GB-102, our lead product, contains a single small molecule compound that inhibits multiple pathogenic angiogenesis pathways known to be involved in the choroidal neovascularization, the cause of neovascular (wet) AMD (nAMD). Blockage of these angiogenesis pathways together has been shown to be more effective than blockage of a single pathway in clinical studies of nAMD. GB-102 is designed to provide the benefits of current multi-product therapies as a single dose administration potentially twice per year. We believe GB-102 may improve both convenience and efficacy compared to current treatments for nAMD.
GB-102 consists of sunitinib malate formulated in Graybug Vision’s ocular delivery technologies to create an injectable intravitreal depot. Sunitinib inhibits the vascular endothelial growth factor receptor (VEGFR) and the platelet derived growth factor beta receptor (PDGFR). Sunitinib malate was approved in 2006 for use as an anti-cancer agent when administered orally. Oral administration of sunitinib malate results in drug levels in the uveal tract above those achieved with the maximum feasible dose of GB-102, and there have been no reports of ocular toxicity in animals or humans from oral dosing of sunitinib malate.
In recent studies in rabbits, GB-102 has demonstrated the ability to provide continuous drug levels for a minimum of 6 months after intravitreal (IVT) injection (Figure 1 below). After a single IVT injection of GB-102 at the maximum feasible dose, no evidence of clinically significant inflammation or toxicity has been noted over the 6 month duration of the study. GB-102 may also provide pharmacologically active levels of sunitinib for 6 months. In a comparative study, GB-102 at 1/20th the maximum feasible dose administered 10 weeks prior to laser treatment was more effective in reducing choroidal neovascularization than aflibercept given within 24 hours of laser treatment (Figure 2 below). Graybug Vision has successfully completed a pre-IND meeting with FDA and is preparing an IND submission to support a Phase 1/2 study in nAMD patients to begin in early 2017.
Features of GB-102:
- Reduced IVT injection frequency to every 6 months to lower the burden and pain for nAMD patients and combining the anti-angiogenic benefits of current single agent therapies. Current treatment standard for nAMD is IVT injections at every 1-2 months and separate injections for each anti-angiogenic approach (e.g. anti-VEGF and anti-PDGF).
- A single agent, sunitinib malate, blocks both VEGF and PDGF activities for anti-angiogenesis in nAMD. Prior evidence has indicated that drugs with this dual activity can potentially result in regression of neovascularization, compared to single agent drugs which are the current standard on the market and suppress but not reverse neovascularization.
- Sunitinib malate, the active pharmaceutical ingredient in GB-102, has been approved by FDA as an anti-cancer agent, and thus the safety profile is well known. Furthermore, the systemic exposure will be substantially lower from the IVT injection compared to the cancer indications.
Pharmacokinetics of GB-102 After a SINGLE Intravitreal Injection
Pharmacokinetics After a Single Intravitreal Injection of GB-102 in Pigmented Rabbits
(10 mg GB-102, 1 mg sunitinib malate; 50 µL injection)
in Selected Ocular Tissues and Plasma
Efficacy of GB-102 in a Choroidal Neovascularization (CNV) Animal Model:
GB-102 efficacy was evaluated in the laser-induced rabbit model of choroidal neovascularization (CNV), which mimics the pathology in wet AMD patients. To assess the ability of GB-102 to block CNV, laser treatment was done 10 weeks after injection of a single dose of GB-102 or within 24 hours after a single injection of aflibercept or a placebo control. Three weeks after laser injury (3 months after GB-102 dosing), the amount of CNV area was measured by intravenous injection of fluorescein dye and fluorescence imaging of the eyes. Increased vessel growth caused by CNV resulted in increased fluorescent area.
CNV Area Three Weeks after Laser Treatment