Antiangiogenic agents move the target from preservation to improvement of vision

Similar to their use in cancer treatment, angiogenesis inhibitors could help clear abnormal blood vessels from the eye.

New treatment options are raising realistic hopes that vision in patients with age-related macular degeneration might be improved and not merely preserved as it was with previous treatments.

“It’s an exciting time for retinal specialists. The discovery that drugs that were previously used in cancer therapy can address the complex mechanism of intraocular neovascularization, treating the cause rather than the symptoms of the disease, has given new impulse to the research,” said Paolo Lanzetta, MD, professor at the University of Udine, Italy. He reviewed recent developments in treatments for retinal disease in an interview with Ocular Surgery News.

In the same way these drugs are used to starve cancer, angiogenesis inhibitors could help clear abnormal blood vessels from the eye, he said.

Most of the research in ocular angiogenesis has been carried out in the field of retinal diseases, particularly diabetic retinopathy and more recently AMD. The formation of new blood vessels seems to be connected with a series of predisposing factors, such as hypoxia, inflammation and diffused thickening of Bruch’s membrane, and the secretion of several angiogenic growth factors, including vascular endothelial growth factor (VEGF).

“The VEGF is a growth factor with a high selectivity for endothelial cells. Initially discovered in 1983 as a peptide secreted by tumor cells, it was later found also in retinal pigment epithelial cells of surgically removed choroidal neovascularization,” Dr. Lanzetta explained. “Upregulated by hypoxia, it has the double function of stimulating angiogenesis and increasing vascular permeability and is in this respect 50,000 times as potent as histamines.”

VEGF antagonists are currently used to reduce neovascular lesions in the retina and choroid, as in AMD and diabetic retinopathy, and to treat conditions correlated with an increased vascular permeability, such as macular edema.

“It is important to remember that by inhibiting the VEGF activity, both these mechanisms are addressed,” Dr. Lanzetta said. Most agents that have been tested for the treatment of CNV are now being studied for the treatment of macular edema, he said.

Triamcinolone acetonide

Triamcinolone acetonide is a cortical steroid used in orthopedics for many years. The use in ophthalmology is currently off-label. It has a direct and indirect effect on angiogenesis, vascular permeability and inflammation. In the treatment of CNV, it is specifically used to re-establish the blood retinal barrier and to downregulate the inflammatory markers, Dr. Lanzetta said.

“The efficacy of triamcinolone has never been proved by large, randomized clinical studies. However, it is widely used intravitreally in conjunction with PDT, and a few published reports on small case series seem to indicate that it is effective in stabilizing or even improving visual acuity and in reducing the need for PDT re-treatments,” Dr. Lanzetta said.

However, he recommended caution in the use of triamcinolone acetonide until larger studies are published.

“Adverse effects of the drug, such as IOP increase, cataract and endophthalmitis, have been demonstrated,” he said.

Anecortave acetate

Retaane (anecortave acetate, in development by Alcon), an angiostatic cortisene with no steroid activity, does not have the conventional pharmacological side effects of steroids. Comparison with placebo has shown mild and transient adverse events connected with the mechanical effects of the injection, such as ocular pain, ptosis and subconjunctival hemorrhage.

“On the other hand, the effects on visual acuity differ significantly from those of placebo. The preliminary results of the C 9803 study of patients with predominantly classic subfoveal lesions showed a 73% proportion of patients losing less than 15 letters in the anecortave group compared to 47% in the placebo-injected group,” Dr. Lanzetta said. “Only 6% of the patients treated with anecortave lost six or more visual acuity lines compared with 23% in the control group.” He noted, however, that the study at this stage had a high dropout rate (41%) before month 12, mainly due to disease progression.

Another trial (C 0199) has demonstrated comparable efficacy between Retaane and PDT with verteporfin, he said.

“It was also found that the reflux of the drug during the injection had a significant impact on the efficacy of the treatment. Consequently, a new counter-pressure device has been created to minimize this problem,” Dr. Lanzetta said.

Pegaptanib

In December 2004, Macugen (pegaptanib sodium injection, Pfizer/OSI) was the first antiangiogenic drug to obtain U.S. Food and Drug Administration approval for all types of CNV, and the European Commission recently granted Macugen regulatory approval.

“Macugen is a pegylated oligonucleotide that specifically binds to the isoform 165 of VEGF, the principle isoform connected with neovascular formation. This high selectivity may also represent its limitation, as it inhibits the angiogenesis and permeability activity of 165, but other isoforms of VEGF remain active,” Dr. Lanzetta said.

Results in patients who received pegaptanib by intravitreal injection every 6 weeks for 2 years were “frankly below expectations,” he said. Although effective at slowing down the progression of AMD and the consequent loss of visual acuity, the treatment does not produce better results than PDT, he said.

“The results of the VISION study of pegaptanib were comparable to those of the TAP and VIP trials of PDT with Visudyne (verteporfin for injection),” Dr. Lanzetta said. The treatment cost is also comparable, and the combination of the two treatments does not increase the reciprocal efficacy, he said.

A recent protocol amendment introducing more sterile measures of administration has significantly reduced the risk of endophthalmitis (less than 0.2%) connected with the procedure.

Macugen is recommended when PDT with Visudyne is of little or no benefit, such as in minimally classic subfoveal lesions or some cases of occult lesions, he said.

“For the classic or predominantly classic subfoveal lesions and for occult lesions smaller than four disc area, PDT is still the treatment of choice,” he said.

Ranibizumab

Promising results are being reported with Lucentis (ranibizumab, Genentech), a recombinant humanized antibody-Fab fragment that binds to and inactivates all isoforms of VEGF.

The results of the MARINA study were “exciting,” Dr. Lanzetta said. Nearly 95% of the patients treated with ranibizumab lost less than 15 letters compared with 62% of placebo-injected patients. At month 12, patients treated with ranibizumab experienced a mean increase of seven letters, while placebo-injected patients had a decrease of 10.5 letters. Thirty-four percent of patients gained 15 or more letters with the 0.5 mg dose, compared with 4.6% of the sham group.

The ANCHOR study also demonstrated that the results of multiple injections of Lucentis every 4 weeks were better than those of PDT with Visudyne every 3 months in patients with predominantly classic lesions, which were traditionally the best PDT-responders. In the ranibizumab group, 94% to 96% of the patients maintained or improved vision over a period of 12 months, compared with 64% of the PDT group.

“For the first time we are experiencing a treatment that can genuinely improve rather than just preserve vision,” Dr. Lanzetta said.

He noted that one of the reasons of the success of ranibizumab is that it binds to all isoforms of VEGF. As a consequence, it leads to complete inhibition of not only angiogenesis, but also vascular permeability.

“Since the post-laser era, we have been aiming at keeping under control rather than destroying the CNV lesion. We have found that significant visual acuity improvements can be obtained by simply reducing its growth and, more importantly, its permeability,” Dr. Lanzetta said.

Bevacizumab

Wide interest has recently been shown regarding Avastin (bevacizumab, Genentech), a molecular cousin of ranibizumab. Approved by the U.S. FDA for the treatment of metastatic colon cancer, it has been tested as a systemic treatment for CNV in an uncontrolled clinical study.

Two to three infusions at 2-week intervals were shown to improve visual acuity as much as 13 letters and to decrease foveal thickness by 128 µm. No adverse events were reported apart from a mild increase in blood pressure.

“Treating CNV systemically would undoubtedly be an advantage for many obvious reasons. However, the risk of thrombosis that is known as a potential side effect of systemic bevacizumab could be somewhat discouraging,” he said.

Intravitreal injection could be a solution, and this way of administration has been tried by some specialists, he said.

The effects seem to be similar to systemic Avastin and comparable to those of intravitreal Lucentis, but presumably at a lower cost.

Further investigation of Avastin is needed to assess its safety and efficacy in larger series of patients over a longer period of time.

Future treatments

Dr. Lanzetta said that these are only a few of the new molecules that are currently being tested and produced as an alternative or complementary way of treating CNV. Among them are other VEGF antagonists such as VEGF-siRNA (Acuity Pharmaceuticals) and VEGF Trap (Regeneron), new steroids such as Posurdex (dexamethasone, Allergan) and Retisert (fluocinolone acetonide, Bausch & Lomb), other angiogenesis inhibitors such as PEDF (currently tested by GenVec) and Evizon (squalamine lactate, Genaera Corp.), or natural food supplements such as green tea.

“The research is also moving on to the investigation of safer and better ways of administering treatments. New delivery systems, systemic administration, cocktail therapy and other alternatives to intravitreal injection may be used in the near future. The number of treatments and the intervals between treatments are also a major issue,” he said.

The larger spectrum of choices for CNV treatment will also require more specific guidelines on indications.

“As new clinical trial data are published, the scenario will become progressively clearer. What we can say so far is that laser is still to be preferred in most cases of extrafoveal CNV lesions, while PDT and/or antiangiogenic agents can share the field of subfoveal and juxtafoveal lesions in a proportion that is yet to be found,” he said.

Antiangiogenic agents will become “part of the armamentarium to treat CNV and are turning our hopes to the new goal of improving rather than just stabilizing vision in these patients,” Dr. Lanzetta added.

For more information:

• Paolo Lanzetta, MD, can be reached at University of Udine, Department of Ophthalmology, Piazza S. Maria della Misericordia, 33100 Udine, Italy; +39-0432-559907; fax: +39-0432-559904; e-mail: paolo.lanzetta@uniud.it. Dr. Lanzetta has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

• Michela Cimberle is an OSN Correspondent based in Treviso, Italy, who covers all aspects of ophthalmology. She focuses geographically on Europe.