Real-world patients often fail to achieve and retain the visual acuity results observed in clinical trials for anti–VEGF-A therapy. Broader therapeutic inhibition of additional angiogenic factors VEGF-C and VEGF-D could change that. (Image Credit: Adobe Stock/pikselstock)
The landmark ANCHOR and MARINA clinical trials over 15 years ago launched a new era in neovascular age-related macular degeneration therapy (nAMD).1,2 With the FDA approval of anti–VEGF-A treatment, retina specialists were able, for the first time, to start addressing a huge unmet need. Scores of nAMD patients owe their vision preservation quite literally to the advent of these therapies. Today, we continue to build on that work with newer anti–VEGF-A agents, biosimilars, the first bispecific drug for nAMD, combination therapies, and a variety of extended treatment approaches.
Treatment gaps remain with anti–VEGF-A
Even with these therapeutic advances, treatment gaps and shortcomings remain in real-world outcomes for many retina patients with VEGF-mediated diseases. Standard-of-care monotherapies for nAMD, including ranibizumab, aflibercept, brolucizumab, faricimab, and off-label bevacizumab, primarily block VEGF-A.3,4 Despite our best efforts, there are patients who do not reach the visual outcomes we—and they—would like.
More than half of patients treated with approved VEGF-A inhibitors fail to achieve 20/40 vision after 12 months of standard-of-care treatment, which impacts their ability to perform routine daily activities like reading and driving.5-9 Up to a quarter of patients receiving VEGF-A monotherapy experience further vision loss.10 Investigators must continue to delve into the multifactorial driving factors of the angiogenic disease process and develop next-generation therapies that can address different aspects of the pathophysiology. The VEGF family, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor, are key drivers of choroidal neovascularization and vascular permeability. Exploring the broader inhibition of the VEGF pathway, ie, beyond VEGF-A, will result in superior outcomes for patients.
Angiogenic factors at work, real-world undertreatment
VEGF-A, VEGF-C, and VEGF-D each display differentiated binding and activation profiles for VEGF receptors 1, 2, and 3 (VEGFR-1, VEGFR-2, and VEGFR-3). VEGF-A binds VEGFR-1 and VEGFR-2. VEGF-C and VEGF-D also bind and activate VEGFR-2, stimulating angiogenesis and vascular permeability independently of VEGF-A. In addition, VEGF-C and VEGF-D, the only known ligands for VEGFR-3, are involved in pathological angiogenesis and vascular permeability, and also upregulated in wet AMD.11-13 In vivo models reveal that, as ligands of VEGFR-2 and VEGFR-3, VEGF-C and
VEGF-D induce vessel growth.14-17 VEGF-C also plays a critical role in the formation of the retinal vasculature11 and is upregulated by inflammatory mediators implicated in the pathogenesis of wet AMD.18,19
When VEGF-A is suppressed, VEGF-C and VEGF-D upregulate and could limit the efficacy of VEGF-A inhibition.20-24 This upregulation may explain why at least 45% of patients show some degree of resistance to VEGF-A inhibitors, failing to improve, maintain, or achieve optimal vision responses.1,5,25-28 Combining anti–VEGF-A inhibition with an agent to suppress VEGF-C and VEGF-D may improve short- and long-term outcomes.
Undertreatment is another factor in real-world outcomes vs clinical trial results. Patients’ nonadherence to treatment schedules is a major reason.16 We know frequent injections are a burden for patients. Years into our experience with anti–VEGF-A therapy, nAMD is still a disease that requires aggressive management. Evidence suggests that real- world patients do not reach outcomes achieved in trial settings.29 A meta-analysis of real-world observational data that included approximately 26,000 patients reported a mean visual gain of 5.0 Early Treatment of Diabetic Retinopathy Study letters after 12 months of treatment, with a mean of 5.4 injections over 8.3 visits.30 A database study looking at aggregated, longitudinal electronic medical records from a geographically and demographically diverse sample of US retina specialists that included 49,485 eyes found a mean gain of only 1 letter after 1 year and a mean of 7.3 injections.31 In another review of 13,859 patients from the American Academy of Ophthalmology’s Intelligent Research in Sight registry, the mean improvement was 2.5 letters with an average of 6.1 injections in 1 year.32
Compare these visual outcomes to the +11.3 letters seen in ANCHOR with monthly ranibizumab1 and +8.9 letters in VIEW1/VIEW26 with every-8-week aflibercept injections. The long-term results from clinical trials and registry data confirmed this finding; more frequent injections consistently showed better visual outcomes.33,34
Biologic inhibition of VEGF-C and VEGF-D
OPT-302 (Opthea Limited), a biologic VEGF-C and VEGF-D “trap” inhibitor, is being investigated in late-stage phase 3 registrational clinical trials in combination with standard-of-care anti–VEGF-A inhibition for the treatment of wet AMD. I was encouraged by the phase 2b results, in which patients assigned to OPT-302 2.0 mg combination therapy gained almost a full line of vision,35 and I look forward to the phase 3 data.
In the 366-patient phase 2b study, patients assigned to combination treatment with 2 mg OPT-302 plus 0.5 mg ranibizumab (n = 123) achieved the primary end point of a significant mean change in best corrected visual acuity (BCVA) from baseline to week 24 of +14.2 letters, representing an additional gain of +3.4 letters (P = .0107) over the ranibizumab plus sham control group in the total population. The safety and tolerability profile was similar between the groups. The trial showed improvements in secondary anatomic end points for OPT-302 combination therapy vs ranibizumab monotherapy, with reductions in retinal thickness, subretinal fluid, intraretinal fluid, lesion size, and neovascular area vs the control group. A prespecified subgroup of participants with minimally classic and occult lesions who received the 2-mg OPT-302 combination (n = 88) had an additional mean improvement in BCVA of +5.7 letters (P = .0002) at 24 weeks over the sham-plus-ranibizumab group (n = 87).
Opthea has initiated 2 concurrent, randomized, controlled, pivotal phase 3 studies, ShORe (2 mg OPT-302 plus 0.5 mg ranibizumab; NCT04757610) and COAST (2 mg OPT-302 plus 2 mg aflibercept, NCT04757636).36,37 The study drug will be administered every 4 or 8 weeks following 3 monthly loading doses in combination with standard-of-care anti–VEGF-A therapy. Control subjects in ShORe will receive ranibizumab 0.5 mg plus sham every 4 weeks, and COAST control subjects will receive aflibercept 2 mg plus sham for 3 loading doses every 4 weeks and then every 8 weeks thereafter. The primary end point for both studies is superiority in visual acuity gains from baseline at 12 months for the OPT-302 combination therapy compared with standard-of-care anti–VEGF-A monotherapy. Participants receive continued dosing through year 2 to assess longer-term safety. Opthea plans to submit registrational regulatory filings after completion of the 12-month primary efficacy phase.
It is important that the retinal community actively support clinical trials. Participating in research is certainly rigorous, but patients have a chance to receive therapy that may be better than standard of care.
Our thoughts on nAMD have changed in 15 years. We went from lines of vision lost and minimizing blindness to the vision our patients could gain while reducing treatment burden and nonadherence. It is an exciting time to build on past advances and explore new targets. As options expand, we can better individualize patient care. •
Veeral Sheth, MD, MBA, FACS, FASRS
Sheth, MD, MBA, FACS, FASRS, is a partner and director of clinical trials at University Retina in Chicago, Illinois.
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OPT-302 with aflibercept in neovascular age-related macular degeneration (nAMD) (COAST). ClinicalTrials.gov. Updated March 2022. Accessed January 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04757636