emixustat (ACU-4429) / Kubota - LARVOL DELTA

Design and synthesis of novel sulfoximine RPE-65 inhibitors for potential treatment of age-related macular degeneration and Stargardt disease (ACS-Fall 2025) - "Our goal is to develop new, orally bioavailable RPE65 inhibitors with improved pharmacokinetics, efficacy, and safety profiles compared to (R)-Emixustat. RPE65-61, a novel non-retinoid inhibitor of RPE65, holds promise as a therapeutic agent to modulate excessive visual cycle activity and protect the retina from degenerative diseases such as AMD and STGD1."

Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders • AOC3

RPE65-bound sulfoximines for Stargardt disease and atrophic age-related macular degeneration (ACS-Fall 2025) - "We propose herein elucidated syntheses and design approaches towards various analogues of (±)-RPE65-61 as part of a structure-activity relationship campaign designed to further improve RPE65 potency while blunting VAP-1-mediated oxidation. Our goal is to identify orally bioavailable RPE65 inhibitors that possess ideal pharmacological characteristics while offering structural stability, integrity, and diversity relative to (R)-emixustat in addition to scaffolds that could broaden the respective scope of our findings."

Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Inherited Retinal Dystrophy • Macular Degeneration • Mood Disorders • Ophthalmology • Retinal Disorders • AOC3

Rationally Designed, Short-Acting RPE65 Inhibitors for Visual Cycle-Associated Retinopathies. (PubMed, J Med Chem) - "These molecules protected against retinal degeneration in mouse models of photic retinopathy and STGD1. These data demonstrate that shorter attenuation of the visual cycle can therapeutically intervene in retinal diseases with fewer visual side effects compared to emixustat."

Journal • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Stargardt's Disease: Molecular Pathogenesis and Current Therapeutic Landscape. (PubMed, Int J Mol Sci) - "Small-molecule therapies target vitamin A dimerization (e.g., ALK-001), inhibit lipofuscin accumulation (e.g., soraprazan), or modulate the visual cycle (e.g., emixustat hydrochloride). Gene therapy trials explore ABCA4 supplementation including strategies like RNA exon editing (ACDN-01) and bioengineered ambient light-activated OPSIN...Trials like DRAGON (Phase 3, tinlarebant), STARLIGHT (phase 2, bioengineered OPSIN) show promise, but optimizing efficacy remains challenging. With the key problem of establishing genotype-phenotype correlations, the future of STGD1 therapy may rely on approaches targeting oxidative stress, lipid metabolism, inflammation, complement regulation, and genetic repair."

Journal • Review • Age-related Macular Degeneration • Gene Therapies • Inflammation • Inherited Retinal Dystrophy • Macular Degeneration • Metabolic Disorders • Ophthalmology • Retinal Disorders • ALK

RPE65 inhibitor emixustat prevents retinal degeneration caused by T4K rhodopsin in rapidly cycling light (ARVO 2025) - "Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Ophthalmology

Rationally tailored short-acting RPE65 inhibitors for prevention and treatment of visual cycle-associated retinopathies (ARVO 2025) - "Here, we developed ester-containing analogs of emixustat characterized by a short duration of action. This new technology maintains its therapeutic efficacy in mouse models of retinal degeneration induced by light and holds promise for clinical translation into a treatment for humans."

Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Unlocking the Therapeutic Potential: Sitagliptin's Multifaceted Approach in Drug-Resistant Epilepsy through a Novel Mechanism Inhibiting Protein Kinase C-γ and a Long-Term Potentiation Pathway. (PubMed, ACS Pharmacol Transl Sci) - "Employing computational modeling and enzyme assay testing, three lead compounds, emixustat, sitagliptin, and distigmine bromide, were evaluated against the target enzyme protein kinase C-γ. In vivo, experiments on a pentylenetetrazolium-induced lamotrigine-resistant epilepsy model were conducted to test sitagliptin's antiseizure effects, compared with the standard phenobarbital treatment...Finally, sitagliptin showed potential neuroprotective properties, limiting pentylenetetrazolium-induced neuronal loss in the hippocampal region. Collectively, our findings suggest sitagliptin's multidimensional therapeutic potential for drug-resistant epilepsy specifically via a long-term potentiation pathway by inhibiting protein kinase C-γ."

Journal • CNS Disorders • Epilepsy • IL1B • IL6

Pharmacological treatment for maculopathies based on oral administration of a new visual cycle modulator (ARVO 2024) - "16e is a promising candidate for the treatment of macular degeneration induced by light. The determination of key pharmacokinetic parameters (oral bioavailability and half-life) based on plasma levels of 16e is under investigation. The study of repetitive administration of 16e will allow the establishment of a suitable posology for this visual cycle modulator."

Age-related Macular Degeneration • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders

Updates on Emerging Interventions for Autosomal Recessive ABCA4-Associated Stargardt Disease. (PubMed, J Clin Med) - "For pharmaceutical therapies ALK-001, deuterated vitamin A shows promise with preliminary data for phase 2 trial, demonstrating a decreased atrophy growth rate after two years...Many other treatment options have ongoing investigations and clinical trials. While multiple potential interventions have shown promise in attenuating disease progression, further exploration is necessary to demonstrate treatment safety and efficacy."

Journal • Review • Age-related Macular Degeneration • Gene Therapies • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders • ALK

Economic Burden and Changing Treatment Landscape in Stargardt Disease: A Literature and Database Review (ISPOR-EU 2023) - "Seven trials investigated 5 drug interventions (emixustat, tinlarebant, STG-001, avacincaptad pegol, ALK-001) with the eighth trial investigating a gene therapy (GT) (vMCO-010). The current healthcare costs associated with SD are not well established. With uncertainty around the current economic burden of SD, it will be difficult to determine the economic impact of new treatment options when making access decisions. Future analysis of analogues from other ocular degeneration disorders may prove useful in determining the current economic burden of SD."

HEOR • Review • Gene Therapies • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders • ALK

Hijaking the retinoid pathway to cure the retinal diseases (ACS-Fall 2023) - "Using VCM metabolic data and structure-activity relationships we will synthesize and test novel VCMs designed to optimize residence time in the body and potentially reduce ocular side effects. We are also examining the role of the retinoid trafficking machinery in selective ocular distribution of both emixustat and the novel VCMs."

Diabetic Retinopathy • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif. (PubMed, J Med Chem) - "We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties."

Journal

Role of the RBP4/STRA6 transport system for tissue-specific delivery of Visual Cycle Modulators (ACS-Sp 2023) - "Using VCM metabolic data and structure-activity relationships we synthesized and test novel VCMs designed to optimize residence time in the body and potentially reduce ocular side effects. We also examined the role of the retinoid trafficking machinery in selective ocular distribution of both emixustat and the novel VCMs."

Diabetic Retinopathy • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Visual cycle modulators targeted to the Eye (ACS-Fall 2022) - "Retinol binding protein 4 (RBP4) is present in blood serum which is synthesized by liver acts as a transporter of retinol (Vitamin A) from liver to the eye. So, the other way is to slow down the transportation of Vitamin A into the eye which results in slowing visual cycle.Visual cycle modulator (VCM) replacing vitamin AFluorescence binding assay on gem-difluoro-Emixustat"

Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

SeaSTAR: Safety and Efficacy of Emixustat in Stargardt Disease (clinicaltrials.gov) - P3 | N=194 | Completed | Sponsor: Kubota Vision Inc. | Active, not recruiting ➔ Completed

Trial completion • Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders

Computational attributes of protein kinase-C gamma C2-domain & virtual screening for small molecules: elucidation from meta-dynamics simulations & free-energy calculations. (PubMed, J Biomol Struct Dyn) - "The screened molecules LIG-41 ([4-Oxo-4-(4-phenylmethoxyanilino) butyl] azanium) and LIG-16 (Emixustat) exhibit overall optimal attributes in the above-mentioned parameters. The two leads are expected to inhibit the Ca-mediated PKC-γ activity.Communicated by Ramaswamy H. Sarma."

Journal • CNS Disorders • Epilepsy

Rational Alteration of Pharmacokinetics of Chiral Fluorinated and Deuterated Derivatives of Emixustat for Retinal Therapy. (PubMed, J Med Chem) - "Crystal structures and quantum chemical analysis of RPE65 in complex with the most potent emixustat derivatives revealed the structural and electronic bases for how fluoro substituents can be favorably accommodated within the active site pocket of RPE65. We found a close (∼3.0 Å) F-π interaction that is predicted to contribute ∼2.4 kcal/mol to the overall binding energy."

Journal • PK/PD data • Retinal Disorders

Visual cycle modulators versus placebo or observation for the prevention and treatment of geographic atrophy due to age-related macular degeneration. (PubMed, Cochrane Database Syst Rev) - "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."

Clinical • Journal • Review • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Dermatology • Diabetic Retinopathy • Dry Age-related Macular Degeneration • Macular Degeneration • Ocular Infections • Ophthalmology • Pruritus • Retinal Disorders • Wet Age-related Macular Degeneration

Randomised study evaluating the pharmacodynamics of emixustat hydrochloride in subjects with macular atrophy secondary to Stargardt disease. (PubMed, Br J Ophthalmol) - "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."

Clinical • Journal • PK/PD data • Age-related Macular Degeneration • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders

Effects of emixustat hydrochloride in patients with proliferative diabetic retinopathy: a randomized, placebo-controlled phase 2 study. (PubMed, Graefes Arch Clin Exp Ophthalmol) - P2 | "Although this pilot study did not demonstrate statistically significant differences in changes in aqueous humor cytokine levels between the emixustat and placebo groups, VEGF levels were slightly reduced in the emixustat but not in the placebo group. In addition, statistically significant differences favoring the emixustat group were observed in CST and TMV among all subjects. These data warrant further investigation of emixustat's potential therapeutic effects in diabetic retinopathy."

Clinical • Journal • P2 data • Diabetic Macular Edema • Diabetic Retinopathy • Ophthalmology • Retinal Disorders • CXCL8 • IL6 • VEGFA

Development of chiral fluorinated alkyl derivatives of emixustat as drug candidates for the treatment of retinal degenerative diseases. (PubMed, Bioorg Med Chem Lett) - "Its inhibition might decrease the rate of the retina's degeneration by limiting the amount of retinal and its toxic byproducts. Two RPE65 inhibitors, (R)-emixustat and (R)-MB001, were recently developed for this purpose."

Journal • Ophthalmology

All-trans-Retinaldehyde Contributes to Retinal Vascular Permeability in Ischemia Reperfusion. (PubMed, Invest Ophthalmol Vis Sci) - "The visual cycle was ablated in the Lrat-/- mice, reduced by dark adaptation or the use of the RPE65 inhibitor and atRAL scavenger emixustat...Outer retinal pathology may contribute to vascular permeability by release of atRAL, which can act directly on vascular endothelial cells to alter barrier properties and induce cell death. These studies may have implications for a variety of blinding eye diseases that include outer retinal damage and retinal vascular permeability."

Journal • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Gene Therapies • Ischemic stroke • Macular Degeneration • Ophthalmology • Reperfusion Injury • Retinal Disorders

Study to Evaluate Effects of Emixustat Hydrochloride in Subjects With Proliferative Diabetic Retinopathy (clinicaltrials.gov) - P2; N=20; Not yet recruiting; Sponsor: Acucela Inc.

New P2 trial • Age-related Macular Degeneration • Biosimilar • Diabetes • Ophthalmology

SeaSTAR: Safety and Efficacy of Emixustat in Stargardt Disease (clinicaltrials.gov) - P3; N=194; Active, not recruiting; Sponsor: Acucela Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Non-photopic and photopic visual cycles differentially regulate immediate, early and late-phases of cone photoreceptor-mediated vision. (PubMed, J Biol Chem) - "The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the non-photopic or photopic visual cycles for mediating vision in bright light."

Journal