Age-related macular degeneration (AMD) is the leading cause of blindness in older adults with the neovascular form of the disease (NVAMD) mainly responsible for severe vision loss. Current NVAMD treatments involve repeated intraocular injections of biologics that neutralize vascular endothelial growth factor (VEGF), an important NV stimulus. Aflibercept, approved in late 2011, provides an incremental benefit over ranibizumab and bevacizumab, as it may reduce injection frequency to every 2 months, from the monthly treatment regimen recommended for the other anti-VEGF agents. However, intraocular injection frequencies of 6-12 times a year remain a major burden on patients and health care providers. GrayBug is developing a novel, long-lasting, fully biodegradable drug-polymer conjugate injectable rod for AMD envisioned to require infrequent administration and improve treatment efficacy. The drug-polymer conjugate has a unique mechanism of action, the inhibition of hypoxia-inducible factor-1 (HIF-1)-regulated gene expression. HIF-1 induces the expression of multiple effectors of ocular NV including VEGF, platelet-derived growth factor-B (PDGF-B), VEGF and PDGF-B associated receptors, stromal derived growth factor-1 (SDF-1), and angiopoietin-2 (Ang2), all demonstrated to be involved in NVAMD pathophysiology. Indeed, blockade of one or more of these in addition to VEGF provides enhanced efficacy in animal models and clinical trials. The drug-polymer conjugate (DXR-PSA-PEG3) contains doxorubicin (DXR), a potent HIF-1 inhibitor, covalently conjugated to sebacic acid (SA) within a copolymer of poly(sebacic acid)-(polyethylene glycol)3 (PSA-PEG3). DXR-PSA-PEG3 particles release DXR as a DXR-SA conjugate slowly over time. DRX-SA has reduced solubility compared to free DXR, ensuring the drug does not reach toxic levels in the eye. Like free DXR, DXR-SA reduces VEGF, PDGF-B, and SDF-1 in the ischemic retina and unlike specific VEGF antagonists, such as ranibizumab or aflibercept, DXR-SA causes regression of preexisting NV. The suppression AND regression of NV is a major advantage that can result in increased efficacy and prolonged duration of effect. A first generation DXR-PSA-PEG3 nanoparticle formulation (0.65 ¿m) displayed in vitro release of only six days but suppressed ocular NV in human VEGF transgenic mice for 5 weeks, more than twice as long as ranibizumab in this model. Importantly, no ocular toxicity of the first generation DXR-PSA-PEG3 particles was observed in rodents, even at 10-100-times the effective dose. GrayBug has an exclusive license to this promising technology. As the DXR-PSA-PEG3 particles degrade via surface erosion, reduction of the surface area will lead to an extended duration of drug release. Here, we propose to produce and fully characterize rod-shaped injectables composed of the DXR- PSA-PEG3 conjugate (Specific Aim 1) and test their duration of drug release and safety in rabbits (Specific Aim 2). Successful completion of this project will lead to a Phase II proposal focused on efficacy evaluations and long-term safety studies in large animals that will enable the filing of an IND. Our ultimate goal is to develop a DXR-PSA-PEG3 product requiring only 1-2 administrations to patients per year to effectively control NVAMD.
Public Health Relevance Statement: Public Health Relevance: Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults. The main cause of severe vision loss is subretinal neovascularization, and although intraocular injections of vascular endothelial growth factor-binding proteins provide benefit, frequent injections are needed due to limited duration of effect. GrayBug seeks to develop a new longer-lasting therapy for AMD that not only controls angiogenesis, but also causes unwanted new blood vessels to regress, potentially leading to improved efficacy and safety.
Project Terms: 1 year old; Affect; Age related macular degeneration; angiogenesis; Angiogenesis Inhibitors; Angiogenic Factor; Angiopoietin-2; Animal Model; Animals; Area; Avastin; base; bevacizumab; Binding Proteins; Biological Process; Blindness; Blood Vessels; Bolus Infusion; Caliber; Chemicals; Clinical; Clinical Trials; comparative efficacy; copolymer; Development; Dexamethasone; Digoxin; Dimensions; Disease; Dose; Doxorubicin; Drug Delivery Systems; Drug Formulations; Drug Kinetics; efficacy evaluation; Elderly; Electroretinography; Ensure; Evaluation; Exposure to; Exudative age-related macular degeneration; Eye; FDA approved; Frequencies (time pattern); Functional disorder; Gene Expression; Generations; Goals; Growth; Growth Factor; Health Personnel; human VEGF protein; hypoxia inducible factor 1; Implant; improved; In Vitro; inhibitor/antagonist; Injectable; Injection of therapeutic agent; Lead; Length; Libraries; Licensing; Lucentis; Mediating; Methods; Modeling; mouse model; Mus; nanoparticle; neovascular; neovascularization; novel; ocular neovascularization; Oryctolagus cuniculus; particle; Patients; Pharmaceutical Preparations; Phase; phase 2 study; Pigments; Polyethylene Glycols; Polymers; Production; Protein Array; Proto-Oncogene Proteins c-sis; public health relevance; ranibizumab; receptor; Retina; Retinal; rho; Rodent; Rods (Retina); Safety; safety study; Saline; scale up; Scheme; screening; sebacic acid; Shapes; small molecule; Solubility; Stimulus; Surface; System; Technology; Testing; Therapeutic; Time; Toxic effect; transcription factor; Transgenic Mice; Treatment Efficacy; Treatment Protocols; Vascular Endothelial Growth Factors; Visual; Visual impairment
