Current anti-VEGF-A therapies have revolutionized the treatment of neovascular age-related macular degeneration (nAMD), yet visual outcomes often plateau, prompting the development of next-generation agents like sozinibercept to further enhance vision and quality of life for patients.
Limitations of Current VEGF-A Therapies
Ranibizumab, the first anti-VEGF-A agent approved by the FDA, has been in use for over 18 years. Subsequent nAMD therapies have shown comparable visual outcomes, with clinical trials like ANCHOR (NCT00061594) and MARINA (NCT00056836) demonstrating visual gains of 8 to 11 letters at 2 years. However, real-world evidence indicates that patients do not consistently achieve these gains or experience the same durability seen in clinical trials. Factors such as treatment regimen and frequency of injections significantly impact visual acuity (VA) outcomes.
Studies like the CATT trial (NCT00593450) showed that while ranibizumab or bevacizumab given monthly or as-needed were effective at 2 years, VA gains were not sustained at 5 years, particularly with as-needed dosing. Long-term data from the ANCHOR, MARINA, and HORIZON extension study (NCT00379795) revealed an overall decline in VA below baseline best-corrected VA (BCVA). In contrast, patients treated with more frequent fixed-dose aflibercept maintained visual improvement at 96 weeks, highlighting the importance of consistent therapy.
Next-Generation Therapies: Targeting Multiple Pathways
Innovations in nAMD treatment are exploring gene therapy, tyrosine kinase inhibitors, and dual-target drugs. Given the multifactorial nature of nAMD, future agents aim to target multiple pathways. Faricimab-svoa, which inhibits both VEGF-A and angiopoietin-2, exemplifies this approach, potentially contributing to increased durability, although visual outcomes were noninferior to aflibercept in clinical trials.
The VEGF family, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, placental growth factor, and their receptors (VEGFR-1, VEGFR-2, VEGFR-3), plays a crucial role in maintaining tissue homeostasis and regulating disease. VEGF-C and VEGF-D are found in the human vitreous and expressed in the retinal pigment epithelium of nAMD patients, with VEGF-C elevated in blood and retinal tissue. Inhibiting VEGF-A can upregulate VEGF-C and VEGF-D, potentially limiting the efficacy of anti-VEGF-A monotherapies.
Sozinibercept: A Novel VEGF-C/D Inhibitor
Sozinibercept (OPT-302; Opthea) is a first-in-class recombinant fusion protein trap that selectively binds to and neutralizes VEGF-C and VEGF-D without binding to VEGF-A. It is being studied in combination with standard-of-care agents to improve VA. In a Phase 2b trial involving 366 patients, sozinibercept plus ranibizumab demonstrated superior visual outcomes compared to monthly ranibizumab alone. Patients receiving combination treatment showed a mean change in BCVA from baseline to week 24 of 14.2 letters, a statistically significant additional gain of 3.4 letters (P = .0107). Subgroup analysis of patients with minimally classic/occult lesions (approximately 85% of nAMD cases) showed even greater VA gains of 5.7 letters compared to the control group.
Currently, two pivotal Phase 3 studies, ShORe (NCT04757610; 2 mg sozinibercept plus 0.5 mg ranibizumab) and COAST (NCT04757636; 2 mg sozinibercept plus 2 mg aflibercept), are fully enrolled and underway. Opthea plans to submit regulatory filings following a 12-month primary efficacy analysis.
Enhancing Visual Acuity and Quality of Life
Improving a patient’s VA from 20/100 to 20/80 can significantly enhance their ability to function at home, while improving from 20/50 to 20/40 may enable them to drive. Sean D. Adrean, MD, FAAO, from Retina Consultants of Orange County, notes that if a therapy requires more frequent injections to achieve greater visual gains and associated quality-of-life benefits, it is more valuable than longer treatment intervals alone. By targeting pathways beyond VEGF-A, next-generation treatments like sozinibercept aim to overcome the limitations of current therapies and improve visual outcomes for nAMD patients.
