PEER REVIEWED

Neovascular AMD: Treatment Beyond Anti-VEGF

With some patients not responding to anti-VEGF, the pipeline offers some alternatives.

LLEWELYN J. RAO, MD • JOSEPH M. CONEY, MD • JEROME P. SCHARTMAN, MD • LAWRENCE J. SINGERMAN, MD

Currently, the treatment of neovascular AMD centers on suppressing VEGF. Intravitreal injections of bevacizumab (Avastin, Genentech, South San Francisco, CA), ranibizumab (Lucentis, Genentech), and aflibercept Eylea, Regeneron, Tarrytown, NY) have dominated discussions among AMD patients, their families, and our vitreoretinal community.

Investigators have examined these medications at various doses, as well as in differing treatment regimens, and their safety and efficacy are well documented.^1-4 However, the need for frequent office visits and seemingly unending ocular injections places the treatment onus on all of us.

QUESTIONS OF SAFETY AND EFFICACY

Despite advances, many patients still do not achieve a significant gain in vision, and some experience visual loss (Figure 1). In addition, researchers in the Comparison of Age-related Macular Degeneration Treatments Trial (CATT), which compared ranibizumab and bevacizumab for neovascular AMD, have found an association between anti-VEGF therapy and an increased risk of developing geographic atrophy⁵. In the CATT cohort, 18.3% of eyes without GA at baseline developed GA over two years of follow-up. The monthly dosing regimen and ranibizumab use were associated with an increased risk of GA.

Figure 1. Neovascular AMD manifests with the development of choroidal neovascularization. Visual loss in AMD ensues with the possible development of edema, hemorrhage, atrophy, and/or fibrosis.

With the goal of reducing treatment burden and potential complications, a myriad clinical trials are investigating new treatments for neovascular AMD (Table, page 26). We will focus on treatments beyond anti-VEGF injections, emphasizing those that look promising from our experience in their clinical trials.

LASER

Thermal laser, as conducted in the Macular Photocoagulation Study (MPS), has not had any important recent updates regarding technique. Although laser is not recommended for subfoveal lesions, the usefulness of MPS laser for extrafoveal choroidal neovascularization, in combination with anti-VEGF therapy or as monotherapy, has persisted.

Photodynamic therapy with intravenous verteporfin (Visudyne, Valeant, Bridgewater, NJ) is approved for predominantly classic subfoveal CNV due to AMD, pathologic myopia, or presumed ocular histoplasmosis.

The use of PDT for neovascular AMD has decreased since the advent of anti-VEGF therapy. Researchers have studied this treatment in combination with intravitreal steroid and anti-VEGF injections, with mixed results.^6-11

INTRAVITREAL INJECTIONS

Anti-PDGF

Investigators have studied the role of pericytes in relation to endothelial cells in CNV due to AMD. Platelet-derived growth factor (PDGF) binds to a receptor on pericytes. To stabilize endothelial cell channels, the angiogenic endothelial cells release PDGF-B to chemoattract PDGF receptor-B containing pericytes.

The pericytes locally supply the endothelial cells with growth and survival factors, including VEGF, and they play a major role in endothelial cell survival (Figure 2). Established CNV vessels that have sufficient pericyte coverage may be resistant to anti-VEGF monotherapy.^12-15

Figure 2. The aim of combination treatment with anti-VEGF and anti-PDGF therapy is to strip pericytes from CNV and subsequently to induce regression of the neovascular complex.

Combination therapy with anti-VEGF/anti-PDGF will “strip” pericytes from CNV, causing the vasculature to become more susceptible to anti-VEGF therapy and inducing neovascular regression.

This does not appear to affect pericytes on mature normal vasculature. It is believed that pericyte coverage of vessels may confer anti-VEGF monotherapy “resistance” to developing new vessels, especially in mature neovascular AMD.¹⁶

Fovista

Fovista (Ophthotech, New York, NY) is an anti-PDGF pegylated aptamer, administered via intravitreal injection, which is currently in phase 3 clinical trials. It binds with high affinity to PDGF and causes pericytes to detach from the vessel basement membrane.

The phase 2b study of Fovista 1.5 mg injection in combination with ranibizumab 0.5 mg provided a statistically significant visual acuity improvement compared with ranibizumab monotherapy.

Patients receiving Fovista in combination with ranibizumab achieved a 62% additional benefit from baseline VA, compared with ranibizumab monotherapy. Patients in the combination group gained a mean of +10.6 letters, compared with a mean gain of +6.5 letters from baseline for patients receiving ranibizumab monotherapy (P=.019).¹⁷

Phase 3 trials are currently evaluating Fovista. Each trial will pair Fovista with a different anti-VEGF agent: bevacizumab, ranibizumab 0.5 mg, or aflibercept. The investigators will compare the combination with the anti-VEGF agent as monotherapy.

iSONEP

Lpath, Inc. (San Diego, CA), a company that develops therapeutic antibodies and bioactive lipid-targeted agents, has initiated Nexus, a phase 2 dosing clinical trial of iSONEP for the treatment of neovascular AMD.¹⁸ iSONEP is a humanized monoclonal antibody that neutralizes sphingosine-1-phosphate (S1P), which has multiple non–VEGF-dependent angiogenic effects.

The double-blind, multicenter trial will evaluate individuals who have not responded completely to VEGF inhibitors. It will assess the efficacy of iSONEP, given alone or in combination with ranibizumab, bevacizumab, or aflibercept in patients with neovascular AMD.

Earlier results from the phase 1 trial in neovascular AMD demonstrated positive effects in most of the 15 individuals who received a single injection of iSONEP after failed treatment with bevacizumab and/or ranibizumab. Among the outcomes was a 30% reduction in lesion size, and some individuals required only one injection.

These benefits are thought to be due to the antiangiogenic, anti-inflammatory, and antifibrotic mechanisms of action of iSONEP, which binds to and neutralizes the bioactive lipid, S1P.

ALG-1001

Another proposed novel approach for treating CNV is targeting integrins instead of VEGF. Integrins are important in cell signaling and in regulating cellular shape, motility, and the cell cycle.

The synthetic anti-integrin oligopeptide ALG-1001 (Allegro Ophthalmics, LLC, San Juan Capistrano, CA) not only inhibits the production of VEGF, but it also turns off the production of aberrant blood vessels, thus inhibiting their growth and leakage.

ALG-1001 prevents cell adhesion mediated by ανβ3, ανβ5, and αν5β1 integrins. Neovascular ocular tissue expresses these integrins in AMD and diabetic retinopathy.

ALG-1001 is currently under investigation as a treatment for AMD, DME, and vitreomacular traction. For AMD, a phase 1b/2a, six-month clinical study evaluating the dose-ranging safety in humans showed no significant toxicities across all study metrics.¹⁹

Fifteen participants received three monthly injections of either 2.0 mg or 3.2 mg of ALG-1001 as monotherapy. The 3.2-mg group experienced an average BCVA improvement of >5 letters after 60 days off treatment and maintained improvement at 120 days off treatment. Final BCVA correlated with a 30% decrease in central macular thickness and improvement in macular anatomy.

This increased dose may reduce the number of injections that patients are currently receiving, and newer, larger trials will evaluate the efficacy of monotherapy vs combination therapy with other antiangiogenic agents to determine the best outcomes.

Designed Ankyrin Repeat Proteins

Designed ankyrin repeat proteins (DARPins) are a new class of drugs with high potency and high binding affinity. These attributes have the potential to provide a greater duration of action than current anti-VEGF therapeutics.

Allergan (Irvine, CA) is currently working in conjunction with Molecular Partners (Zürich, Switzerland) to develop and evaluate a DARPin-based, small therapeutic protein with dual activity inhibiting PDGF-B as well as VEGF-A.²⁰

Allergan and Molecular Partners have ongoing clinical trials assessing an anti-VEGF DARPin-based drug, but the dual-activity drug is still in preclinical testing.

RADIATION THERAPY

Ionizing radiation impairs the ability of cells, including vascular endothelial cells, to replicate. CNV depends on the rapid proliferation of endothelial cells to thrive, and it is susceptible to damage by ionizing radiation.

Brachytherapy uses concentrated doses of radiation therapy placed very close to the CNV to cause regression of the CNV, as well as to prevent complications, such as radiation retinopathy, optic neuropathy, and cataract, that can occur with unfocused radiotherapy sources, including traditional external-beam radiotherapy.

Neovista (Newark, CA) designed a novel intraocular beta-radiation delivery system called Vidion to deliver 24 Gy of strontium-90/yttrium-90 in three to four minutes during pars plana vitrectomy.

Epimacular brachytherapy (EMBT) is under study in several trials, including MERITAGE, CABERNET, and MERLOT. Recent trails have studied radiotherapy in sub-Tenon’s and focused external delivery systems.

Epimacular Brachytherapy Trials

CABERNET. The CABERNET trial was a multicenter, randomized, phase 3 clinical trial that recruited 494 treatment-naïve patients with a spectrum of CNV lesions.²¹

Two hundred twenty-seven patients were randomized to EMBT, combined with a loading dose of two monthly ranibizumab 0.5-mg intravitreal injections.²² A control group of 119 patients received a loading dose of three monthly ranibizumab injections, followed by quarterly injections. Both arms received PRN treatment with ranibizumab monthly.

The study showed a greater anatomic benefit, both in lesion size and center-point thickness, for ranibizumab monotherapy in the control group. EMBT resulted in a greater percentage of eyes with VA loss and a smaller percentage of eyes gaining lines of VA, compared with ranibizumab monotherapy.

While the visual results favored ranibizumab monotherapy, the EMBT patients required fewer treatments, receiving a mean total of 6.2 injections of ranibizumab over two years (mandated plus PRN injections) vs 10.4 in the control group.

Overall, the two-year data did not support EMBT, because it failed to demonstrate noninferiority to ranibizumab monotherapy. In addition, the EMBT group exhibited a higher rate of serious adverse effects. The EMBT probe is designed to deliver concentrated radiotherapy, and the dose decreases exponentially with increasing distance from the probe tip.

While this reduction minimizes bystander damage, such as radiation retinopathy and optic neuropathy, it also introduces a possible confounder of decreased dose due to variable probe positioning with surgeon technique.

MERITAGE. The MERITAGE study is a three-year, prospective, multicenter, interventional, noncontrolled clinical trial that recruited 53 patients with previously treated, chronic, active CNV requiring frequent anti-VEGF intravitreal injections. On enrollment, these eyes had received treatment for a mean of 28 months.

The participants underwent EMBT with a 24-Gy dose of strontium during pars plana vitrectomy. The patients then received retreatment with PRN ranibizumab monthly. One-year results showed nonsignificant changes in OCT thickness and lesion size on fluorescein angiography. Predominantly classic lesions showed the best response.

However, despite the reduction in the classic component, total lesion size showed little change, perhaps due to fibrosis and/or occult leakage. Radiotherapy presumably would be more effective in less mature vascular membranes with more actively proliferating endothelial cells.

Overall, EMBT produced stable VA in most patients with previously treated, active CNV, with less need for frequent ongoing anti-VEGF injections. In the second year of follow-up, the rate of reinjection was not as evident, and the moderate rate of reduction in VA continued.²³

One participant developed radiation retinopathy, but it was not considered to be vision-threatening, and the overall safety profile remained favorable.

MERLOT. Based on the promising results of MERITAGE, a larger clinical trial has been designed. MERLOT is a randomized, controlled trial of EMBT for previously treated neovascular AMD.²⁴ The UK National Health Service is its sponsor, whereas Neovista sponsors CABERNET.

MERITAGE includes 363 subjects with persistent CNV despite anti-VEGF injections. Both the EMBT and control arms have the same injection regimens, which will allow for detection of a treatment effect. Results are pending.

Sub-Tenon’s

Another brachytherapy device called SMD-1 has been developed by Salutaris Medical Devices (Tucson, AZ).^25,26 SMD-1 applies 24 Gy of radiation to the macula via a posterior sub-Tenon’s approach.

Six patients were treated in a phase 1 trial. No serious adverse effects resulted. All six patients experienced improvement of VA at three months (mean 19-letter improvement). However, by 12 months, three patients experienced loss of VA. Patients also received anti-VEGF injections in this trial.

External Beam

A recent phase 1 trial studied external-beam radiation therapy (EBRT). This trial involved the IRay device (Oraya, Newark, CA), using an eye-tracking device and a low-voltage X-ray source delivering 24 Gy to the fovea via the inferior pars plana in three overlapping beams.

Nineteen patients have completed six months of follow-up. No significant adverse effects have occurred, and the visual results have been promising. Based on this preliminary study, a larger trial has been designed.

The INTREPID trial has completed enrollment of 230 patients in Europe.²⁷ On enrollment, the participants had received three or more anti-VEGF injections over the preceding year and needed additional treatment due to active CNV at the time of enrollment.

The patients were randomized to one of three groups: 16-Gy EBRT, 24-Gy EBRT, and sham radiotherapy. All groups received a ranibizumab injection at baseline and PRN thereafter with monthly follow-up. Patients in both radiotherapy groups had significant reductions in numbers of injections vs those who received sham.

Central OCT thicknesses decreased by 26% and 23% in the 24-Gy and 16-Gy groups, respectively, vs 11% in the sham group. VA improved early and then returned to approximately baseline levels at one year. No serious adverse events appeared.

TOPICAL

Effective topical therapy for neovascular AMD could confer an enormous benefit for patients and physicians. The idea of convenient self-administration is extremely attractive from an economic, as well as convenience, standpoint.

Ohr Pharmaceuticals (New York, NY) has developed a topical formulation of squalamine that is undergoing evaluation in phase 2 clinical trials for the treatment of neovascular AMD. The FDA awarded the medication fast-track designation for neovascular AMD in May 2012.

Squalamine acts against neovascularization by inhibiting VEGF, PDGF, and basic fibroblast growth factor (bFGF) signaling through chaperoning of the modulatory protein calmodulin.

Preclinical studies have shown the medication is safe and does reach therapeutic levels in the posterior segment when administered topically. Importantly, in contrast to earlier intravenous studies of this drug, in which we also participated, topical administration reaches therapeutic levels on once-daily dosing.

With twice-daily dosing, this level is safely exceeded, and the possibility of incomplete administration of the drops minimized. This therapy, when administered in combination with anti-VEGF therapy, may reduce the number of injections needed for comparable or possibly superior visual results.²⁸

ENCAPSULATED CELL TECHNOLOGY

Although anti-VEGF monotherapy has been remarkably effective in halting and slowing the progression of neovascular AMD, even if this requires a burden of long-term monthly treatments, no treatments are available for vision loss associated with advanced dry AMD.

Ciliary neurotrophic factor (CNTF), delivered by the encapsulated cell technology (ECT) implant, appears to slow the progression of vision loss in GA from dry AMD. ECT implants are capable of continuously producing recombinant biotherapeutics for up to two years in the eye.

Perhaps as important, the implant durability and the long-term delivery kinetics ECT provides also justify expansion of the platform technology to potentially improve standard-of-care treatment modalities for a variety of ocular diseases, including neovascular AMD.

A poster presented at ARVO 2013 showed the ability of ECT to sustain production of a PDGF antagonist, as well as a mixed cell line that simultaneously delivers PDGF/VEGF antagonists and that may have practical application with anti-VEGF therapy.²⁹

Currently, the NT-503 device (Neurotech USA, Cumberland, RI), which is ECT that produces a soluble VEGF receptor, is undergoing evaluation in early studies for neovascular AMD.³⁰

GENE THERAPY

RetinoStat (Oxford BioMedica, Oxford, UK) is a gene therapy for the treatment of neovascular AMD. It inserts genes, via a lentiviral vector expressing endostatin and angiostatin, into the RPE cells for local production.

Endostatin and angiostatin are naturally occurring angiogenesis inhibitors. The currently enrolling phase 1 trial is a dose-escalation safety study of subretinally injected RetinoStat in patients with advanced disease and subretinal fibrosis.^31,32

Genzyme (Boston, MA) and Avalanche Biotechnologies (San Francisco, CA) are also conducting VEGF-binding gene therapy studies. These studies involve intravitreal and subretinal administration, respectively. Because these are anti-VEGF in mechanism, they are beyond the scope of this article.

CONCLUSION

As clinical trials enroll patients and data are scrupulously analyzed, we all look forward to new therapies that will help our patients achieve better visual results with the least amount of risk, inconvenience, and cost.

We do not know whether the use of combination therapies, sustained-release devices, or novel medications will lead to a new gold standard in the treatment of neovascular AMD. Anti-VEGF injections have brought hope to patients and physicians, who continue to await more durable and efficacious treatments. RP

REFERENCES