Poised for the Next Breakthrough in AMD Therapy

The combination of anti-PDGF and anti-VEGF therapy has shown results in patients with exudative disease.

VIRGINIA PICKLES, Contributing editor

Since the release of topline results from a 24-week Phase IIb clinical trial of a combination therapy for exudative (wet) age-related macular degeneration (AMD), the ophthalmic community has been abuzz about its potential.

In June 2012, Ophthotech Corporation reported its anti-platelet-derived growth factor (PDGF) agent, Fovista, administered with ranibizumab (Lucentis; Genentech), demonstrated efficacy.¹ Could this combination therapy supplant anti-vascular endothelial growth factor (VEGF) monotherapy as the gold standard for treating wet AMD?

Anti-VEGF limitations

In the October 2012 issue of Retinal Physician, a sister publication of OM, Pravin U. Dugel, M.D., a clinical investigator in the Phase IIb trial, noted that all anti-VEGF monotherapy trials show a similar pattern of visual acuity improvement: Vision improves in the first two or three months, stabilizes around the fourth month and then continues on that plateau for an extended period — “probably, alas, forever.”² Several studies suggest some reasons for this pattern.

In 1995, researchers determined that roughly 50% of retinal neovascularization was not inhibited by anti-VEGF treatment, suggesting a role for other angiogenic substances.³

A 2006 study demonstrates that neovascularization becomes refractory to VEGF-A deprivation through time and that it is more effective to inhibit both VEGF-A and PDGF-B signaling than to inhibit VEGF-A alone to cause vessel regression.⁴ These findings validate the potential for a combination therapy.

A key component in the development of wet AMD is the presence of pericytes. In the initial stage of angiogenesis, endothelial cells proliferate and enlarge the neovascular complex, forming an angiogenic sprout. These tip cells secrete PDGF-B, which recruits pericytes that form a protective shield around the vessel walls.

During this process, the tip cells continue to produce new sprouts, but pericyte attachment and maturation lag behind, leaving the new tip cells unprotected and susceptible to anti-VEGF therapy.

“Ophthalmologists must continue to give anti-VEGF injections because the unprotected tip cells that are sensitive to VEGF persist at the ends of the vessels,” says Glenn J. Jaffe, M.D., professor of ophthalmology, chief, vitreoretinal service and director of the Duke Reading Center in Durham, N.C., the reading center for the Fovista Phase IIb trial. “If we interrupt or stop the anti-VEGF therapy, the cells that form buds at the tips of the vessels can once again respond to VEGF in the environment, and they will then continue to grow and leak. In other words, we are never really curing the disease. This mechanism of action is supported by the Comparison of AMD Treatment Trials (CATT) study, which found that when patients treated monthly were switched to treatment on an as-needed basis, their vision regressed as if they had never received monthly treatment.”⁵

The next advancement in therapy for wet AMD appears to lie with the anti-PDGF-B agent. Fovista binds to PDGF-B with high specificity and affinity and inhibits its functions in vitro and in vivo.¹ In preclinical studies, concurrent inhibition of PDGF-B and VEGF-A demonstrates the potential to induce neovascular regression.

Phase IIb trial results

In a prospective, randomized, double-masked Phase IIb clinical trial, 449 wet AMD patients were randomly assigned to receive monthly intravitreal injections of ranibizumab 0.5mg plus either Fovista 0.3mg, Fovista 1.5mg or a sham drug. The primary efficacy endpoint: the mean change in Early Treatment Diabetic Retinopathy Study visual acuity from baseline to week 24.

Patients receiving Fovista 1.5mg and ranibizumab monthly gained a mean of 10.6 letters of vision, representing a 62% additional benefit. They also had better visual acuity outcomes than those who received mono-therapy. The benefit of the combination therapy was consistent across all subgroups. In addition, the relative magnitude of visual benefit continued to increase through time. The growing divergence of the efficacy curves suggests a continuing benefit of chronic anti-PDGF combination therapy.

“Researchers have taken the gold standard of monthly intravitreal injections of anti-VEGF therapy, added a PDGF inhibitor and achieved a 60% improvement in visual acuity, and these results are statistically significant across all lesion types,” says David S. Boyer, M.D., a clinical professor of ophthalmology at the University of Southern California who practices at Retina-Vitreous Associates Medical Group in Los Angeles, Calif. Dr. Boyer was an investigator in the Phase I and Phase II trials of Fovista.

“This was the largest Phase II trial ever conducted in retina,” Dr. Boyer notes. “No significant safety issues were observed in any treatment arm during the trial, and we saw marked anatomic improvements on optical coherence tomography. I suspect this therapy may have more effect on other parameters, such as scotoma size and reading speed.”

Cautious optimism

Retina specialists are tempering their excitement, awaiting results from further studies.

Could anti-PDGF/anti-VEGF therapy be a game-changer?

“Yes. I think it could be,” Dr. Boyer says. “First, it brings us into an era of combination therapy for wet AMD, which is something we’ve not seen before. Second, with this combination, we can improve upon an existing monotherapy. Any patient receiving treatment for wet macular degeneration would want that extra visual boost.”

What’s next?

Although results from the Phase IIb trial of Fovista have been promising, they must be validated in a Phase III trial. Also, certain questions must be answered: Will gains in visual acuity continue to increase over time? Must therapy be given monthly, or can the time between treatments be extended? Can Fovista be combined with bevacizumab (Avastin; Genentech) or aflibercept (Eylea; Regeneron) with similar outcomes?

In a June 13 press release, Samir Patel, M.D., co-founder, president and CEO of Ophthotech, stated the company plans to “expedite the preparation of a Phase III registration program with the goal of bringing Fovista anti-PDGF therapy to patients as soon as possible.”

As comanaging doctors, optometrists are keeping a close eye on further studies of Fovista and on other agents for treating AMD in clinical trials.

“We are learning just how complicated the processes of angiogenesis and neovascularization are,” says Mark Dunbar, O.D., director of optometry at Bascom Palmer Eye Institute at the University of Miami (Fla.). “Treating CNV, especially in AMD, is not as simple as inhibiting VEGF. There are other factors involved.”

The introduction of this new combination therapy will not necessarily change how optometrists refer patients, says Dr. Dunbar.

“As referring doctors, we know the key to saving vision is to recognize wet AMD at the earliest possible stage and to refer patients appropriately for evaluation and treatment by an ophthalmologist,” he said. “A combination anti-PDGF/ anti-VEGF therapy would be another step toward targeted therapy and possibly the one-two punch that’s needed to improve vision and anatomy in these patients.” OM

Drs. Jaffe, Boyer and Dunbar have disclosed no financial relationships with Ophthotech Corporation.

1. Ophthotech’s Novel Anti-PDGF Combination Agent Fovista Demonstrated Superior Efficacy Over Lucentis Monotherapy in Large Controlled Wet AMD Trial. Princeton, NJ: BusinessWire; June 13, 2012.

2. Dugel PU. Anti-PDGF Drug Targets Heart of Angiogenesis. Retinal Physician. 2012 Oct; http://www.retinalphysician.com/articleviewer.aspxiarticleID=107523 (Accessed 12/5/12’)

3. Aiello LP, Pierce EA, Foley ED, et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA. 1995 Nov 7;92:10457-10461.

4. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of antivascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. 2006 Jun;168 (6):2036-2053.

5. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012 Jul;119(7):1388-1398.