(ALK-001) has Breakthrough Therapy Designation
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Stargardt disease, which affects more than 30,000 people in the United States, is one of the most common genetic causes of blindness in children and young adults. No treatment exists.
WITH More than 30,000 pEOPLE in the U.S. Stargardt disease IS MORE COMMON THAN OTHER GENETIC DISEASES SUCH AS CF, PKU and SMA
Of the six most common genetic, autosomal recessive diseases, Stargardt disease is the only one without a treatment.
*Reference: Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases, 2019. Approximately 5% of the population is a carrier for an ABCA4 variant
The Root Cause: Defects in the ABCA4 Gene
Sight is made possible by a biochemical chain reaction in the eye: Vitamin A enables photoreceptors in the eye to convert light into electrical signals that are sent to the brain. Vitamin A is essential to the eye’s ability to see but also has a propensity to form dimers – or clumps – that are toxic to retinal pigment epithelium (RPE) layer.
Mutations in the ABCA4 gene were identified as the cause of Stargardt disease in 1997. The normal role of the ABCA4 protein is to ensure the flow of n-retinylidene-PE, a vitamin A isomer, through the photoreceptor membrane.
In Stargardt patients the ABCA4 protein is defective or absent, which allows excess vitamin A concentration and dimerization, and results in toxic by-products that irreversibly damage the RPE layer, leading to progressive vision loss.
Gildeuretinol (ALK-001) for the Treatment of Stargardt Disease
Gildeuretinol (ALK-001) is the first and only medicine in clinical development to selectively address the underlying mechanism of Stargardt disease, by reducing the rate of vitamin A dimerization in the eye.
Gildeuretinol was designed to perform all of the functions of vitamin A needed to support sight, but without the tendency to dimerize or clump, thus avoiding the toxic by-products that damage the retina. Researchers engineered gildeuretinol as a novel, selectively modified version of vitamin A, where three hydrogen atoms are replaced with deuterium atoms. This modification is what dramatically reduces the rate of dimerization.
In in vitro studies, researchers have demonstrated that gildeuretinol slowed dimerization of vitamin A by 4-5 fold, and in in vivo models, gildeuretinol has reduced vitamin A dimer formation in the eye by 80%, leading to preservation of visual function in animal models of Stargardt disease.
- 2021 – C20D3-Vitamin A Prevents Retinal Pigment Epithelium Atrophic Changes in a Mouse Model
- 2021 – Vitamin A cycle byproducts impede dark adaptation
- 2016 – Can Vitamin A be Improved to Prevent Blindness due to Age-Related Macular Degeneration, Stargardt Disease and Other Retinal Dystrophies?
- 2016 – The Rate of Vitamin A Dimerization in Lipofuscinogenesis, Fundus Autofluorescence, Retinal Senescence and Degeneration
- 2015 – Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization
- 2015 – Morphological and physiological retinal degeneration induced by intravenous delivery of vitamin A dimers in rabbits
- 2014 – Vitamin A dimers trigger the protracted death of retinal pigment epithelium cells
- 2013 – The retina rapidly incorporates ingested C20-D₃-vitamin A in a swine model
- 2011 – C20-D3-vitamin A slows lipofuscin accumulation and electrophysiological retinal degeneration in a mouse model of Stargardt disease
- 2011 – Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin A dimers in wild-type rodents
Gildeuretinol Clinical Results: A First for Stargardt Patients
In 2022, clinical investigators reported results from a double-blind, placebo-controlled, randomized Phase 2 study of gildeuretinol (ALK-001) in 50 patients with advanced Stargardt disease at the American Academy of Ophthalmology.
gildeuretinol SlowS the Growth Rate of Atrophic Lesions in Stargardt Patients
Gildeuretinol met the pre-specified primary efficacy endpoint with high statistical significance, with a consistent trend of clinical benefit seen in secondary efficacy analyses.
In the clinical trial known as TEASE-1, gildeutretinol dosed once a day resulted in decreased retinal damage as compared to placebo, based on observed growth rates in atrophic lesions as measured by fundus autofluorescence (FAF). Gildeuretinol was well-tolerated with a safety profile consistent with the well-characterized safety profile of vitamin A.
In addition, an innovative, open-label study in children, known as TEASE-3, has indicated an ability for gildeuretinol, when given early, to halt the disease process before progressive retinal damage and vision loss occurs. Results from this clinical trial are anticipated to be presented in an upcoming medical forum.
Alkeus’ Clinical Program with gildeuretinol is designed to support broad use in Stargardt Disease
References: Visual acuity loss and clinical observations in a large series of patients with Stargardt disease, 2003;
Visual Acuity Change over 12 Months in the Prospective Progression of Atrophy Secondary to Stargardt disease (ProgStar) Study, 2016.
Four clinical trials of gildeuretinol in Stargardt Disease are ongoing or completed, with the first two data readouts demonstrating positive clinical efficacy data.
Pursuing a Rapid Path to Market
The U.S. FDA has granted Breakthrough Therapy Designation and Orphan Drug Designation to gildeuretinol (ALK-001) for the treatment of Stargardt disease. Alkeus is engaged in discussions with regulatory authorities to define the most appropriate path to bring gildeutretinol to Stargardt disease patients as rapidly as possible. Alkeus plans to submit an NDA for approval of gildeuretinol in Stargardt disease in 2024.
Broad Potential to Treat Eye Disease
The pathological features of Stargardt disease—lesions in the retinal pigmental epithelium (RPE) layer, visible using high-resolution optical imaging —are common across several degenerative eye diseases.
There is mounting scientific evidence that the same process—excessive vitamin A dimerization, leading to toxic by-products that irreversibly damage photoreceptors in the retina—drives the progressive lesion growth not just in Stargardt disease but in these other diseases as well.
In addition to Stargardt disease, gildeuretinol is being evaluated Geographic Atrophy (GA), an advanced form of dry age-related macular degeneration (dry AMD). More than 1 million people in the United States and more than 5 million people worldwide have GA.
In addition to Stargardt disease, gildeuretinol is being evaluated in Geographic Atrophy (GA), an advanced form of dry age-related macular degeneration (dry AMD). More than 1 million people in the United States and more than 5 million people worldwide have GA.
Dry AMD is common in people over the age of 50. In dry AMD, layers of the retina slowly deteriorate over time. GA may occur in later-stage dry AMD patients, and is characterized by discrete areas of damage to the RPE layer, which leads to a progressive decline in central vision.
Although multiple mechanisms are associated with dry AMD and GA, it is clear that the toxic by-products of vitamin A are significant drivers of damage to the RPE layer.
In 2019, Alkeus initiated a Phase 3 study of gildeuretinol in Geographic Atrophy, with a primary goal of measuring ALK-001’s ability to slow the growth rate of GA lesions. The trial is fully enrolled with 200 patients.
Alkeus was co-founded by Leonide Saad, Ph.D. and Ilyas Washington, Ph.D. with the goal of treating degenerative eye diseases in a completely new way: developing a molecule that could reduce the potential for toxicity when vitamin A dimerizes —clumps —in the eye. This dimerization is a key underlying contributor to the irreversible retinal damage that is common to a number of eye diseases.
Alkeus has steadily progressed its lead molecule gildeuretinol (ALK-001), demonstrating its tremendous promise and advancing a comprehensive clinical program.
Alkeus is co-founded by Ilyas Washington, Ph.D and Leonide Saad, Ph.D
Publication of preclinical studies demonstrating that gildeuretinol (ALK-001) significantly reduces formation of vitamin A dimers, and slows retinal damage in genetic models of Stargardt disease
Gildeuretinol enters Phase 1 clinical development
First Phase 2 clinical study of gildeuretinol begins, for patients with advanced Stargardt disease
Phase 2 studies of gildeuretinol begin in children and young adults with early-stage and moderate disease
Alkeus initiates a Phase 3 study of gildeuretinol in Geographic Atrophy (GA) secondary to dry AMD
FDA grants breakthrough therapy designation to gildeuretinol for Stargardt disease
Phase 2 results presented at American Academy of Ophthalmology Annual Meeting show that gildeuretinol slows the growth rate of atrophic lesions in patients with advanced Stargardt disease
Alkeus secures $150 million in Series B funding to support rapid registration path for gildeuretinol in Stargardt disease; Joshua Boger, Ph.D. named Executive Chairman