The advanced or “wet” form of age-related macular degeneration is characterized by the growth of abnormal blood vessels. This is sometimes referred to as “choroidal neovascularization” or CNV. Although there can be several types of CNV (subfoveal, classic, occult), the characteristics are similar. These blood vessels begin to leak fluid and blood which dries and forms a “disciform” scar. This scarring destroys central vision and the eye is left with peripheral vision only.

Until recently the only available treatment to seal these leaking vessels was with a laser. The best known treatment is Photodynamic Therapy (PDT) with Visudyne® (a drug injected intravenously and used to help direct the laser to the affected area) and was not suitable for all types of lesions. The cost of one treatment averages about $3,000. The blood vessels may again begin to leak and further treatment may be required. The laser treatment itself may cause scarring. Researchers and physicians have looked for a follow-up to this treatment that might maintain vision for a longer period of time without repeated laser use. They are also looking for new therapies which would be effective for all types of wet AMD.

One line of thought stems from work done into cancer research and the causes of angiogenesis – the growth of new blood vessels. It was discovered that there is a protein in the eye which encourages the development of blood vessels called “vascular endothelial growth factor” (VEGF) and drugs are being developed to inhibit VEGF by trapping it or preventing it from binding with elements which will stimulate growth. Chemically synthesized short strands of RNA (nucleic acid) called “aptamers” prevent the binding of VEGF to its receptor.

The most publicized anti-VEGF drug is Macugen (pegaptanib sodium injection), developed by EyeTech Pharmaceuticals and licensed in conjunction with Pfizer. It is an aptamer which binds to the VEGF 165 protein and was approved by the FDA on December 20, 2004 for all types of wet macular degeneration.

Macugen is an intravitreal injection, an injection directly into the vitreous of the eye, which is repeated every six weeks. During clinical trials, patients injected with Macugen showed less vision loss that those who received a placebo injection. Macugen is by prescription delivered only by an ophthalmologist or retinal specialist in the doctor’s office. Results will vary with each individual and your physician will determine the length of treatment based on a case by case basis. Side effects may result from the injection process and should be discussed with your physician before therapy.

Macugen is used to treat active choroidal neovascular tissue and not the bleeding itself. If a patient has been declared “legally blind,” treatment may still be of value to arrest any further deterioration, but usually will not lead to restoration if associated with profound loss due to atrophy. When leakage is shown to be present, Macugen can be used to decrease the leakage and secondarily the bleeding.

There has been no data for the use of Macugen in the following related eye diseases. Bleeding is not usually associated with Stargardt’s disease but growth of new blood vessels rarely may occur after blunt trauma. In theory, those with Best’s disease who develop CNV may benefit from the use of Macugen. As retinitis pigmentosa (RP) is a degenerative disease not associated with CNV, there are no indications that Macugen would be useful.

There are no contraindications for the use of Macugen for patients with glaucoma who develop wet macular degeneration. Eye pressure is monitored closely after injection and is usually transient.

For those suffering with diabetic macular edema, a Phase 2 clinical trial reported in the October 2005 issue of Ophthalmology showed that those treated with Macugen were more likely to have a reduction in swelling and less likely to need additional laser therapy than those with sham injections. A study for the use of Macugen for macular edema from central retinal vein occlusion (CRVO) has completed enrollment but results have not yet been reported.

Clinical trials are underway to evaluate the use of Macugen in combination with Photodynamic Therapy versus the use of Macugen alone.

Ongoing clinical trials with pegaptanib sodium (Macugen):

• Pegaptanib Sodium (Macugen) Compared to Sham Injection in Patients with Diabetic Macular Edema (DME) Involving the Center of the Macula - ClinicalTrials.gov identifier NCT00148811. Call 866.MACUGEN (866.622.8436).
• A Clinical Trial to Compare the Safety and Efficacy of Macugen (Pegaptanib Sodium) Alone, Vs Macugen in Combination with PDT (Photo Dynamic Therapy) with Visudyne (Verteporfin) in Patients with AMD - ClinicalTrials.gov identifier NCT00134667. Call 866.MACUGEN (866.622.8436). Patients must not have had previous PDT in study eye.

At present there is no national listing of physicians who are prescribing Macugen. You must ask your doctor if he is providing the therapy. The cost of Macugen is close to $1,000 per injection. Medicare will cover 80% of each injection with an allowable cost of $1,054.70 for patients who meet the FDA approved diagnosis.

MAP, the Macugen Assistance Program, is available to help patients deal with insurance coverage. Information about enrollment in the program is available at 866.272.8838. For medical information about Macugen, call 800.438.1985 and select option #6.

There are other anti-VEGF drugs mentioned in the news that have not received FDA approval. These are Avastin and Lucentis from Genentech; Retaane from Alcon; and an intravenous injection from Geneara Corp.

Lucentis (ranibizumab) originally made the news as rhuFab. Promising results from the first year indicated that many patients’ vision not only stabilized but may have actually improved. Lucentis is injected directly into the eye. Four different studies with Lucentis are ongoing and have completed enrollment.

In July 2005, one-year results of two clinical trials of Lucentis were presented at meeting of the American Society of Retinal Specialists. The first, named MARINA, compared two different dosages (0.3mg and 0.5 mg) of Lucentis with a sham injection. 716 patients with minimally classic or occult lesions were enrolled. Regardless of the dosage, a quarter of patients treated with Lucentis had an increase in visual acuity, while those who received the sham injection had a loss. The second clinical trial reported at the ASRS meeting, FOCUS, consisted of 162 patients with predominantly classic subfovel wet AMD. Some received Lucentis injections in combination with Photodynamic Therapy (PDT). Others were given sham injections along with PDT. 25% of patients who received Lucentis in combination with PDT showed a gain in visual acuity while only 5% in the control group had improvement.

“...Patients treated with Lucentis not only experienced an improvement in vision, but were significantly less likely to require retreatment with PDT during the first year of the study,” said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer. Another larger trial using Lucentis alone has shown that vision may improve compared with sham injections.

The PIER study is evaluating less frequent dosing of Lucentis. 184 patients with all types of lesions received either the 0.3 mg or the 0.5 mg injection. Three monthly injections are followed by quarterly dosing for 24 months. Data is anticipated in the first half of 2006.

In the ANCHOR study, 423 patients with predominantly classic subfoveal lesions received 24 monthly intravitreal injections of either the 0.3mg dose or the 0.5 mg dose, or Photodynamic Therapy. Complete data is yet to be reported.

A larger study, SAILOR, is recruiting patients that will evaluate the safety of the two different dosages.

• A Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization (CNV) Secondary to Age-Related Macular Degeneration (AMD) - A 5,000 patient PhaseIIIb study for all types of wet AMD has now begun enrollment. All patients will receive Lucentis. Call 1.888.662.6728 for more information. Please refer to this study by ClinicalTrials.gov identifier NCT00251459

Genentech, who has partnered with Novartis (the manufacturer of Visudyne® used in Photodynamic Therapy), plans to seek FDA approval for Lucentis at the end of this year (2005).

Side effects of intravitreal injections may include:

• Serious eye infection that may include eye pain, light sensitivity, vision changes.
• Increased eye pressure
• Retinal detachment
• Vitreous floaters
• Consult with your retinal specialist to make certain you understand what all the side effects might be.

Philip J. Rosenfeld, MD, PhD. and the Bascom Palmer Eye Institute (University of Miami) are researching the use of Genentech’s Avastin (bevacizumab), a drug which is FDA approved for colorectal cancer only. (This is an “off-label” use of Avastin, which is not manufactured to meet ophthalmic standards.) This is intravenous rather than intraocular injection. It inhibits blood vessel growth and may improve vision within one week. No large randomized trials are being done at present.

The FDA has issued a caution that Avastin, when used to treat cancer patients, has been shown to increase risk of stroke and heart attack. Patients who are receiving blood thinning agents, included aspirin, must be precluded from using Avastin. Any patient with any history of abnormal blood chemistry and urinalysis must be excluded from using this drug the researchers cautioned.

Geneara Corporation is investigating the intravenous use of squalamine lactate as a safe and effective treatment of CVN. A small trial headed by Charles A. Garcia, M.D., a consultant for Geneara, conducted a trial with 40 patients who had both classic and occult wet AMD. Improvement in vision in some patients appeared within one week of injection, and leakage and blood were reduced. Originally planned for a much longer time period, infusion time decreased to about 45 minutes at the end of the study. A larger trial is required and is now recruiting.

• A Safety and Efficacy Study of Squalamine Lactate for Injection (MSI-1256F) for “Wet” Age-Related Macular Degeneration ClinicalTrials.gov identifier NCT00139282 Jamila Watkins 800.299.9156

Retaane® (anecortave acetate suspension), not technically an anti-VEGF drug, is an angiostatic cortisone. It is delivered behind the eye not into the eye itself and therefore avoids the risks associated with intraocular injections. Alcon has conducted trials over the past five years. One trial showed that patients maintained their vision as compared with those who received the sham dosage. The second compared Retaane to PDT with Visudyne®, with similar results.

• Open-Label Posterior Juxtacleral Injections of Anecortave Acetate 15mg Dose for Long Term Use in Patients with AMD Please refer to this study by ClinicalTrials.gov identifier NCT00065728, Alcon Call Center 866.692.5959, wetamd@inveresk.com, Alcon Clinical 817.568.6747, intldev@alconlabs.com
• Treatment of Retinal Vein Occlusion (RVO) with Open-Label Anecortave Acetate (15mg.) ClinicalTrials.gov identifier NCT00211354 New York, Manhattan Eye, Ear & Throat Hospital, New York, NY 10021, Leandro Maranan 212.605.3777, lmaranan@retinal-research.org, Lawrence A. Yannuzzi, MD, Principal Investigator

-- Massachusetts Eye and Ear Infirmary, Genentech Corp., www.macugen.com, www.clinicaltrials.gov, Ophthalmology Times, BioWorld Online, Alcon, Inc.

A note from the American Macular Degeneration Foundation

For those of you who have been diagnosed with macular degeneration, this can be a confusing and frightening time. Your visit to the doctor may leave you stunned and unable to comprehend just what is happening to your vision or the options that are available to you. If it is possible for you to bring a family member or friend with you to your office visits, please do so. They can help you understand what has been said when you return home.

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