Healio
Healio
ByMark W. Johnson, MD
February 01, 2006
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Antiangiogenic therapy an advanced treatment for AMD

ByMark W. Johnson, MD

Photodynamic therapy has been used to treat patients with age-related macular degeneration since 1999. PDT works by damaging new choroidal vessels, reducing vascular leakage and growth. Although PDT slows vision loss, its benefits are modest and visual improvement occurs in a small percentage of patients. Antiangiogenic drugs inhibit vascular endothelial growth factor, preventing vessel leakage and growth of harmful new vessels. Pegaptanib was approved in 2005 by the Food and Drug Administration for use in neovascular AMD. Other antiangiogenic drugs, such as ranibizumab and bevacizumab, are in various stages of preclinical and clinical development.

VEGF activity

Vascular endothelial growth factor (VEGF), which has emerged as the key target for antiangiogenic therapy, stimulates angiogenesis, induces vascular permeability and leakage and serves as a vascular survival factor, a proinflammatory factor and a neuroprotectant for the central nervous system and retina.1

VEGF plays a key role in the development of neovascular AMD. VEGF binds to and activates VEGF receptors on the endothelial cell, stimulating the release of cytokines, degradation of the extracellular matrix, loosening of tight junctions and proliferation and migration of endothelial cells. As a result, new capillary tubes are formed, which mature by the addition of pericytes.

The objectives of anti-VEGF therapy include stabilizing vision by inhibiting neovascular proliferation and limiting the size of the fibrovascular scar, and improving vision by eliminating the subretinal fluid and macular edema that result from VEGF-induced leakage. This treatment does not cause tissue damage and may reduce VEGF-induced inflammation.

Pegaptanib

Pegaptanib is an anti-VEGF aptamer composed of RNA, which binds to VEGF-165. VEGF-165 is a pathologic isoform that spares normal vasculature.

The effectiveness of anti-VEGF therapy was valid- ated by the VEGF Inhibition Study In Ocular Neovascularization (VISION) trials, which investigated pegaptanib and led to its approval. The primary endpoint for the VISION trials showed that 70% of patients treated with 0.3 mg of pegaptanib intravitreally every 6 weeks lost fewer than 15 letters at 1 year. Of patients who received sham treatment, 55% lost fewer than 15 letters at 1 year.

The effectiveness of anti-VEGF therapy was validated by the VEGF Inhibition Study In Ocular Neovascularization (VISION) trials.

— Mark W. Johnson, MD

In the VISION trials, for predominantly classic, minimally classic and occult subfoveal lesions, no one subgroup drove results. Plotting the change in mean visual acuity over the first year showed that patients treated with pegaptanib and patients receiving sham treatment lost vision, but patients treated with pegaptanib did so at a slower rate.

The VISION trials were disappointing because only a small percentage of patients had a significant improvement in VA. At the end of 1 year, 6% of pegaptanib-treated eyes gained three or more lines of vision, compared with 2% of sham-treated eyes.

In summary, pegaptanib has been shown to reduce the risk of visual loss in large randomized, clinical trials, but with a modest 15% treatment effect over sham. Inconsistent trial results were suggested for some subfoveal lesion subtypes. The safety profile was favorable through 2 years, but no visual improvement occurred in a meaningful portion of patients.

Ranibizumab

Ranibizumab is a recombinant antibody fragment derived from a monoclonal mouse antibody against VEGF-A and has a high affinity for all isoforms of VEGF-A.4,5 After intravitreal injection of ranibizumab, minimal systemic exposure occurs. The small amount of ranibizumab that theoretically enters the bloodstream is more rapidly eliminated from the systemic circulation than a full-length antibody.

The Minimally Classic/Occult trial of the Anti-VEGF antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trial was a phase 3 randomized, controlled clinical trial that evaluated the efficacy and safety of ranibizumab in patients with minimally classic lesions or occult lesions with no classic subfoveal choroidal neovascular membrane secondary to AMD. The primary endpoint in this trial was the percentage of patients who lost fewer than 15 letters from baseline at month 12. Of patients who received monthly ranibizumab injections, 94.6% who received 0.5 mg and 94.5% who received 0.3 mg lost fewer than 15 letters, compared to 62.2% of patients who received sham treatment.

At 1 year, 40% of patients treated with 0.5 mg of ranibizumab and 38.7% of patients treated with 0.3 mg had 20/40 or better vision. Only 10.9% of patients who received sham treatment had 20/40 vision. The number of patients receiving ranibizumab who had severe (six lines or more) vision loss was negligible (0.8% and 1.2% of patients receiving 0.3 mg and 0.5 mg, respectively). In contrast, 14% of patients who received sham treatment experienced severe vision loss over the first year of the study.

The mean VA change in sham-treated eyes over the first year of the MARINA study was a loss of 10.5 letters, whereas the mean change in eyes receiving ranibizumab was a gain of seven letters (Figure). These results suggest an average benefit of more than three lines of vision from treatment with either dose of ranibizumab.

Secondary Endpoint: Mean Change in VA Over Time

Figure

Figure. The mean VA change in sham-treated eyes over the first year of the MARINA study was a loss of 10.5 letters, whereas the mean change in eyes receiving ranibizumab was a gain of seven letters.

Source: Johnson M.W.

A second ranibizumab trial was the RhuFab V2 Ocular Treatment Combining the Use of Verteporfin to Evaluate Safety (FOCUS) study. This was a phase 1 and 2 single-masked, multicenter sham-controlled trial comparing ranibizumab (0.5 mg) in combination with PDT to PDT alone in patients with predominantly classic subfoveal choroidal neovascularization secondary to AMD. Of patients who received PDT with ranibizumab, 90.5% lost fewer than 15 letters, whereas 67.9% of patients receiving PDT alone lost fewer than 15 letters. Patients who received PDT alone had a VA loss of 8.2 letters for the year, whereas patients who received ranibizumab and PDT had a mean gain in VA of 4.9 letters.

The MARINA and FOCUS trials provide promising data, establishing the groundwork for future ranibizumab trials.

Bevacizumab

Bevacizumab is a humanized monoclonal anti-VEGF antibody that was developed in parallel with ranibizumab. Ranibizumab was developed for use in the eye, and bevacizumab was developed to treat patients with systemic malignancies.

Bevacizumab was approved by the FDA at the end of 2004 for the treatment of patients with metastatic colorectal cancer. It was used in an off-label study in a patient with neovascular AMD. In this study, bevacizumab was administered intravenously and showed promising visual and anatomic results. However, concerns about systemic toxicity, including hypertension and arterial thromboembolic events, arose. A case report was published in July 2005 describing intravitreal bevacizumab as a salvage therapy for a patient failing other treatments. Since then, anecdotal experience with bevacizumab has expanded and results appear to be promising.

Combination therapy

Angiogenesis is a complex process involving redundant pro- and antiangiogenic stimuli. CNV membranes resemble granulation tissue histologically, including components of inflammation and fibrosis in addition to new blood vessels. CNV-induced vision loss is also multifactorial, involving photoreceptor damage by fibrovascular tissue and inflammation, intraretinal edema, subretinal fluid and blood, and treatment-related tissue injury. Because of this complexity, targeting a single pathogenic mechanism with a single agent is unlikely to be effective in the treatment of neovascular AMD.

Key cell types in the development of CNV membranes and disciform scarring include endothelial cells, pericytes, inflammatory cells and fibroblasts. The future of CNV membrane therapy is likely to involve drug combinations that target multiple cell types and stages in the angiogenic cascade. A variety of agents target endothelial cells. At least one drug is being developed to target pericytes, and it may facilitate regression of established neovascularization.

A number of clinical trials on various combination treatments are underway. One familiar combination therapy is PDT and intravitreal triamcinolone, but various combinations of anti-VEGF agents with PDT, angiostatic steroids and/or anti-PDGF (platelet derived growth factor) aptamers may also be studied in the future.

Conclusion

PDT and pegaptanib are modestly effective in treating neovascular AMD by reducing the risk of vision loss. Ranibizumab, and possibly bevacizumab or similar drugs, hold promise of providing better treatment. Although pegaptanib is the only antiangiogenic drug approved by the FDA for the treatment of neovascular AMD, antiangiogenic drugs such as ranibizumab are in clinical development and likely to be available in the near future. Off-label usage of bevacizumab shows promise, but long-term safety and efficacy issues remain. Combining an anti-VEGF drug with PDT, an angiostatic steroid or other agents may ultimately prove to have added efficacy. Safety concerns with combination therapy remain, in part because the effects of combined drug interaction are unknown. Clinical trials investigating various combination therapies are underway and others are likely to be carried out in the future.

References

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