OPT-302 VEGF-C/D “trap” molecule for AMD promising in Phase 2b, moves to Phase 3

Cases of age-related macular degeneration (AMD)—the most common cause of irreversible vision loss among elderly patients in the industrialized world—are expected to reach to 288 million worldwide by 2040.^1,2 AMD can be nonneovascular (dry) or neovascular (wet). The latter, which constitutes 10% of cases, is characterized by choroidal neovascular (CNV) membrane formation that results in exudation and leads to significant loss of central vision.^3,4,5

Disease process

Neovascular AMD is driven by increased levels of the proangiogenic family of vascular endothelial growth factor (VEGF) ligands, including VEGF-A, -C, and -D, each of which displays differentiated binding and activation profiles for VEGF receptors 1, 2, and 3.^6,7 Whereas VEGF-A, -C, and -D simultaneously bind and activate VEGF receptor 2 (VEGFR-2), the most validated receptor signaling pathways for choroidal angiogenesis and vascular permeability—VEGF-C and -D—are the only known ligands for another part of the angiogenic disease process: VEGF receptor 3 (VEGFR-3).⁷

Standard-of-care monotherapies, including ranibizumab, aflibercept, brolucizumab, and off-label bevacizumab, primarily block VEGF-A.^6,7 Their benefits have been well studied; however, these drugs have limitations and many patients require ongoing therapy for persistent disease and variable visual acuity gains. For example, 20% of patients lose vision despite treatment, and half never achieve 20/40 visual acuity.^8,9 Hence, new treatments are needed to optimize outcomes and improve neovascular AMD management.

Role of other angiogenic factors

The circulating ligands VEGF-C and -D stimulate angiogenesis, while VEGF-C and VEGF-A induce vascular leakage and permeability. In addition, in clinical specimens of neovascular AMD, theVEGFR-2 and -R3 receptors have been shown to be co-localized with increased levels of VEGF-C in retinal tissue, and circulating plasma concentrations of this ligand are elevated in patients with this disease.It has also been demonstrated that VEGF-A suppression upregulates the release of VEGF-C and -D, and clinical data suggests that these mediators of angiogenesis may contribute to the suboptimal response of patients treated with anti-VEGF-A monotherapy.^10-14

Combination therapy that targets these alternative angiogenic factors could therefore provide additional benefit over the current standard of care. One such agent is OPT-302 (Opthea), a first-in-class biologic specifically designed to “trap” and sequester VEGF-C and -D.⁷ OPT-302 is the only therapy to directly target VEGF-C and -D.⁷ A recent phase 2b study of 366 treatment-naive patients with neovascular AMD who received intravitreal OPT-302 and ranibizumab combination therapy met the primary end point: a statistically significant superior mean gain in visual acuity over ranibizumab plus sham at week 24.¹⁵

Two global pivotal phase 3 trials are currently investigating OPT-302 in combination with anti-VEGF-A therapy in treatment-naive patients with wet AMD^16,17 to evaluate whether combination therapy is superior to ranibizumab and aflibercept at improving visual acuity at 12 months from baseline. In recognition of the unmet need in wet AMD, the FDA has granted fast track designation to OPT-302 .

Current Phase 2b trial results

In the phase 2b multicenter, randomized, double-masked, sham-controlled study, 366 treatment-naive participants were randomized to 1 of 3 intravitreal treatment groups, with injections delivered every 4 weeks for 24 weeks: sham treatment plus 0.5 mg ranibizumab (n = 121), 0.5 mg OPT-302 plus 0.5 mg ranibizumab (n = 122), and 2 mg OPT-302 plus 0.5 mg ranibizumab (n = 123).

Key inclusion criteria were active CNV lesion ≥50%, classic/minimally classic/occult lesions, and a best corrected visual acuity (BCVA) of between 25 and 60 letters (20/63 to 20/320). Key exclusion criteria were subfoveal fibrosis >25% of lesion, hemorrhage >50% of lesion, or other clinically significant ocular disease. The 2-mg OPT-302 combination therapy group achieved the primary end point of a statistically significant mean change in BCVA at 24 weeks, with an additional gain of 3.4 letters (P = .0107) over ranibizumab plus sham in the total population. The trial also met the secondary anatomic end points: the 2-mg OPT-302 combination showed greater reductions in retinal thickness, subretinal fluid, intraretinal fluid, lesion size, and neovascular area versus sham plus ranibizumab.

A prespecified subgroup of participants with minimally classic and occult lesions who received the 2-mg OPT-302 combination (n = 88) were analyzed and found to have an additional mean improvement in BCVA of 5.7 letters (P = .0002) at 24 weeks over the sham-plus-ranibizumab group (n = 87). OPT-302 was well tolerated, with a very low incidence of ocular inflammation that was comparable to ranibizumab monotherapy.

On to Phase 3

Based on these results, Opthea initiated 2 concurrent, randomized, controlled, 3-arm pivotal phase 3 studies—ShORe and COAST—to investigate OPT-302 (administered every 4 or 8 weeks following 3 monthly loading doses) in combination with standard-of-care anti-VEGF-A therapy. ShORe (OPT-302 plus ranibizumab, Study OPT-302-1004) and COAST (OPT-302 plus aflibercept, Study OPT-302-1005) have a primary end point of superiority in visual acuity gains at 12 months for the combination therapy compared with standard-of-care monotherapy. Participants will also receive continued dosing through year 2 and will be assessed for longer-term safety. Opthea plans to submit applications for biologics license and marketing authorization to the FDA and European Medicines Agency, respectively, after the trials’ 12-month primary efficacy phase.

With OPT-302 plus a standard-of-care anti-VEGF-A agent, visual acuity outcomes may be optimized in patients with wet AMD. Although anti-VEGF-A treatment with ranibizumab, brolucizumab, bevacizumab, and aflibercept (which also blocks VEGF-B and PIGF) has revolutionized neovascular AMD management, a subset of patients continues to achieve limited visual acuity gains. Many fail to reach 20/40 visual acuity in their better seeing eye and hence cannot drive. Due to the limitations of current therapy, drugswith new mechanisms of action are being sought to improve functional vision and help patients regain independence.

Conclusion

Anti-VEGF-A agents revolutionized the treatment of wet AMD, but the need remains to optimize visual acuity. VEGF-C and -D naturally upregulate when VEGF-A is downregulated. OPT-302 blocks VEGF-C and -D for better wet AMD control. The phase 2b trial of OPT-302 showed a statistically significant 3.4-letter improvement after treatment with 2 mg of OPT-302 plus 0.5 mg of ranibizumab without any safety concerns. The ongoing ShOre and COAST phase 3 studies are designed to confirm superior benefit with the addition of OPT-302 to ranibizumab or aflibercept. OPT-302 is the only molecule in late-stage development with the potential to improve visual acuity when administered in addition to standard of care and thus may lead to improved quality of life and greater independence for patients.

Arshad M. Khanani, MD, MA, FASRS

E: arshad.khanani@gmail.com

Khanani is a clinical associate professor at the University of Nevada, Reno School of Medicine and a managing partner and director of both clinical research and fellowship at Sierra Eye Associates. He is also a consultant for and has received research funding from Opthea.

References

1. Friedman DS, O’Colmain BJ, Muñoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122:564-572. doi:10.1001/archopht.122.4.564

2. Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2(2):e106-e116. doi:10.1016/S2214-109X(13)70145-1

3. Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102(11):1640-1642. doi:10.1001/archopht.1984.01040031330019

4. Al-Khersan H, Hussain RM, Ciulla TA, Dugel PU. Innovative therapies for neovascular age-related macular degeneration. Expert Opin Pharmacother. 2019;20(15):1879-1891. doi:10.1080/14656566.2019.1636031

5. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol. 1967;63(3):1-139.

6. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246(4935):1306-1309. doi:10.1126/science.2479986

7. Dugel PU, Boyer DS, Antoszyk AN, et al. Phase 1 Study of OPT-302 inhibition of vascular endothelial growth factors C and D for neovascular age-related macular degeneration. Ophthalmol Retina. 2020;4(3):250-263. doi:10.1016/j.oret.2019.10.008

8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419–1431. doi:10.1056/NEJMoa054481

9. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548. doi:10.1016/j.ophtha.2012.09.006

10. Tammela T, Zarkada G, Nurmi H, et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol. 2011;13(10):1202-1213. doi:10.1038/ncb2331

11. Zhou H, Zhao X, Yuan M. et al. Comparison of cytokine levels in the aqueous humor of polypoidal choroidal vasculopathy and neovascular age-related macular degeneration patients. BMC Ophthalmol. 2020;20(1):15. doi:10.1186/s12886-019-1278-8

12. Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J. Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res. 2004;94(5):664-670. doi:10.1161/01.RES.0000118600.91698.BB

13. Lashkari K; Ma J, Teague G, Arroyo J. Expression of VEGF-C, VEGF-D and their cognate receptors in experimental choroidal neovascularization and clinical AMD. Invest Ophthalmol Vis Sci. 2013;54(15):. https://iovs.arvojournals.org/article.aspx?articleid=2149913.

14. Cabral T, Lima LH, Mello LGM, et al. Bevacizumab injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers. Ophthalmol Retina. 2018;2(1):31-37. doi:10.1016/j.oret.2017.04.004

15. Jackson T. A multicenter, randomized, double-masked, sham-controlled clinical trial of intravitreal OPT-302, a novel anti-VEGF C and D drug for the treatment of neovascular age-related macular degeneration. EURETINA Congress; 2019; Paris, France. Accessed October 31, 2022. Presentation at https://wcsecure.weblink.com.au/pdf/OPT/02144122.pdf.

16. OPT-302 with ranibizumab in neovascular age-related macular degeneration (nAMD) (ShORe). ClinicalTrials.gov. Updated March 2022. Accessed October 19, 2022. https://clinicaltrials.gov/ct2/show/NCT04757610.

17. OPT-302 with aflibercept in neovascular age-related macular degeneration (nAMD) (COAST). ClinicalTrials.gov. Updated March 2022. Accessed October 31, 2022. https://clinicaltrials.gov/ct2/show/NCT04757636.