular Structure; Phenyl Ethers; Propanolamines; Retinal Dystrophies; Stargardt Disease; Vitamin A; Vitamins

Emixustat is a visual cycle modulator that has entered clinical trials as a treatment for age-related macular degeneration (AMD). This molecule has been proposed to inhibit the visual cycle isomerase RPE65, thereby slowing regeneration of 11-cis-retinal and reducing production of retinaldehyde condensation byproducts that may be involved in AMD pathology. Previously, we reported that all-trans-retinal (atRAL) is directly cytotoxic and that certain primary amine compounds that transiently sequester atRAL via Schiff base formation ameliorate retinal degeneration. Here, we have shown that emixustat stereoselectively inhibits RPE65 by direct active site binding. However, we detected the presence of emixustat-atRAL Schiff base conjugates, indicating that emixustat also acts as a retinal scavenger, which may contribute to its therapeutic effects. Using agents that lack either RPE65 inhibitory activity or the capacity to sequester atRAL, we assessed the relative importance of these 2 modes of action in protection against retinal phototoxicity in mice. The atRAL sequestrant QEA-B-001-NH2 conferred protection against phototoxicity without inhibiting RPE65, whereas an emixustat derivative incapable of atRAL sequestration was minimally protective, despite direct inhibition of RPE65. These data indicate that atRAL sequestration is an essential mechanism underlying the protective effects of emixustat and related compounds against retinal phototoxicity. Moreover, atRAL sequestration should be considered in the design of next-generation visual cycle modulators.

Topics: Alcohol Oxidoreductases; Animals; ATP-Binding Cassette Transporters; Catalytic Domain; Cattle; cis-trans-Isomerases; Crystallography, X-Ray; Enzyme Inhibitors; Female; Free Radical Scavengers; Macular Degeneration; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Phenyl Ethers; Propanolamines; Retinal Degeneration; Retinaldehyde; Schiff Bases; Stereoisomerism