Wet (neovascular) age-related macular degeneration (wet AMD) and diabetic macular edema (DME) are the leading causes of visual impairment in the elderly and diabetic populations respectively.
Wet AMD is the leading cause of blindness in the developed world in people aged over 50 years. The disease affects central vision and the ability to see fine detail, such as that required to read, distinguish faces and drive a car. Wet AMD is caused by the abnormal growth and leakage of blood vessels at the back of the eye, which causes degeneration of the retina and vision loss.
The abnormal growth and leakiness of vessels can be stimulated by members of the vascular endothelial growth factor (VEGF) family of proteins, which includes VEGF-A, VEGF-C and VEGF-D. Elevated levels of these signals and their receptors are associated with retinal disease progression.
Current treatments for wet AMD target VEGF-A. Whilst VEGF-A inhibitors represent a major advance in the management of the disease, many patients respond sub-optimally.
OPT-302 is an inhibitor of VEGF-C and VEGF-D that is being developed as a complementary medicine to be used in conjunction with VEGF-A inhibitors to improve vision outcomes in wet AMD and DME patients.
Diabetic Macular Edema (DME) is the leading cause of blindness in diabetics. Chronically elevated blood glucose levels in Type 1 and Type 2 diabetics can lead to inflammation, vascular dysfunction and hypoxia, causing upregulation of members of the VEGF family of growth factors, particularly VEGF-A and VEGF-C. Elevated levels of VEGF-A and VEGF-C can lead to fluid accumulation in the macula at the back of the eye and retinal thickening which affects vision.
Existing standard of care treatments for DME are limited and include inhibitors of VEGF-A, steroids and laser therapy. Despite these treatments, many patients remain refractory and have sub-optimal response to therapy with persistent fluid and impaired vision.
OPT-302 blocks the activity of VEGF-C and VEGF-D. Used in combination with a VEGF-A inhibitor, OPT-302 has the potential to improve clinical outcomes in DME patients.
OPT-302 Clinical Program
Two ongoing randomised controlled clinical trials in nAMD & DME
Wet AMD and DME represent large commercial opportunities for novel therapies.
Current treatments for wet AMD and DME share a common mechanism of action by inhibiting VEGF-A. However, at least 45% of wet AMD patients experience some degree of resistance to treatment, with sub-optimal vision gain and persistent retinal fluid despite receiving regular anti-VEGF-A therapy. In addition, a substantial proportion of patients with DME have persistent macular edema and suboptimal vision gain following anti-VEGF-A therapy.
Combination therapy with OPT-302 and a VEGF-A inhibitor has the potential to improve patient outcomes by more completely blocking the signalling pathways involved in disease progression and addressing mechanisms of resistance to existing therapies.
With very few combination therapies in development that may offer improved outcomes for retinal disease patients, Opthea’s OPT-302 is a promising drug candidate with encouraging early stage clinical data and large commercial potential.
Technology / Mechanism
Opthea’s technology is based on two members of the Vascular Endothelial Growth Factor (VEGF) family of proteins, VEGF-C and VEGF-D, and their activation of VEGF receptors.
VEGF-C and VEGF-D promote blood vessel development (angiogenesis) by binding and activating VEGFR-2 and VEGFR-3, and lymphatic vessel development (lymphangiogenesis), by activation of VEGFR-3. In addition, VEGF-C is a potent inducer of vascular permeability and leakage.
OPT-302 is Opthea’s lead molecule, a soluble form of VEGFR-3 that acts as a VEGF-C/VEGF-D ‘trap’. Blockade of VEGF-C and VEGF-D by OPT-302 inhibits blood and lymphatic vessel development, as well as vessel leakage, which are characteristic hallmarks of several eye diseases, including wet AMD and DME.
By combining administration of OPT-302 with a VEGF-A inhibitor, complete blockade of important signalling pathways that contribute to the pathophysiology of retinal disease can be achieved, which may improve visual acuity and retinal swelling in patients. Also, as both VEGF-C and VEGF-D can be upregulated to compensate for VEGF-A inhibition, OPT-302 may block mechanisms of resistance to existing therapies, which may then result in improved and more durable clinical responses.
Existing Therapies Primarily Target VEGF-A
OPT-302 is a fusion protein comprising immunoglobulin-like domains 1 to 3 of the extracellular domain of VEGFR-3 fused to the Fc fragment of human immunoglobulin G1 (IgG1).
OPT-302 binds human VEGF-C and VEGF-D with high affinity and neutralises the activity of both proteins by preventing binding to both VEGFR-2 and VEGFR-3. OPT-302 is formulated as a solution for intravitreal injection, and in Opthea’s current clinical trials OPT-302 is administered via sequential intravitreal injection following administration of standard of care anti-VEGF-A therapy.
Opthea has reported encouraging results from a Phase 2b study in wet AMD patients and has an ongoing clinical trial investigating OPT-302 as a combination therapy in diabetic macular edema (DME):
Opthea has completed treatment of 366 treatment-naïve patients in a randomised, controlled Phase 2b clinical trial investigating OPT-302 administered in combination with the VEGF-A inhibitor ranibizumab (Lucentis®) compared to ranibizumab alone. The results of this trial were reported in August 2019.
Opthea has reported outcomes from a Phase 1b dose-escalation study of OPT-302 administered in combination with aflibercept (Eylea®). Patient recruitment into a ~144 patient Phase 2a trial in persistent DME is ongoing, with primary data analysis anticipated in the first half of calendar 2020, subject to ongoing patient recruitment.