Because I was denied the opportunity to tell you how the combined therapy works, as told by Dr. Pravin Dugel (see AMD Update 19
), I decided to take another tack. With the permission of Ophthotech, I would like to explain and illustrate how the combined therapy of anti-VEGF and anti-PDGF works to provide improved vision compared to monotherapy with anti-VEGF drugs alone, for those suffering from neovascular, exudative wet AMD.
AMD is a disease characterized by progressive degenerative abnormalities in the macula of the eye, a small area in the central portion of the retina. AMD is characteristically a disease occurring in patients older than 50 years of age and has long been recognized as the leading cause of severe and irreversible loss of central vision in adults over the age of 50 in the U.S. and other developed countries around the world. AMD is exceptionally common, currently affecting about 8 million Americans and an additional 8 million Europeans.
Of those affected, approximately 10% are afflicted with the wet form of AMD. (Dry AMD can and usually does progresses into the wet form of the disease.)
It has been estimated that there are approximately 200,000 new cases of wet AMD each year in the U.S. This type of AMD results when abnormal blood vessels proliferate under and/or within the retina. These blood vessels leak blood and fluid into and under the retina, which results in vision loss. The natural history of wet AMD is that of scarring with progressive destruction of the central retina and loss of vision.
Until 2005, there was no treatment for wet AMD that could stop its progression and provide some improved vision for those suffering from the disease. In mid-2005, Dr. Phil Rosenfeld, of Bascolm Palmer in Miami, presenting at Retina 2005, told an enthralled audience about his experiments with Avastin, an anti-VEGF agent used in cancer treatment, and how he was able to stop the progression of wet AMD. The following year, Genentech introduced the FDA-approved anti-VEGF Lucentis and history was made. (Avastin, also made by Genentech, a similar molecule approved for cancer treatment, was and still is used off-label for treating wet AMD, primarily because of its much lower cost.)
Figure 1 illustrates a normal, disease-free retina. Figure 2 shows a retina with signs of neovascular, exudative wet AMD.
Monotherapy Anti-VEGF Treatment
Monotherapy with an anti-VEGF agent (Lucentis, Avastin or Eylea) is the current standard of care for wet AMD. Anti-VEGF agents mediate their efficacy primarily through their potent anti-permeability effect. However, limitations of anti-VEGF strategies include lack of disease modification (neovascular regression). Therefore, a therapeutic regimen that induces disease modification would likely result in enhanced visual outcome for patients.
Further, as pointed out by Dr. Dugel in his blog in OSN
, as shown by several studies, despite giving injections on a monthly basis for up to two years, the size of the neovascular membrane does not decrease. In fact, in some cases, despite excellent visual acuity results, the size of the neovascular membrane actually increased, leading to the questions, why was there anti-VEGF mono-therapy resistance and what was the biological basis for this?
It turns out there is an answer to these questions, which was found in the study of cancer treatments. As explained by Dr. Dugel, “As it turns out, the neovascular complex does not expand in a random fashion but rather expands with a specific, specialized group of cells known as the tip cells. These are the only naked endothelial cells in the neovascular complex.”
“These cells act as scout or lead cells in expanding the size of the neovascular membrane. These are the only naked endothelial cells in the neovascular complex. And they produce platelet derived growth factor (PDGF), which matures and recruits pericytes that back cover the neovascular complex. The pericytes act as a “protective armor” against anti-VEGF monotherapy. This simple but eloquent set of events explains a lot of the clinical observations that have been made in retina over the last 5 years.”
“With anti-VEGF monotherapy, it is clear that treatment needs to be given on a strictly monthly basis forever (bi-monthly with Eylea) because only the tip cells are killed. While the pericyte coverage of the neovascular complex provides a protective armor, the anti-VEGF treatment stops it from expanding. However, once anti-VEGF monotherapy stops, then the lead cells will grow and the complex will continue to expand. Therefore, treatment has to be given strictly on a monthly basis forever.”
Combined Anti-VEGF Plus Anti-PDGF Therapy
Ophthotech's anti-PDGF-B aptamer, Fovista (E10030), targets PDGF, which regulates neovascular pericytes. In pre-clinical models, Fovista successfully induced neovascular regression when administered in combination with anti-VEGF agents. This effect is further supported by published studies in which inhibition of the binding of PDGF-B to its receptor, PDGFR-ß, plus an anti-VEGF agent cause neovascular regression in ocular angiogenesis models, as shown below.
Figures 3-7 illustrate the action of Fovista and the combined therapy with the anti-VEGF agent in reducing neovascularization.
|Figure 3. Action of PDGF|
|Figure 4. Formation of Pericytes|
|Figure 5. Anti-VEGF Action|
|Figure 6. Combination Therapy|
|Figure 7. Combo Therapy Regresses Neovascularization|
As Dr. Dugel further pointed out, “Given this scientific explanation for anti-VEGF resistance, it would make sense that a scientifically logical combination treatment model would consist of anti-PDGF treatment combined with anti-VEGF treatment. The goal would be to have the anti-PDGF treatments chemically strip pericytes from the neovascular complex, rendering it susceptible to the anti-VEGF treatment. There is indeed a solid scientific foundation for this treatment combination.”
Mural cells (pericytes) provide neovascular endothelial cell survival signals by juxtacrine secretion of growth factors such as VEGF and other pro-angiogenic factors. Therefore, neovascular tissue is resistant to regression during a monotherapy anti-VEGF attack.
PDGF is a molecule which regulates the recruitment and maturation of pericytes. Increased PDGF expression leads to enhanced pericyte coverage of neovascular tissue. Conversely, its inhibition has been shown to cause pericyte stripping.
Fovista strongly binds to PDGF-B resulting in pericyte stripping in ocular and oncological models of pathologic neovascularization. Co-administration of Fovista and an anti-VEGF agent, thereby targeting pericytes and endothelial cells respectively, has been shown to induce significant neovascular regression in multiple pre-clinical ocular and tumor models of angiogenesis.
The results of the recently completed Ophthotech prospective, randomized, controlled, Phase 2b clinical trial of 449 patients showed that the combined therapy was successful in producing a 62% increase in lines of vision compared to monotherpy alone.
Q&A With Samir Patel, CEO of Ophthotech:
Q. I know that your Phase 2b study of Fovista was done with Lucentis, but would you expect both Avastin and even Eylea to work as well, or in the case of Eylea, even better than Lucentis?
A. With respect to the currently available data, it is very difficult to claim superiority of one anti-VEGF over the other. Furthermore, it is apparent that we are at the ceiling of anti-VEGF efficacy as increasing the concentration of the anti-VEGF agent does not result in enhanced visual outcome. We believe all anti-VEGF agents would perform equally well in combination with Fovista.
Q. I anticipate that with the way the combined therapy works, perhaps less frequent retinal injections might be required to provide and hold the gains in vision shown in your initial study. Do you have any thoughts on the frequency of required injections?
A. The data from our large (449 patient) randomized study showed superiority of Fovista combination over Lucentis monotherapy on the basis of the pre-specified primary endpoint (Mean VA at 24 weeks) with statistical significance at 6 months. Furthermore, this relative benefit was increasing in magnitude at each time point resulting in divergence of visual acuity curves over time. Therefore, this enhanced visual outcome required continuous (every four weeks) of Fovista combination. I cannot comment on any alternative regimen as the trial did not address that question. However, preclinical studies published in "Nature", "Archive of Ophthalmology" and elsewhere suggest that anti-VEGF administration leads to increase in PDGF and neovascular maturation. Therefore, administration of Fovista (anti-PDGF) very time an anti-VEGF agent is used would likely be required for maximal visual benefit.
The remaining question, will further studies show that the combined therapy can effectively reduce the need for multiple injections to control the gains in vision achieved?