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. Both diseases are associated with blood vessel dysfunction and fluid accumulation at the back of the eye in a region of the central retina or ‘macula’ that is needed for sharp, central vision. Blood vessel growth and integrity are controlled by the vascular endothelial growth factor (VEGF) family of proteins, which comprises VEGF-A, VEGF-B, VEGF-C, VEGF-D and placenta growth factor (PlGF). Elevated levels of these growth factors, and in particular VEGF-A and VEGF-C, are linked to abnormal blood vessel growth and vascular leakage associated with retinal disease progression.
Wet AMD is the leading cause of vision loss in the developed world in people over the age of 50. Wet AMD affects approximately 1 million people in the United States and 2.5 million in Europe. As the risk of developing wet AMD increases with age, it is predicted that the overall aging of the population will result in a significant increase in the number of wet AMD cases worldwide. 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. Current treatments for wet AMD target VEGF-A.
Diabetic Macular Edema (DME) is the leading cause of blindness in diabetics. It is currently estimated that between 1.3 million and 2 million people worldwide have DME, with the prevalence increasing due to the growing diabetic population and life expectancy. Chronically elevated blood glucose levels in Type 1 and Type 2 diabetics can lead to inflammation, blood vessel 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. Current treatments for DME include inhibitors of VEGF-A, steroids and laser therapy.
Despite these treatments, many patients remain refractory and have sub-optimal responses 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 Randomised controlled clinical trials in wet AMD & DME
Current standard-of-care treatments for wet AMD and DME share the common mechanism of inhibiting VEGF-A. Lucentis® (ranibizumab) and Eylea® (aflibercept), the market-leading VEGF-A inhibitors approved for the treatment of wet AMD and DME, had combined annual worldwide sales of over US$11.9 billion in 2019. In addition, nearly half of wet AMD patients are treated with off-label Avastin® (bevacizumab) as a lower cost alternative anti-VEGF-A therapy.
Although VEGF- A inhibitors, including Lucentis® and Eylea®, have achieved widespread adoption and commercial success, many patients experience suboptimal clinical responses. At least 45% of wet AMD patients treated with a VEGF-A inhibitor experience some degree of suboptimal clinical response, with a majority of patients failing to achieve 20/40 vision after 12 months of treatment, providing further opportunity for visual acuity improvement. In addition, a substantial proportion of patients with DME have persistent macular edema or do not show a clinically meaningful improvement in visual acuity following anti-VEGF-A therapy. Furthermore, many wet AMD and DME patients have persistent retinal fluid and insufficient gains in visual acuity to resume routine daily activities such as driving and reading following regular treatment with a VEGF-A inhibitor.
OPT-302 is an inhibitor of VEGF-C and VEGF-D being developed for use in combination with VEGF-A inhibitors to improve vision outcomes in wet AMD and DME patients. Combination therapy with OPT-302 and a VEGF-A inhibitor has the potential to improve patient outcomes by more broadly inhibiting the VEGF family and addressing mechanisms of resistance associated with existing therapies.
Technology / Mechanism
Opthea’s technology is based on targeting the incomplete response to VEGF-A inhibition when treating retinal diseases by inhibiting two other members of the VEGF family of proteins, VEGF-C and VEGF-D, that are involved in blood vessel development and vascular permeability. VEGF-C and VEGF-D promote blood vessel development (angiogenesis) by binding to and activating the receptors VEGFR-2 and VEGFR-3, and promote lymphatic vessel development (lymphangiogenesis) by activation of VEGFR-3. VEGF-C is also a potent inducer of vascular permeability and leakage.
OPT-302 is a soluble form of VEGFR-3 that ‘traps’ VEGF-C and VEGF-D. Blockade of VEGF-C and VEGF-D by OPT-302 inhibits blood and lymphatic vessel development, as well as vessel leakage, characteristic hallmarks of several eye diseases, including wet AMD and DME.
By using a combination of OPT-302 and a VEGF-A inhibitor, complete blockade of the important signalling pathways that contribute to the pathophysiology of retinal disease can be achieved, which may improve visual acuity and retinal swelling in patients. In addition, as both VEGF-C and VEGF-D can be upregulated to compensate for VEGF-A inhibition, OPT-302 targets the 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 first-in-class VEGF-C/D inhibitor. It is a soluble fusion protein comprising immunoglobulin-like domains 1 to 3 of the extracellular domain of vascular endothelial growth factor receptor 3 (VEGFR-3) fused to the Fc fragment of human immunoglobulin G1 (IgG1).
OPT-302 is a soluble form of VEGFR-3 which binds (“traps”) human VEGF-C and VEGF-D with high affinity, neutralising their activity by preventing them from 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 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 trial in wet AMD patients and evidence of improved clinical outcomes in a Phase 1b/2a clinical trial in patients with treatment-refractory diabetic macular edema (DME).
Wet AMD Clinical Trials
Opthea has completed a randomised, controlled, double-blinded Phase 2b clinical trial in 366 treatment-naïve patients investigating the VEGF-A inhibitor Lucentis® (ranibizumab) administered in combination with OPT-302, compared to Lucentis® administered alone. The trial met the primary endpoint, with OPT-302 administered in combination with Lucentis® demonstrating superiority in visual acuity gain compared to Lucentis® administered alone.
DME Clinical Trials
In Opthea’s Phase 1b dose escalation clinical trial in patients with persistent DME, promising evidence of a dose response was observed following OPT-302 and Eylea® combination treatment, including further improvements in visual acuity despite patients’ having been previously treated with anti-VEGF-A therapy. In Opthea’s Phase 2a clinical trial, improved visual acuity outcomes and evidence of a reduction in retinal thickness was observed in DME patients following OPT-302 combination therapy.