Macular Week: Recent advances in pharmacotherapy for Stargardt disease

Macular Week is all about sensitizing and informing patients, associations, professionals and society of latest achievements on macular degenerative pathologies. In this publication, we will focus on the news on orphan drugs that are currently in the clinical or preclinical phase for the treatment of Stargardt disease. Stargardt disease, the most common inherited macular dystrophy, is characterized by the progressive loss of central vision due to the degeneration of the photoreceptor cells in the macula, the central part of the retina, rich in cones. Cones are responsible for color vision and visual acuity at high intensities of light. These cells allow us to perform tasks such as reading, watching television or recognizing faces. The first symptoms of Stargardt disease usually appear during childhood or adolescence, therefore, the age of onset and its progression is variable. Most Stargardt disease cases are caused by mutations in the ABCA4 gene and follow an autosomal recessive pattern (both parents are carriers). ABCA4 is a transporter protein that plays a crucial role in the elimination of the toxic products generated during phototransduction. Mutations in ABCA4 cause the accumulation of these toxic agents and eventually lead to a progressive degeneration of the photoreceptor cells. In a small percentage of cases, Stargardt disease is caused by mutations in two other genes, ELOV4 and PROM1, both responsible for autosomal dominant inheritance.

Drugs are being developed to treat the effects associated to ABCA4 mutations and reduce the accumulation of toxic vitamin A dimers (bisretinoids), including N-retinylidene-N-retinylethanolamine (also referred to as A2E). The C30-D3-vitamin A or ALK-001 developed by Alkeus Pharmaceuticals, is a modified and less reactive vitamin A that decreases the formation of toxic dimers. This treatment is based on replacing the source of vitamin A in the diet with this modified version. The promising results in preclinical studies have prompted clinical trials in patients. A first phase 1 trial in healthy volunteers has been completed to study the safety of treatment and a phase 2 clinical trial in Stargardt patients is underway, which is estimated to be completed within two years. Another drug, in the preclinical study phase, is the VM200 molecule developed by Vision Medicine. VM200 is a primary amine designed to sequester the all-trans-retinal toxic compound, preventing the formation of A2E and thus preserving retinal cells.

On the other hand, two drugs have been studied for their inhibitory function. Isotretinoin, marketed under different names is used for the treatment of severe acne. It inhibits the protein 11-cis-retinol dehydrogenase, thus decreasing the formation of toxic retinaldehydes, without causing cellular degeneration (Radu et al., 2003). It is important to highlight that this inhibitory compound has been used in diabetic retinopathy patients but not yet in Stargardt cases.

The second drug under study is Emixustat (ACU-4429) of the company Acucela Inc. This drug inhibits the protein encoded by the RPE65 gene, which hydrolyses the precursor of the ester A2E, the final toxic molecule. A phase 3 clinical trial started in November 2018 with more than 150 Stargardt disease patients. The results of this study are expected to be reported at the end of 2021.

The toxic activity of A2E and bisretinoids cause an inflammatory effect that activates the complement system of the immune system and the formation of inflammasomes. This process leads to the death of photoreceptor cells. The drug Avacincaptad pegol (trade name Zimura®) developed by Ophthotech Corporation is an inhibitor of the C5 protein, and aims to prevent the degeneration of retinal cells by delaying the neurodegenerative progress of Stargardt disease and other macular pathologies. Nearly 100 patients with Stargardt disease are currently participating in a phase 2 clinical trial, expected to finish by September 2020.

Finally, the drugs Fenretinide from Sirion Therapeutics and A1120 (ICR-14967), both agonists of the RBP4 protein, restrict the transport of retinol into the cells of the retinal pigment epithelium. Both are in preclinical phase and are promising candidates for new treatments.

Personalized medicine for Stargardt disease and other retinal inherited dystrophies are already at the fore. Within this context, the genetic diagnosis of patients is a prerequisite step to opt for appropriate and effective treatments.



Hussain, R. M., Ciulla, T. A., Berrocal, A. M., Gregori, N. Z., Flynn Jr, H. W., & Lam, B. L. (2018). Stargardt macular dystrophy and evolving therapies. Expert opinion on biological therapy, 18(10), 1049-1059.

Hussain, R. M., Gregori, N. Z., Ciulla, T. A., & Lam, B. L. (2018). Pharmacotherapy of retinal disease with visual cycle modulators. Expert opinion on pharmacotherapy, 19(5), 471-481.

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