Modern randomized clinical trials competing in the VEGF space have focused on achieving increased durability (measured by longer treatment intervals) without trying necessarily to improve visual outcomes. The thought process is that there is a ceiling effect on vision and that new drugs cannot improve best-corrected visual acuity (BCVA) beyond what is currently being achieved. As such, these studies are established as noninferiority trials with the implied superiority being less injections given over 1 to 2 years within the study. There may even be a beneficial anatomic effect seen as less intraretinal or subretinal fluid relative to the current FDA-approved anti-VEGF standard, but this is frequently a secondary endpoint in clinical trials.

Opthea has challenged the current paradigm with their phase 2b study that required a superiority endpoint (BCVA letters gained) to demonstrate the benefit of combination OPT-302 with ranibizumab (Lucentis; Genentech) vs ranibizumab alone. The premise is that broad inhibition of VEGF-A, VEGF-C, and VEGF-D with OPT-302 combination therapy will yield a superior outcome to just VEGF-A inhibition alone.

To better understand OPT-302 and some recent clinical trial data, we have asked 2 retina specialists to discuss this novel biologic “trap” molecule and promising results in a recently reported phase 2b clinical trial. Opthea’s director of clinical research and CEO weigh in with additional commentary.

Jason Slakter, MDNYU School of Medicine

Although anti-VEGF-A monotherapy has been shown to stabilize disease progression and improve vision, it is not always sufficient in many patients to achieve or maintain significant improvement in visual acuity. Therefore, a need exists for new treatments to improve the management of neovascular age-related macular degeneration (nAMD). VEGF-C/D function independent of, but in parallel with, VEGF-A to drive angiogenesis and vascular leakage, seen in exudative AMD. In addition, suppression of VEGF-A alone leads to upregulation of VEGF C/D and may be a so-called escape mechanism for neovascular lesions that seem to be resistant to anti-VEGF-A monotherapy with less-than-optimal outcomes.

OPT-302, from Opthea Ltd, is a trap molecule, which binds and sequesters both VEGF-C and VEGF-D, preventing these 2 ligands from activating VEGF receptors 2 and 3. When used in combination with anti-VEGF-A therapy, this generates a broader inhibition of mediators of angiogenesis and exudation, potentially leading to better visual and anatomic outcomes.

At this year’s ARVO meeting, I presented the results of a prespecified subgroup analysis of subjects with polypoidal choroidal vasculopathy (PCV type CNV) enrolled in a phase 2b randomized, sham-controlled study of patient with treatment-naive nAMD.¹ In this study, subjects received either monotherapy with ranibizumab (Lucentis; Genentech) or combination therapy with ranibizumab and 1 of 2 doses of OPT-302. Of the 366 subjects participating, 66 were identified as having PCV lesions based on multimodal imaging analysis with color fundus photography, fluorescein angiography, and spectral domain optical coherence tomography (SD-OCT).

OPT-302 at the 2.0 mg level, used in combination with ranibizumab 0.5 mg, achieved superior visual acuity gains and anatomic improvements compared to monthly ranibizumab monotherapy in these subjects with PCV type CNV. Specifically, following combination therapy over the 6 months of the study, an additional 6.7 letter gain was achieved over ranibizumab monotherapy; a greater proportion gained 5, 10, and 15 letters from baseline; more subjects achieved 20/40 vision or better; fewer subjects lost 5 letters or more of vision; and greater improvements in anatomic measures were seen, including less subretinal and intraretinal fluid, decreases in central subfield thickness on SD-OCT, and greater reduction in total lesion area on FA.

OPT-302 combination therapy was well tolerated with no clinically significant safety findings. Additional data on PCV lesions will be obtained from the ongoing OPT-302 phase 3 ShORe and COAST trials, which are also expected to enroll a significant number of treatment-naive patients with PCV. Given the difficulty in managing this particular type of neovascularization, OPT-302 would represent a valuable addition to our treatment armamentarium. Furthermore, given the high prevalence of PCV in Asian countries, additional studies of dual inhibition of VEGF-C/-D and VEGF-A focused on the treatment of PCV in this population would be valuable.

Aleksandra Rachitskaya, MDColy Eye Institute

OPT-302 is a soluble form of vascular endothelial growth factor receptor 3 (VEGFR-3) that blocks the activity of VEGF-C and VEGF-D. The phase 2b clinical trial was designed to evaluate the clinical efficacy and safety of 2 doses of OPT-302 (0.5 mg or 2.0 mg) administered in addition to 0.5 mg of ranibizumab and compare those groups to the ranibizumab alone group in patients with wet AMD. Overall, the study showed that OPT-302 combination therapy was well tolerated. The combination treatment resulted in better BCVA gains compared to ranibizumab monotherapy. The 2.0 mg OPT-302 combination group gained a mean of 14.2 letters of vision from baseline at week 24, compared to 10.8 letters gained in the ranibizumab alone group (P=.0107).² The phase 2b trial included patients with a variety of lesion types, including occult, minimally classic, and predominantly classic lesions, as well as patients with polypoidal morphology.

Polypoidal choroidal vasculopathy is a subtype of neovascular AMD and can be a challenging condition to treat, requiring use of anti-VEGF agents sometimes in combination with verteporfin photodynamic therapy (PDT). In clinical practice, retina specialists use the guidance of such clinical trials as EVEREST II and PLANET to treat PCV patients. The EVEREST II data showed that the combination therapy of ranibizumab and PDT resulted in superior BCVA gains, increased odds of polypoidal lesion regression, and required fewer treatments compared with ranibizumab monotherapy.³ The PLANET study, albeit different in study design, showed that visual acuity improvement was achieved in more than 85% of study participants treated with aflibercept monotherapy. With fewer than 15% of study subjects meeting the criteria to receive PDT, the potential benefit of adding PDT could not be determined in that study.⁴

The OPT-302 phase 2b trial included 66 participants with PCV. The mean BCVA change from baseline to week 24 showed a dose response in participants with PCV. The 2.0 mg OPT-302 combination group gained a mean of 13.5 letters of vision from baseline at week 24, compared to 6.9 letters gained in the ranibizumab alone group (P=.0253). Although the results are promising, one has to keep in mind that in this subgroup analysis, the numbers are small: 22 subjects in the 2 mg OPT-302 combination group, 24 in the 0.5 mg OPT-302 combination group, and 20 in the ranibizumab control group compared to 322 subjects in EVEREST II and 318 subjects in PLANET. Moreover, the patients were identified as having PCV based on fundus photos, fluorescein angiography, and OCT imaging. The current study did not mandate indocyanine green angiography testing, which is believed to be important for diagnosing PCV, helping to visualize the polypoidal lesions.²

The ongoing OPT-302 phase 3 trials, ShORe and COAST, are investigating the efficacy and safety of 2.0 mg OPT-302 in combination with anti-VEGF-A therapy, compared to standard of care anti-VEGF-A monotherapy in both 4-week and 8-week dosing regimens. The anti-VEGF studied is ranibizumab in ShORe and aflibercept (Eylea; Regeneron) in COAST.

Given the results of EVEREST II and PLANET, it will be interesting to see if there is a difference in BCVA in PCV patients depending on what anti-VEGF agent OPH-302 is combined with. The results of the OPH-302 phase 2b study in regards to PCV are promising, but the role of combination inhibition of VEGF-A, VEGF-C, and VEGF-D in polypoidal choroidal vasculopathy remains to be elucidated.

Ian Leitch, PhD, and Megan Baldwin, PhDOpthea

Despite the success of anti-VEGF-A monotherapy for wet AMD, an incomplete visual and anatomic response and/or need for frequent injections for persistent disease activity is seen in many patients. In addition, for patients with PCV, a subtype of AMD that is particularly prevalent among Asian populations, heterogeneity in lesion morphology has been associated with variable responses to anti-VEGF-A treatment. Thus, there is an unmet need to improve therapeutic options for patients by also targeting alternative mediators that drive the disease progression, because VEGF-A inhibition alone does not address the multifactorial pathophysiology. Combination treatment with OPT-302 is a novel therapeutic strategy of pan-VEGF (A, C, D) blockade that may offer benefits that exceed the inhibition of VEGF-A alone.

Because PCV is one of the most common forms of wet AMD globally, we are encouraged by the improved outcomes in the prespecified subgroup analysis of patients with PCV in the phase 2b study, which further demonstrate the potential of OPT-302 to be a truly differentiated treatment option that, when used in combination, may offer patients improved vision outcomes over standard of care anti-VEGF-A monotherapy. The improved vision gains observed at 6 months in patients with PCV are consistent with the statistically superior visual acuity gains following OPT-302 combination therapy observed in the larger total phase 2b wet AMD study population.

Following on from the promising results from the phase 2b nAMD study, recruitment is ongoing for treatment-naive patients into 2 concurrent global, multicenter, randomized, double-masked, sham-controlled phase 3 wet AMD studies known as ShORe (Study of OPT-302 in combination with Ranibizumab) and COAST (Combination OPT-302 with Aflibercept Study). Additional efficacy, safety, and durability data in a larger number of patients will be obtained from these phase 3 trials, which will include enrollment of patients with PCV including those from sites in the Asia Pacific region. There is increasing evidence suggesting that Asian patients with neovascular AMD may have a different presentation and responses to treatment. Thus, it will be important to conduct clinical investigations that also specifically target Asian populations, particularly given the greater prevalence of PCV. Based on the positive phase 2b results, it is our hope that OPT-302 combination therapy holds promise in the management of patients with PCV. RP

REFERENCES

1. Slakter J. Efficacy and safety of OPT-302 in combination with ranibizumab for polypoidal choroidal vasculopathy. Poster presented at: Association for Research in Vision and Ophthalmology (ARVO) annual meeting; May 1, 2022; Denver, CO.
2. Opthea. Opthea meets primary endpoint in phase 2b study of OPT-302 in wet AMD. News release. Accessed September 14, 2022. https://opthea.com/wp-content/uploads/2019/08/OPT.-2019_08_07_ASX_Ph2b-wAMD-Results_Final.pdf
3. Koh A, Lai TYY, Takahashi K, et al. Efficacy and safety of ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: a randomized clinical trial. JAMA Ophthalmol. 2017;135(11):1206-1213. doi:10.1001/jamaophthalmol.2017.4030
4. Lee WK, Iida T, Ogura Y, et al. Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy in the PLANET study: a randomized clinical trial [published correction appears in JAMA Ophthalmol. 2018;136(7):840]. JAMA Ophthalmol. 2018;136(7):786-793. doi:10.1001/jamaophthalmol.2018.1804