Article Date: 10/1/2012

Anti-PDGF Drug Targets Heart of Angiogenesis
PEER REVIEWED

Anti-PDGF Drug Targets Heart of Angiogenesis

Novel combination AMD therapy yields startlingly good outcomes, a study investigator reports.

Pravin U. Dugel, MD

Amid the justifiably positive fanfare surrounding the birth of anti-VEGF therapy, one important fact went largely unnoticed. In the pioneering ANCHOR and MARINA studies, which essentially laid the groundwork for anti-VEGF AMD therapy as we know it today, patients in general did not experience neovascular membrane regression.

At the time, visual acuity benefits were cause enough for celebration. Subjects' angiograms clearly showed reduced vascular permeability, leakage, and edema, but the actual structures underlying exudative disease remained untouched by the treatment. In fact, a significant number (20% in ANCHOR and 15% in MARINA) saw their choroidal neovascular lesions grow over the course of the study, despite strict adherence to monthly injections.

Also worth remembering is that despite functional outcomes unimaginable for their time, two-thirds of study subjects failed to achieve significant visual gains, and to this day, most patients do not regain three or more lines of vision.

Then there is treatment burden, a more widely acknowledged anti-VEGF challenge, which was recently highlighted in the CATT year 2 results.1 These data reinforced an already substantial body of literature (APPEAR, EXCITE, SAILOR, HARBOR, etc.) indicating that not only do we get our best outcomes with a strict monthly injection schedule, but any deviation from that schedule results in decreased vision, even among patients who maintained disciplined monthly visits for years.

The HORIZON extension study, which continued to follow ANCHOR and MARINA subjects, has shown that despite receiving anti-VEGF therapy on a monthly basis for two years, patients switched to as-needed dosing saw their VA fall almost back to baseline.2 In CATT, when monthly patients were switched to PRN dosing after receiving monthly injections for one year, their vision fell back to nearly the same level as those receiving PRN dosing from the outset.

A combination therapy currently undergoing clinical trials may help us to overcome these obstacles. When combined with traditional anti-VEGF therapy, a new, anti-platelet derived growth factor (PDGF) agent has shown exciting choroidal neovascular membrane regression and significantly greater vision gains than anti-VEGF monotherapy. (Results on the patients' neovascular membranes are not yet available.)

ROOTS OF RESISTANCE

Before we explore the potential strengths of the new drug, it is important to understand what causes anti-VEGF resistance, or at least what we think causes it. At issue here is angiogenesis, the process of new blood vessels sprouting from existing ones. Angiogenesis seems at first like a straightforward event, but its intricacies have proved difficult to unravel. While angiogenesis is still not completely understood, studies over the last decade have made significant breakthroughs.

The challenges lie in its complexity. Angiogenesis involves hundreds, if not thousands, of chemical factors. As we well know, VEGF is an important factor, but perhaps not the most vital. Angiogenesis occurs over many stages: initiation, progression, differentiation, maturation, and remodeling. Numerous cell types, in addition to endothelial cells, contribute to vascular growth during these stages.

Cells called pericytes appear to play a crucial role. Research shows significant cell signaling, or “cross-talk,” occurs between endothelial cells and pericytes, and this communication is accomplished by chemical agents such as VEGF and PDGF, among several others.3

In the initial stage of angiogenesis, a group of endothelial cells, known as tip cells, blaze the trail, proliferating and expanding the size of the neovascular membrane. These cells shape the leading edge of the angiogenic sprout.

They also secrete platelet-derived growth factor B (PDGF-B), which in turn recruits pericytes to proliferate and migrate along the growing neovascularization. The presence of pericytes is a hallmark of vascular maturation; pericytes protect and stabilize the endothelial cells that constitute to the vascular wall.

While this process is unfolding, the tip endothelial cells continue to build new sprouts. Pericyte attachment and maturation and endothelial cell protection lag behind tip endothelial cell proliferation. Throughout angiogenesis, tip cells are the only endothelial cells unprotected by a shield of pericytes.

Researchers believe that one of the main factors driving anti-VEGF resistance is this protective coating of pericytes. One line of thinking states that current anti-VEGF therapy only impacts the leading tip cells, temporarily abrogating the vascular permeability, leakage, and edema that causes exudative vision loss, but leaving the pericyte-guarded neovascular complex intact. Soon after anti-VEGF therapy ceases or slows down, the pericyte-protected endothelial lesions stand ready to sprout new vessels.

INTERDISCIPLINARY DATA

A great deal of evidence supports the above view, much of it from our colleagues in oncology, in which angiogenesis also plays a large role in tumor formation and survival. Investigators have found that when anti-VEGF and anti-PDGF agents are used in combination to target both the endothelial cells and pericytes, more neovascular regression occurs than either agent could have accomplished on its own.

This combined effect was shown in a mouse model of pancreatic islet cancer4 and in an experimental tumor model that compared anti-VEGF therapy alone to anti-VEGF combined with anti-PDGF therapy.5 The latter paper concluded that “pericytes may provide escape strategies to anti-angiogenic therapies” and to therapies “that target not only endothelial cells, but also pericyte-associated pathways involved in vascular stabilization and maturation exert potent anti-vascular effects.”

After examining a corneal neovascular model, a 2006 study published in a pathology journal arrived at similar conclusions.6 “We demonstrate neovessels become refractory to VEGF-A deprivation over time,” the article states. “We also show that inhibition of both VEGF-A and PDGF-B signaling is more effective than blocking VEGF-A alone at causing vessel regression in multiple models of neovascular growth.”

Significantly, this paper found that pericytes on normal, nonpathologic vasculature remained unaffected by anti-PDGF therapy.

BEATEN TO THE PUNCH

It bears mentioning that the eyecare world was not completely caught off guard by the emergence of pericytes in neovascularization. As far back as 1995, an ophthalmic team studying laser-induced neovascularization in primate models discovered pericyte involvement in the maturation of the endothelial cells that form subretinal new vessels.7

In 2009, a study of AMD patients undergoing anti-VEGF therapy sought to determine whether phosphorylated VEGF receptors shed into the vitreous reflect the ongoing retinal and choroidal signal pathway activity in the disease.8 These investigators discovered not only activated forms of VEGF receptors but PDGF receptors as well, which they speculated could lead to “discovery of new therapeutic targets.”

Finally, a recent case report of a surgically removed neovascularization secondary to punctate inner choroidopathy (PIC) found that the left eye membrane, which had proved more unresponsive to anti-VEGF treatment than the right eye, displayed well-formed neovascular units consistently exhibiting pericytes.9 “This is the first pathological study employing human tissue that points to pericytes as a potential critical therapeutic target with the aggravating influence of inner choroidal chronic inflammation in PIC,” the paper concluded.

In other words, we were hot on the trail, but oncology got there first.

EXCEEDED EXPECTATIONS

Ophthotech Corp., Princeton, NJ, recently developed an anti-PDGF aptamer, formerly known as E10030 and now called Fovista. My practice serves as one of the study centers for the clinical trials of this drug. The phase 1/2a, dose-escalating, multicenter, uncontrolled, single and multiple-dose study included 22 patients who were given three monthly intravitreal injections of combination therapy, Lucentis (ranibizumab, Genentech, South San Francisco, CA) with Fovista. No dose-limiting toxicities nor any adverse events were reported. All doses (up to 3 mg) were well tolerated.

Functional outcomes in this early phase study were excellent (Figure 1). Fifty-nine percent of patients gained three lines of VA or more, a result that would have been outstanding among any cohort, but among these patients, who all had exceedingly unresponsive disease, it was all the more so. Additionally encouraging, all of the patients displayed some degree of neovascular regression, with an 86% average magnitude of regression (Figure 2).

Figure 1. Vision improvement and CNVM reduction in a patient in the phase 1/2a combination therapy study.

Figure 2. The average magnitude of CNVM regression in the phase 1/2a study was 86%.

Based on these results, a phase 2b clinical trial was designed involving 449 patients. Three groups received one of three treatments every four weeks: Fovista 0.3 mg combined with Lucentis 0.5 mg; Fovista 1.5 mg combined with Lucentis 0.5; or a placebo combined with Lucentis 0.5mg.

Press releases for this phase 2b study mirrored the earlier trial results with a mean +10.6 letters of vision improvement at six months, or a 62% improvement over Lucentis monotherapy. Full details of the study will be reported shortly. In particular, we are awaiting the imaging results to see whether the regression seen in the phase 1/2a study holds in the larger phase 2b study.

With any luck, we have here a combination therapy that inhibits pericyte recruitment, strips pericytes from the neovascular complex without negatively affecting host non-cardiovascular vessels, and causes both inhibition and regression of the neovascular complex (Figure 3).

Figure 3. “Chemical stripping” of pericytes (green antibody stain) from neovascular complexes after combination treatment with anti-PDGF. Compare to pretreatment (inset).

IMAGE ADAPTED FROM MITCHELL TS, BRADLEY J, ROBINSON GS, SHIMA DT, NG YS. RGS5 EXPRESSION IS A QUANTITATIVE MEASURE OF PERICYTE COVERAGE OF BLOOD VESSELS. ANGIOGENESIS. 2008;11:141-151 WITH KIND PERMISSION FROM SPRINGER SCIENCE + BUSINESS MEDIA BV.

SUSTAINABLE ALTERNATIVE

If Fovista proves as efficacious as these clinical trials suggest, it would arrive at an opportune moment in medical history. Mounting evidence indicates that the overwhelming treatment burden of anti-VEGF monotherapy cannot be sustained.

In every anti-VEGF monotherapy clinical trial undertaken, going back to ANCHOR and MARINA, a similar pattern of VA improvement occurs. Vision recovers in the first two or three months, stabilizes around month 4, and then continues on that plateau for an extended period of time — probably, alas, forever.

Any hope that we may have had of anti-VEGF monotherapy providing some degree of long-term structural benefit vanished when studies such as CATT and HORIZON demonstrated how quickly vision worsened in the presence of decreased dosing frequency.

Not only do studies show that optimal VA results require strict monthly injections with little hope of a treatment endpoint, they also show how infrequently patients actually receive such care. Recent evaluations of Medicare claims indicate that in the United Staters, the average number of injections in the first year of neovascular AMD treatment is not 12 but rather slightly fewer than six. Therefore, nationwide VA outcomes must be far worse than we as a profession would care to admit.

The last decade has been a remarkable period for the treatment of neovascular AMD. We have gone from having no effective treatment and simply watching our patients go blind to providing anti-VEGF monotherapy, allowing for some, albeit temporary, stabilization of vision. Combination anti-VEGF and anti-PDGF therapy offers hope that we may provide our patients with a more permanent and sustainable treatment model to combat the blinding effects of this common disease. RP

REFERENCES

1. 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;119:1388-1398.
2. Singer MA, Awh CC, Sadda S, et al. HORIZON: An open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119:1175-1183.
3. Gaengel K, Genové G, Armulik A, Betsholtz C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arteríoscler Thromb Vasc Biol. 2009;29:630-638.
4. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287-1295.
5. Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338-340.
6. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. 2006;168: 2036-2053.
7. Ishibashi T, Inomata H, Sakamoto T, Ryan SJ. Pericytes of newly formed vessels in experimental subretinal neovascularization. Arch Ophthalmol. 1995;113:227-231.
8. Davuluri G, Espina V, Petricoin EF 3rd, et al. Activated VEGF receptor shed into the vitreous in eyes with wet AMD: a new class of biomarkers in the vitreous with potential for predicting the treatment timing and monitoring response. Arch Ophthalmol. 2009;127:613-621.
9. Pachydaki SI, Jakobiec FA, Bhat P, et al. Surgical management and ultrastructural study of choroidal neovascularization in punctate inner choroidopathy after bevacizumab. J Ophthalmic Inflamm Infect. 2012;2:29-37.

Pravin U. Dugel, MD, is managing partner of Retinal Consultants of Arizona in Phoenix and a founding member of Spectra Eye Institute in Sun City, AZ. Dr. Dugel reports moderate financial interest in Ophthotech. He can reached via e-mail at pdugel@gmail.com.


Retinal Physician, Volume: 9 , Issue: October 2012, page(s): 15 - 18