Our lead molecule, GB-102, is a clinical stage depot formulation of sunitinib malate (referred to as sunitinib) encapsulated within bioabsorbable microparticles intended for the intravitreal (IVT) treatment of patients with wet AMD, a leading cause of vision loss in adults.

GB-102 represents the next generation of IVT therapies for retinal disease that has a drug-elution profile supporting the potential for twice-yearly IVT injections, thus reducing the burden of care associated with frequent IVT injections for patients and retinal specialists. Sunitinib is a small molecule receptor tyrosine kinase inhibitor (TKI) that potently blocks several intracellular receptors known to be associated with angiogenesis, proliferation, vascular permeability, and fibrosis (Figure 1).  Additionally, sunitinib has demonstrated neuroprotective effects of retinal ganglion cells and photoreceptors in preclinical models of neuronal injury.

The proprietary formulation allows for the microparticles to aggregate into a single biodegradable depot in the inferior vitreal cavity away from the visual axis. The unique surface treatment of the particles minimizes localized inflammation that have commonly been observed with traditional PLGA microparticles.

Graybug is planning on clinical development of GB-102 in other VEGF-driven diseases of the retina including diabetic macular edema (DME) and retinal vein occlusion (RVO).

Wet AMD is a leading cause of irreversible vision in the adult population in the industrialized world; DME is the leading cause of vision loss in persons with diabetes mellitus. RVO is the second most common cause of blindness from retinal vascular disease after diabetic eye disease.

Figure 1.  Mechanism of action of sunitinib, a multiple receptor tyrosine kinase inhibitor

 

Sunitinib, the active pharmaceutical ingredient of GB-102, is a multiple receptor TKI that selectively inhibits vascular endothelial factor receptors (VEGFR-1, -2, -3), platelet-derived growth factor receptors (PDGFR-α, -β), stem cell growth factor receptor (KIT), colony stimulating factor receptor (CSFR-1), and Fms-related tyrosine kinase receptor (FLT3).  Inhibition of multiple receptors associated with choroidal neovascularization may provide a more complete blockade of the neoangiogenesis process associated with  wet AMD compared to currently available monotherapy agents (aflibercept, bevacizumab, or ranibizumab) without need for co-administered IVT agents.

Sunitinib malate is the active pharmaceutical product in SUTENT® (Pfizer) approved in 2006 for the oral treatment of advanced renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. GB-102, an encapsulated sustained-release formulation of sunitinib, is intended for intravitreal injection enabling high retinal tissue exposure with minimal systemic bioavailability.

In preclinical models, sunitinib has demonstrated reduction in vascular leakage in mouse laser injury models of choroidal neovascularization when administered orally (Takahashi, 2006 – link to paper) or with IVT administration of GB-102 (Formica, 2016 – link to poster). In preclinical pharmacologic studies in rabbits, IVT GB-102 (1.0 mg sunitinib) provides sustained levels of sunitinib in the retinal pigmented epithelium and choroid 2- to 3- log orders above the inhibitory concentration needed to suppress VEGFR-1, -2, -3 and PDGFR-???? and -???? up to 6 months following a single IVT injection (Peterson, 2016– link to poster) (Figure 2).

Figure 2. Ocular tissue levels of sunitinib (ng/g) following a single intravitreal injection of GB-102 in pigmented rabbits supports the potential for dosing twice a year (Peterson 2016).

GB-103

GB-103 is similar to GB-102 but has been formulated to elute sunitinib over a longer duration that may enable once yearly dosing instead of twice yearly dosing.  By tuning the polymer composition of the PLGA microparticles, slower release rates of encapsulated drug can be engineered (Peterson 2017 – link to ARVO poster)