Background ScienceQ B1: What are VEGF inhibitors and VEGF...

Background Science

Q B1: What are VEGF inhibitors and VEGF traps?

A: VEGF inhibitors are drugs designed to block the action of Vascular Endothelial Growth Factor (VEGF), a protein that promotes the growth of new blood vessels. VEGF traps are a type of VEGF inhibitor that binds VEGF molecules and prevents them from interacting with their natural receptors. By inhibiting VEGF, these drugs help reduce abnormal blood vessel growth and leakage in retinal diseases such as wet AMD. Common examples include Eylea (aflibercept), which acts as a VEGF trap.
.

Q B2: What is the significance of VEGF-C and VEGF-D in retinal diseases?

A: VEGF-C and VEGF-D are members of the VEGF family that are involved in the formation of lymphatic and blood vessels. In the retina, these factors can contribute to abnormal blood vessel growth and fluid leakage, similar to VEGF-A. Sozinibercept (OPT-302) targets VEGF-C and VEGF-D in addition to VEGF-A, providing a broader inhibition of the pathways responsible for the progression of retinal diseases like wet AMD.
.

Q B3: What is RAP, and why is it significant in retinal disease treatment?

A: Retinal Angiomatous Proliferation (RAP) is a subtype of wet AMD characterized by the growth of new blood vessels from the retina into the subretinal space. RAP is often more difficult to treat and is associated with worse visual outcomes. Because of its complexity, certain clinical trials, like Opthea’s Phase 3 trials for Sozinibercept, exclude patients with RAP to better assess the drug’s efficacy in the broader wet AMD population.
.

Q B4: What are the current treatments for wet AMD?

A: The current standard treatments for wet AMD primarily involve anti-VEGF therapies, such as Eylea (aflibercept) and Lucentis (ranibizumab). These treatments inhibit VEGF-A to reduce abnormal blood vessel growth and leakage. Eylea acts as a VEGF trap, binding to VEGF-A, VEGF-B, and PlGF (placental growth factor), while Lucentis is a monoclonal antibody fragment that specifically binds to VEGF-A. These treatments are administered through intravitreal injections and have significantly improved visual outcomes for patients with wet AMD.
.

Q B5: What are biosimilars, and how do they relate to wet AMD treatment?

A: Biosimilars are biologic medical products that are nearly identical to an original product that is manufactured by a different company. Biosimilars of anti-VEGF therapies like Lucentis are emerging in the market, providing more affordable treatment options for wet AMD. The global market for anti-VEGF therapies, including biosimilars, is substantial, with annual sales exceeding several billion dollars.
.

Q B6: What emerging therapies are being developed for wet AMD beyond anti-VEGF treatments?

A: In addition to anti-VEGF therapies, several emerging treatments for wet AMD are in development, targeting alternative pathways involved in disease progression. These therapies aim to address the limitations of current treatments and offer new options for patients who do not respond adequately to anti-VEGF drugs.

• Angiopoietin-2 (Ang-2) Inhibitors: Ang-2 is a protein that plays a role in blood vessel maturation and stabilization. Inhibitors targeting Ang-2, such as faricimab, are being developed to be used in combination with anti-VEGF therapies. Faricimab is designed to block both Ang-2 and VEGF-A, potentially providing better outcomes by stabilizing blood vessels while inhibiting abnormal growth.
• Complement Inhibitors: The complement system is part of the immune response and has been implicated in the development of AMD. Complement inhibitors, such as pegcetacoplan, target components of this system to reduce inflammation and slow the progression of AMD.
• Gene Therapy: Gene therapy approaches, such as RGX-314, aim to provide a long-lasting treatment option by delivering genes that produce anti-VEGF proteins directly within the eye. This could reduce the need for frequent injections and improve patient compliance.

.

Q B7: What have clinical trials revealed about the efficacy of Sozinibercept (OPT-302) for wet AMD?

A: Clinical trials for Sozinibercept, particularly the Phase 2b trial and ongoing Phase 3 trials (COAST and SHORE), have provided promising data on its efficacy in treating wet AMD.

• Phase 2b Trial: The Phase 2b trial involved 366 participants and was designed to evaluate the efficacy of Sozinibercept in combination with ranibizumab (Lucentis). The trial demonstrated a statistically significant improvement in visual acuity, with patients in the Sozinibercept combination group showing a +5.7 letter improvement in Best Corrected Visual Acuity (BCVA) at 24 weeks compared to the control group. This result was particularly notable in a subgroup of patients who represented about 75% of the wet AMD population.
• Phase 3 Trials (COAST and SHORE): These ongoing trials are pivotal in determining the safety and efficacy of Sozinibercept in a broader patient population. The COAST trial, which completed enrollment in February 2024, and the SHORE trial, which completed enrollment in May 2024, are both expected to report top-line data in 2025. The trials are focused on the same subgroup identified in the Phase 2b trial to maximize the likelihood of replicating the earlier positive outcomes.

.

Q B8: What are occult, classic, and minimally classic lesions in wet AMD, and why are they hard to treat with current medications?

A: Occult, classic, and minimally classic lesions refer to different types of choroidal neovascularization (CNV) in wet AMD:

• Occult Lesions: Characterized by poorly defined, less visible new blood vessels under the retina. These lesions are often more difficult to detect and treat effectively, leading to slower and less predictable responses to treatment.
• Classic Lesions: Well-defined, visible new blood vessels that grow rapidly and are more likely to cause severe vision loss. Current treatments like anti-VEGF therapies are generally more effective against classic lesions, but they still pose challenges in terms of recurrence and long-term management.
• Minimally Classic Lesions: A combination of both occult and classic features, making them particularly challenging to treat. The variability in lesion types within a single patient can complicate treatment strategies and outcomes.

Newer drugs, including Sozinibercept (OPT-302), aim to provide broader and more effective treatment options by targeting multiple pathways involved in CNV, potentially offering improved outcomes for patients with these challenging lesion types.