Envisioning Better Neovascular Eye Disease Treatment

Pathways to new therapeutic targets and sustained drug delivery systems. Roibeard Ó hÉineacháin reports

Research continues to reveal potential new therapeutic targets for retinal and choroidal vascular disease while advances in biotechnology bring new means of delivering vascular endothelial growth factor (VEGF) suppression, says Peter Campochiaro MD, FARVO, Wilmer Eye Institute, Baltimore, Maryland, USA.

“In the future, sustained delivery of anti-VEGF agents and sustained expression of anti-VEGF proteins by gene transfer will largely replace repeated intraocular injections. They will combine with sustained activation of TIE-2 in patients with suboptimal outcomes from sustained VEGF suppression,” Dr Campochiaro predicted in his Proctor Award Lecture delivered at the ARVO 2021 meeting.

THE ROAD TO ANTI-VEGF THERAPY Since the late 1990s, laboratory and clinical studies have shown VEGFs’ importance in the molecular pathogenesis of these diseases. Ultimately, this led to the use of intravitreal anti-VEGF agents as the first treatment for neovascular age-related macular degeneration (AMD).

What has greatly facilitated that process for AMD, he said, was the generation of animal models. For example, mice with disrupted Bruch’s membrane develop consistent ingrowth of vessels from the choroid or subretinal space at Bruch’s membrane sites, called type 2 CNV, which is the most common type of CNV in AMD patients.

Studies using animal models showed aflibercept—a potent, specific VEGF binding protein—strongly suppressed choroidal neovascularisation. The VIEW 1 and VIEW 2 clinical trials confirmed those findings, showing aflibercept provided a strong improvement in visual acuity and anatomic benefit, leading to its FDA approval.

DIABETIC RETINOPATHY ROAD BUMPS Oxygen-induced retinopathy in mice mimics many diabetic retinopathy features, such as retinal non-perfusion and retinal neovascularisation. Research using this model has demonstrated that two hours after the onset of retinal hypoxia, there is a marked increase in the transcription factor hypoxia-induced factor-1 alpha (HIF-1α) in the inner retina followed by increased VEGF expression in the same cells four hours later.

Other research showed a marked increase in retinal neovascularisation in adult mice that underwent injections of an adenoviral vector expressing VEGF and induced expression of angiopoietin 2 (Ang-2), a TIE-2 inhibitor HIF-1α upregulates. HIF-1α inhibitors markedly suppressed ischemia-induced retinal and choroidal neovascularisation at Bruch’s membrane rupture sites.

“These data indicate HIF-1α plays a central role in the development of both choroidal and retinal neovascularisation. In ischaemic retinopathies, retinal vessel closure causes retinal hypoxia that activates HIF-1. That stimulates transcription of multiple vasoactive proteins and their receptors,” Dr Campochiaro noted.

It was not known whether retinal hypoxia contributed to diabetic macular oedema (DME), which can occur independently of retinal neovascularisation. However, supplemental inspired oxygen reduced DME, demonstrating how retinal hypoxia contributes. The READ-2 multicentre trial showed intravitreal ranibizumab provided significant improvement in visual acuity compared to focal laser therapy—the previous standard of care for DME. The RISE and RIDE multicentre trials showed ranibizumab injections provide large, sustained improvements in visual acuity and antiVEGF injections became standard care for DME. MAPPING OUT DELIVERY STRATEGIES Dr Campochiaro reported how there are multiple strategies under investigation that may provide a more sustained suppression of VEGF with fewer interventions, thereby easing patients’ treatment burden and improving outcomes.

Furthest along is the Port Delivery System (PDS), an implantable refillable reservoir for ranibizumab delivery. In the phase three ARCHWAY trial, eyes implanted with the port delivery system and given ranibizumab refills or exchanges every six months had equal visual outcomes to eyes receiving monthly injections.

Gene therapy for choroidal and retinal vascular diseases is also on the horizon. In a clinical trial in which neovascular AMD patients underwent subretinal injections of RGX-314—an AAV8 vector that expresses an anti-VEGFfab similar to ranibizumab—there was good RGX-314 expression, stable or improved visual acuity, and leakage suppression at the longest time point for which data are available (three years for cohort 3 and 1.5 years for cohorts 4 and 5).

Suprachoroidal injection provides a new non-invasive route of delivery that allows gene therapy in an outpatient setting. Clinical studies are also underway testing the efficacy of suprachoroidal RGX-314 injection for neovascular AMD and diabetic retinopathy.

INVESTIGATING NEW THERAPEUTIC TARGETS Dr Campochiaro noted recent phase two clinical trials indicate the addition of TIE-2 activation to VEGF-suppression provides supplementary benefits in treating DME.

The TIME2 trial demonstrated that ranibizumab plus AKB9778—an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates TIE-2—provided greater DME reduction than aflibercept alone. In the RUBY trial, a combination of aflibercept and an anti-Ang-2 antibody also provided greater DME reduction than aflibercept alone. In those trials, there was no difference in visual outcomes because they included patients with chronic DME and poor visual potential.

The BOULEVARD trial investigated faricimab, a bi-specific antibody that blocks VEGF and Ang-2, in patients with treatment naïve DME and better visual potential. It showed those who received faricimab had better visual recovery as well as better control of macular oedema. By contrast, the YOSEMITE and RHINE trials showed faricimab had a greater reduction in macular oedema but no additional visual benefit at nine months compared to aflibercept.

In summary, retinal and choroidal vascular diseases are prevalent causes of vision loss, which were previously treated with ablative treatments that provided minimal benefit. Presently, they are treated by repeated injections of anti-VEGE neutralising proteins that provide substantial benefit when given frequently and regularly. But in clinical practice, undertreatment is common and leads to poor outcomes. In the future, these diseases will be treated by one of a variety of approaches that provide sustained VEGF suppression. This will be sufficient for most patients, but in those with incomplete response, it will be supplemented by agents that activate TIE-2 or target other hypoxia-regulated vasoactive proteins not yet validated in clinical trials.