Macular dystrophies are a group of inherited eye conditions that affect the macula. The macula is in the center of the retina, the light sensitive part at the back of the eye. In people with macular dystrophies, some of the cells in the macula gradually stop working and may die over time. This leads to vision loss in the center of the eye. Side vision (peripheral vision) is mostly unaffected. Stargardt disease (STGD) is a type of macular dystrophy which is caused by 1 faulty gene (ABCA4). Vision loss most typically happens in childhood, but many people do not develop it until they are adults. As well as STGD, there are other macular dystrophies that look very similar to STGD but that are caused by many other different genes. Together, STGD and STGD-like conditions can be called STGD-type macular dystrophies. This is because they look the same clinically and have similar symptoms. Since different genes can cause these conditions, genetic testing is the only way to be sure which specific condition a person has.

In this study, researchers want to learn if the disease progresses in a similar way in people with STGD and STGD-like macular dystrophies. People taking part in the study will continue to manage their condition, as agreed with their own doctor. People will visit their clinic every 6 months to have various standard eye tests and imaging. The information collected will include questions about people's wellbeing, general health, medication and supplements taken, and daily activities.

Children over 6 years old and adults with STGD-type macular dystrophies may take part in this study. They will be in the study for up to 24 months (2 years). The study sponsor (Astellas) will not decide how people's condition is managed. However, the sponsor will provide instructions on when people visit their clinic and what is recorded during the study. If available, medical records, clinical and imaging data from previous visits going back 24 months will also be reviewed.

Inclusion Criteria:

• Participant has a documented clinical diagnosis of macular dystrophy expressing a STGD-type clinical presentation and molecular confirmation, defined as either:

  • ABCA4-associated disease: presence of biallelic (pathogenic or likely pathogenic) ABCA4 variants, or one definite disease-causing ABCA4 variant together with a typical phenotype consistent with STGD.
  • STGD-like macular dystrophy: presence of one or more pathogenic variants in a gene known to cause macular dystrophy, as appropriate for its expected inheritance mode. Note: All genetic testing should be performed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or equivalent whenever possible. Acceptable documentation includes a copy of the genetic test report, laboratory certification statement, or clinical notes explicitly referencing CLIA certification. Predicted pathogenic variant of uncertain significance (VUS) that cannot be confirmed by standard laboratory criteria as certainly disease-causing (novel mutations) will be considered on a case by-case basis.

• Participant has sufficiently clear ocular media and adequate pupillary dilation to allow for all imaging procedures.

• Participant has intraocular pressure (IOP) both at screening and baseline of ≤ 21 mmHg measured by applanation tonometry. Note: Participant who is on topical IOP lowering treatment may also be included.

• Participant has a spherical equivalent refractive error between + 8.00 D and - 10.00 D. Eyes with high myopia (> -10.00 D) are permitted only if there are no signs of myopic degenerative macular changes.

• Participant has a BCVA ranging from 20/500 to 20/40 (equivalent to 15 to 70 ETDRS letters read at 1 meter)

  • For participants in the > 20/80 to ≤ 20/40 BCVA range (moderate visual impairment [MVI]): presence of a visible definite or probable residual EZ on SD-OCT (no minimum residue size required) and a minimum central mean subfield retinal thickness on optical coherence tomography (OCT) ≥ 150 µm
  • For participants in the ≥ 20/500 to ≤ 20/80 BCVA range (SVI): presence of a residual outer nuclear layer (ONL) within the macular OCT scan area and measurable within the Age-Related Eye Disease Study (AREDS) grading grid and no residual EZ or minimal thickness of the ONL required

• Participant has evidence of retinal pigment epithelium (RPE) disease/damage on SD-OCT (hypertransmission defects [HTDs]) and/or FAF imaging.

• Participant has evidence of at least questionably decreased autofluorescence (QDAF) (incomplete retinal pigment epithelial and outer retinal atrophy [iRORA]), defined as mottled or speckled hypo-autofluorescence (AF) signal, mixed with or without hyper- AF, on FAF imaging. Note: At study onset, having patches of definitely decreased autofluorescence (DDAF) within the FAF image and/or patches of complete retinal pigment epithelial and outer retinal atrophy (cRORA) on SD-OCT ≥ 250 µm will not be a requirement for participation but will be acceptable for inclusion, so long as:

  • DDAF/cRORA areas are contained within the limits of the AREDS grading grid (≤ 12 disc areas), and physically distinct and separate from other areas of QDAF, DDAF and/or hyper-AF that may be present outside the AREDS grading grid, and
  • the other BCVA and SD-OCT required inclusion criteria are also met.

• Participant is able to comply with the protocol and willing to undertake all scheduled visits and assessments during the total study period.

• Participant is deemed capable of performing reliably all tests required for participation.

Exclusion Criteria:

• Participant has a known history of significant systemic disease (e.g., uncontrolled hepatitis, pancreatitis, cirrhosis, liver failure, uncontrolled thyroid disease or immunocompromising conditions such as human immunodeficiency virus [HIV]) that could impact ocular health or confound study assessments, based on medical history or prior clinical documentation.

• Participant has an autoimmune condition that requires treatment with immunomodulatory therapy and/or biologics that cause immunosuppression.

• Participant has a known diagnosis of diabetes mellitus with a documented hemoglobin A1c (HbA1c) value ≥ 7% 3 months prior to screening and based on available medical records. If the documented HbA1c is ≥ 7% and there is no clinical history of diabetic symptoms, diabetic retinopathy, abnormal renal function (e.g., elevated creatinine), or glycosuria noted in medical records, the participant may be enrolled.

• Participant has a known history of any systemic or metabolic condition, or physical examination finding that may significantly affect ocular health or interfere with the interpretation of study assessments.

• Participant has a history or evidence of severe cardiac disease (e.g., New York Heart Association Functional Class III or IV), clinical evidence of unstable angina, acute coronary syndrome, myocardial infarction or revascularization within 6 months prior to screening.

• Participant has a history or evidence of ventricular tachyarrhythmia requiring ongoing treatment.

• Participant has a significant cardiovascular or cerebrovascular disease, including a history of stroke within 12 months prior to screening.

• Participant has any complicating systemic disease or active malignancy. Squamous cell carcinomas will be an exclusionary criterion if lesions are recurrent and/or > 2 cm in diameter and/or affect the lip or ear area. Basal cell carcinomas are permitted, provided they are not located in the immediate periocular facial region. A history of any prior malignancy is allowed if the treating physician or oncologist confirms that the participant has been free of recurrence or metastasis for at least 5 years prior to screening.

• Participant has another known or suspected molecular diagnosis of macular or retinal disease (e.g., pathogenic mutations in other genes) that could confound interpretation of study outcomes, indicate a second concomitant retinal condition or suggest a different etiology for the macular disease.

• Participant has evidence or history of choroidal neovascularization.

• Participant has macular atrophy due to any cause other than a genetically or clinically confirmed diagnosis of STGD or STGD-like macular dystrophies.

• Participant has a known diagnosis of any form of uncontrolled glaucoma (for high tension glaucoma IOP > 25 mmHg).

• Participant has and/or is receiving treatment for thyroid eye disease.

• Participant has diabetic retinopathy in excess of mild nonproliferative diabetic retinopathy (i.e., presents with widespread retinal microaneurysms, dot-blot hemorrhages, and cotton-wool retinal spots).

• Participant has any other disease(s) affecting the optic nerve.

• Participant has a history of anterior or posterior uveitis and/or presence of intraocular inflammation (≥ trace anterior chamber cell or flare), or history of idiopathic or autoimmune-associated uveitis in either eye. Note: A single, sporadic episode of anterior uveitis without recurrences in the past 5 years and not associated with chronic conditions that increase the likelihood of recurrence may be accepted on a case-by-case basis in consultation with the sponsor's medical monitor/lead.

• Participant has corneal or lenticular opacities impeding the visualization of the fundus and/or the reliable performance of the visual function tests required by the protocol.

• Participant has sufficiently narrow iridocorneal angles contraindicating pupillary dilation that have not been previously treated with preventative laser iridotomies.

• Participant has any other ocular disorders that could interfere with or confound visual acuity and other ocular assessments, including OCT or FAF.

• Participant has a clinically significant epiretinal membrane or evidence of clinically significant vitreomacular traction syndrome. Note: A mild enhancement of the vitreoretinal interface seen on OCT without any alteration of the foveal profile would not be considered an exclusion criterion.

• Participant has presence of or recurrent vitreous hemorrhages. Note: A one-time episode of a traumatic vitreous hemorrhage would not result in exclusion, so long as resolved.

• Participant has aphakia.

• Participant has anticipated need for cataract surgery during the study period.

• Participant has a macular hole, evident by ophthalmoscopy and/or by SD-OCT examinations, or history of prior macular hole surgery.

• Participant has a history of any of the following procedures: posterior vitrectomy, retinal detachment surgery, glaucoma filtering surgery (e.g., trabeculectomy), glaucoma drainage device implantation, selective laser trabeculoplasty, full-thickness or partial-thickness corneal transplant (e.g., Descemet's stripping endothelial keratoplasty, Descemet's stripping automated endothelial keratoplasty or Descemet's membrane endothelial keratoplasty).

• Participant has any lesion that is considered to pose a risk of retinal detachment during the study. Any preexisting lesion may be treated to allow eligibility, but treatment must be completed at least 3 months prior to screening.

• Participant has had any prior thermal laser or photodynamic therapy treatment in the macular region, regardless of indication. Peripheral retinal thermal laser treatments for holes, lattice degeneration, and/or other lesions with rhegmatogenous potential are permitted within 3 months prior to screening, subject to their potential impact on a future pars plana vitrectomy surgery.

• Participant has had any intraocular surgery within 3 months of screening.

• Participant has a history of intraocular metallic foreign bodies.

• Participant has received any treatment including gene therapy, stem cell therapy, surgical implantation of prosthetic retinal chips, or any prior intravitreal treatment for any indication in either eye that may be considered to potentially interfere with the study participation or its conduct.

• Participant is receiving concomitant treatment with any ocular or systemic medication known to be toxic to the lens, retina or optic nerve.

  • Participant is using hydroxychloroquine (Plaquenil), chloroquine, pentosan polyphosphate (Elmiron), tamoxifen, chlorpromazine, thioridazine (Mellaril), isotretinoin (Accutane) or any related retina-toxic compounds at screening.

• Participant has received therapeutic radiation in the region of the study eye.

• Participant has had any major surgical procedure within 1 month prior to screening or anticipates having one during the study, which may interrupt study participation.

• Participant is taking glucagon-like peptide-1 (GLP-1) receptor agonists and is unable or unwilling to stop the medication at least 4 weeks prior to screening. A history of treatment with a GLP-1 receptor agonist is allowed.

• Participant is taking metformin and is unable or unwilling to stop this medication at least 4 weeks prior to screening. A history of treatment with metformin is allowed.

• Participant is participating in an interventional study of a vitamin A metabolism inhibitor, a vitamin A analog/derivative, or another investigational drug product within 3 months prior to screening. After a 3 month washout period, participants can be considered for enrollment. Participation in a noninterventional study (NIS) is allowed.

• Participant has a known or suspected hypersensitivity to eyedrops used for IOP measurement or pupil dilation.

• Participant has any condition that makes the participant unsuitable for study participation.

Participants aged ≥ 6 years at baseline with clinically confirmed macular dystrophy of STGD-type clinical presentation

Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.