Thursday, June 14, 2012
Pravin U. Dugel, MD
Anti-VEGF monotherapy will go down in medical history as a treatment model that was both insurmountable and unsustainable.
It was insurmountable because of the historic gains that were seen in a disease, neovascular macular degeneration, that had miserable treatment results earlier. We went from essentially not being able to treat our patients at all and watching them go blind to being able to maintain vision in 90% of our patients with exudative macular degeneration. We were able to actually improve vision in 30% to 40% of our patients with neovascular macular degeneration with anti-VEGF monotherapy.
However, as we gained experience in the treatment of neovascular macular degeneration with anti-VEGF monotherapy, we also learned that this treatment was unsustainable in order to achieve the best results possible. It became clear through numerous studies that in order to gain the best possible vision, strictly monthly injections were required perhaps forever. The bottom line is that as good as the results were in seminal clinical trials, such as ANCHOR and MARINA, realistically no one was getting such results because no one was able to treat the patients strictly on a monthly basis forever. The treatment burden was simply too great.
The fundamental scientific question to be asked was why anti-VEGF monotherapy encountered resistance. It was clear from the numerous studies that despite the giving of injections on a strictly monthly basis for a year or two, the size of the neovascular membrane did not decrease. In fact, in some cases, despite excellent visual acuity results, the size of the neovascular membrane actually increased. Moreover, even in the best of studies, such as the ANCHOR and MARINA studies, two-thirds of patients didn’t gain significant visual acuity. So the fundamental question that had to be asked is: Why is there anti-VEGF monotherapy resistance, and what is the biological basis for this?
It turns out that there is an answer for this question, and this answer has been known for almost a decade. However, this answer doesn’t lie in the realm of retina or even ophthalmology but rather the realm of general medicine, more specifically in oncology. Ironically, the answer is quite simple and makes good common sense. 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 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.
Understanding the biological process of choroidal neovascularization also explains the familiar curve when visual acuity is plotted with time following anti-VEGF monotherapy. Regardless of the clinical trial, the curve is quite consistent. There’s an initial period of improvement of visual acuity over 2 to 4 months followed by a plateau that seems to be indefinite. One can imagine that initially anti-VEGF monotherapy kills the tip cells that are vulnerable as they are the only naked endothelial cells.
This will result in decreased exudation and improve visual acuity, resulting in an improvement of visual acuity in the first 2 to 4 months. Thereafter, the pericyte armor will prevent penetration of anti-VEGF monotherapy to the rest of the neovascular complex. Therefore, a plateau will occur that will require anti-VEGF treatment forever. As soon as anti-VEGF monotherapy is stopped, the neovascular complex will grow again. This is the scientific basis for anti-VEGF monotherapy resistance.
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.
Ophthotech sponsored a clinical phase 1 trial using a drug at that time named E10030 in combination with Lucentis (ranibizumab, Genentech) to treat patients with advanced exudative macular degeneration. As in any other phase 1 study, the patients are recruited who had advanced severe disease and were not expected to improve. The purpose of the study was simply to show safety and a biological signal. Unexpectedly, 59% of patients in this small phase 1 study showed an improvement of three lines or more. The mean magnitude of regression of the neovascular complex was 86%.
These results were surprising and unexpectedly encouraging. Based on these results, a large phase 2b study was conducted to compare this combination regimen with anti-VEGF monotherapy alone. This large study was a prospective, randomized, controlled, phase 2b clinical trial that evaluated 449 patients with neovascular macular degeneration. The study showed that E10030 (renamed Fovista) administered in combination with Lucentis anti-VEGF therapy gained a mean of 10.6 letters of vision at 24 weeks, compared with 6.5 letters of vision for patients receiving Lucentis alone. In other words, patients with a combination treatment regimen had a 62% additional benefit. This result was nothing short of astounding.
How does this affect my patients? It is clear that no one is able to inject anti-VEGF monotherapy on a strictly monthly basis forever. Therefore, none of our patients get the visual acuity that is expected from the ANCHOR and MARINA trials. The bottom line is that we are unable to sustain the treatment burden that is required with anti-VEGF monotherapy and our patients gradually lose vision over time as the treatment burden gets unbearable.
The significance of the combination therapy of Fovista with Lucentis is that for the first time, superior efficacy to Lucentis monotherapy has been shown. Lucentis is a phenomenal drug. The threshold of efficacy is extremely high, and thus far, no drug has been able to surpass it. The fact that this combination treatment shows a 62% relative benefit over anti-VEGF monotherapy is astonishing and unexpected. As mentioned, the possibility of this combination agent being able to actually shrink or eradicate the neovascular membrane gives us hope that a sustainable treatment model will finally be available for our patients. The possibility of having both better efficacy and an improved and sustainable treatment model is a grand slam.
The significance of this Ophthotech phase 2b trial is profound. However, as a scientist and a clinical researcher, it is important to temper this enthusiasm with the tasks that are yet to be performed. Most importantly, the results of this trial, as encouraging as they are, need to be vetted by our colleagues in a critical fashion and need to be validated in a peer-review publication. If this is confirmed, the combination of Fovista with Lucentis would truly change the paradigm of our treatment for patients with neovascular macular degeneration.
We will have evolved from a treatment model that destroys tissue (laser photocoagulation) to a treatment model that preserves tissue (anti-VEGF monotherapy) to a treatment model that actually enhances visual function (Fovista-Lucentis combination treatment). There’s great comfort in knowing that this combination treatment is based on a foundation of hard science and is almost a decade old. The science makes sense, and the clinical trial results confirm the science. We have the potential to finally fulfill our holy grail of a combination treatment that is both more efficacious and sustainable.
- Disclosure: Dr. Dugel is a consultant to Genentech and a consultant to and minor shareholder in Ophthotech.
RELATED: Read "Combination therapy offers improved visual outcome compared with anti-VEGF monotherapy, trial finds."
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