Pegaptanib finds roles in non-AMD retinal diseases

Studies show the selective anti-VEGF agent to have a beneficial effect in other retinal diseases, such as retinal vein occlusion.

The use of pegaptanib sodium for treatment of age-related macular degeneration fell last year with the introduction of alternative vascular endothelial growth factor inhibitors, but recent studies show that the drug has the potential to play a role in the treatment of other retinal diseases.

Carl D. Regillo

“We’ve known all along that VEGF inhibition was potentially good not only for wet AMD but for a variety of retinal applications, particularly diabetic retinopathy related manifestations such as macular edema and neovascularization,” Carl D. Regillo, MD, OSN Retina/Vitreous Section Member, told Ocular Surgery News. “It comes as no surprise to start to hear about these agents showing some benefits.”

The alternative uses of Macugen (pegaptanib sodium, [OSI]Eyetech/Pfizer) were discussed on the podium and at other venues during the American Academy of Ophthalmology annual meeting in Las Vegas. Its potential uses as a treatment for retinal disorders such as branch and central retinal vein occlusions, macular edema and diabetic retinopathy were discussed by a number of presenters.

“I think the impact of this drug is going to be very important,” said one of those presenters, Victor H. Gonzalez, MD, in a follow-up interview with OSN. “We’re looking at diseases that sometimes have no treatments. I think the applications of these medications are going to be very important.”

Retinal vein occlusion

One of the positive aspects of pegaptanib use in other diseases, such as retinal vein occlusion, is its rapid onset of action, some investigators said.

John A. Wells III, MD, FACS, presented a study of pegaptanib for treatment of central retinal vein occlusion (CRVO) in a poster at the AAO meeting and in a presentation at an OSI-sponsored event. He discussed its implications in a follow-up interview with OSN.

“For some reason not only in CRVO, but in BRVO (branch retinal vein occlusion) as well,” Dr. Wells explained, “there is this really rapid onset of treatment effect.”

The study Dr. Wells presented included patients with vein occlusions less than 6 months in duration and visual acuity between 20/50 and 20/400.

Over the course of 30 weeks, in which patients received injections of pegaptanib 0.3 mg or 1 mg or sham every 6 weeks, Dr. Wells said he observed improvement in visual acuity, reduction of macular edema and no adverse side effects.

“I know from this phase 2 trial that it has an effect,” he told OSN. “On average, if patients got the 1 mg dose of Macugen, which is not the commercially available dose, they gained 10 letters of vision at week 30 vs. losing three letters in the sham group. Even with the commercially available dose of 0.3 mg, they gained seven letters vs. losing three, so you still would have had a two-line gain compared to no treatment.”

In addition, Dr. Wells said, CRVOs often reached normalization of macular edema within 72 hours of injection. He said other colleagues had seen the same response in BRVO within 36 hours.

“I think uniformly, in all the patients with CRVO or BRVO that I’ve treated with Macugen, I’ve seen that,” he said.

Dr. Wells suggested that the rapid onset of effect may be because the cause of vision loss in CRVO is cystoid macular edema in the neurosensory retina, which the medication can reach quickly after intravitreal injection. He also suggested that AMD is a more complex disorder, with more causes of vision loss for the drug to address, such as macular edema, subretinal fluid and hemorrhage, photoreceptor loss, retinal pigment epithelium damage, and pigment epithelial detachment.

“Maybe retinal vein occlusion is just a much more simplistic disorder,” he said.

In addition, Dr. Wells said, pegaptanib could theoretically be a safer treatment. The selective action of pegaptanib could, in theory, pose less threat to nerve fibers in the retina than less-selective VEGF blockers.

Pegaptanib selectively inhibits the isoform VEGF-165, he noted, whereas the other VEGF inhibitors currently in use for retinal disorders, ranibizumab and bevacizumab, inhibit all known forms of VEGF-A.

“VEGF has a lot of effects, not just bad ones, but good ones too,” Dr. Wells said. “The concern is, if you block all VEGF in this condition you may actually exacerbate tissue damage because VEGF is known to have some neuroprotective effects. So selective VEGF inhibition looks very attractive.”

Dr. Wells noted that there is no evidence that blocking all isoforms of VEGF in the eye is harmful, but it is a theoretical concern.

“If I saw a patient with a central retinal vein occlusion and cost were not an issue, my treatment of choice would be Macugen,” he said. Unfortunately, cost is a factor, and Dr. Wells said many patients are not able or willing to pay for this off-label use of the drug.

Diabetic macular edema

Also at the AAO meeting, Neil M. Bressler, MD, reported the results of a phase 2 randomized clinical trial of pegaptanib for the treatment of macular edema.

Dr. Bressler presented 36-week data from a study in which subjects were randomly assigned to one of three doses of pegaptanib or sham injection. The study included 172 subjects with diabetic macular edema at 39 participating centers. The results have been published in Ophthalmology.

The treatment or sham was repeated at week 6 and week 12, and then, at the investigator’s discretion, additional injections could be given at weeks 18, 24 and 30. The primary outcome was at week 36, and follow-up continued through week 52.

The results showed outcomes that support further study of anti-VEGF drugs for the treatment of diabetic macular edema, Dr. Bressler said.

“The mean visual acuity changed, with somewhat better results in the pegaptanib group by week 36,” he said. “The five-letter mean gain at week 36 suggests that there might be a beneficial effect on visual acuity for these subjects.”

The evidence that the effect was not sustained was suggested by the decrease in average visual acuity after the injections were completed at week 30.

In addition, there was an average 50 µm to 75 µm change in mean center point retinal thickness in the treatment groups vs. no change in the sham group. Fluorescein leakage from retinal neovascularization also diminished or resolved at week 36 in some of the pegaptanib-treated subjects, but not in sham-treated subjects. Also, no adverse effects on diabetic retinal vessels were identified after week 36, he said.

“This study was not designed to determine if pegaptanib should now be given for treating diabetic macular edema,” Dr. Bressler explained. “The study was designed to determine if an anti-VEGF drug, such as pegaptanib, should be considered for further trials in the treatment of macular edema. This trial did indeed show that the retinal thickness from diabetic macular edema decreased to a greater extent, on average, in the pegaptanib-treated studies compared with sham-treated subjects. However, the study design and numbers of cases evaluated are too small to know if this outcome is definitively better than focal photocoagulation alone.”

Dr. Bressler suggested further study of anti-VEGF drugs in the treatment of diabetic macular edema.

Regression of neovascularization elsewhere can be seen by week 36 of pegaptanib therapy, when treatment is stopped. Recurrence is seen at week 52. Images: Gonzalez VH

Proliferative diabetic retinopathy

Dr. Gonzalez said that, after seeing the results of the phase 2 study described above, he and colleagues undertook a pilot study of the effect of pegaptanib on proliferative diabetic retinopathy.

“Our group asked the question, ‘What would happen if you used the drug in patients who have active proliferative disease?’” Dr. Gonzalez said.

In presentation at the AAO and at an OSI-sponsored event during the AAO meeting, he presented interim results of this small study in 10 patients receiving pegaptanib for the treatment of diabetic retinopathy.

In the study, 0.3 mg of pegaptanib was injected every 6 weeks for 30 weeks, at which time the patients were evaluated for visual acuity and level of neovascularization. If neovascularization was not reduced at least 50% by week 3, the patient was offered panretinal photocoagulation (PRP).

“The earliest time point that we had fluorescein angiography was at 3 weeks, but clinically we could tell within a week or so that there had been significant changes in the neovascular membrane,” Dr. Gonzalez told OSN. “We could tell that the membrane was beginning to regress, and by the third week when we did the fluorescein, it was ‘wow.’ It was unbelievable how well this drug had caused regression of the neovascular membrane.”

In nine of 10 patients treated, neovascularization completely resolved at week 3, and the other patient showed about 90% regression, Dr. Gonzalez said. None required PRP.

“The interesting finding, also, was the fact that there was a mean improvement in the visual acuity,” he said.

“It appears that 0.3 mg of pegaptanib stabilizes or improves visual acuity, induces significant regression of the proliferative neovascular membrane, improves the ETDRS severity indices, and has a favorable safety profile in these diabetic patients,” Dr. Gonzalez said. “The response to the drug is rapid and detectable as early as 3 weeks after the intravitreal injection.”

Given these results, Dr. Gonzalez said, he hoped pegaptanib therapy could decrease the number of laser treatments needed to manage high-risk diabetic patients.

“We have a proven therapy for both macular edema and proliferative diabetic retinopathy, which is laser, but laser therapy is not without side effects,” he said. Laser patients can experience metamorphopsia, loss of peripheral or night vision, or a decrease in visual acuity or teleperception, he said.

If pegaptanib continues to be effective in larger studies, its use instead of laser could improve patients’ quality of life, Dr. Gonzalez suggested.

“You can have a patient who is 20/20 but has a visual field of 20° because of heavy peripheral laser. Is that patient going to be more functional than a patient who is 20/25 and has a more normal visual field?” he asked. “While we’ve been comfortable with laser and it works well, the challenge now is for us to control this disease and decrease severe vision loss and at the same time preserve some of the patient’s function.”

Currently, Dr. Gonzalez said, he and colleagues are enrolling patients for a study of dosing, timing and possible combination of pegaptanib with laser treatment for proliferative diabetic retinopathy.

“We don’t think we will necessarily be able to eliminate laser altogether, but I think in combination with laser, especially more selective laser, just going after areas that have the ischemia, we may be able to decrease the side effects caused by the laser,” he said.

Macugen progresses in Europe by Andy Moskowitz Pfizer, which holds exclusive international rights to Macugen (pegaptanib, OSI/Pfizer), has begun gradually rolling it out across Europe. By January, Pfizer expected the drug to have been launched in Spain, France, Italy, the United Kingdom and Germany, according to a company representative. “Pfizer Ophthalmology is committed to ensuring the best level of care to preserve and protect a patient’s sight; therefore, ensuring the availability of and access to Macugen across Europe is our No. 1 priority,” the representative told Ocular Surgery News. Macugen has faced reimbursement challenges in a number of European countries despite being approved by the European Medicines Agency in September and European Commission in February. According to a recent survey conducted by the AMD Alliance UK, for example, 90% of Primary Care Trusts in England have not offered funding for the drug to National Health Service patients. In an effort to demonstrate Macugen’s efficacy to European physicians, Pfizer is currently enrolling patients in a number of European studies, including a phase 4 study of pegaptanib sodium for the preservation of visual function in subjects with early neovascular AMD. The purpose of these studies is to “build the product’s dataset, ... potentially extend the product license [and] to show how specific VEGF inhibition can effectively and safely help thousand more patients,” according to the Pfizer representative. The Scottish Medicines Consortium has recommended that the drug be accepted for “restricted use, in all lesion sub-types.” A similar authority in Spain “agreed with the cost/efficacy rationale of Macugen for patients treatment,” the Pfizer representative said. Pfizer has been running an extensive “unmet medical need” initiative in countries where the drug has yet to be approved to ensure that patients begin treatment during the early stages of the disease. “As in the U.S., we recognize that patients appear to respond better when treated earlier, and we have the advantage that we can share these learnings from the widespread use in the U.S.,” the Pfizer representative said. Lucentis approval pending Although Macugen is currently Europe’s only approved VEGF inhibitor for the treatment of age-related macular degeneration, the drug will soon face competition from Lucentis (ranibizumab, Genentech/Novartis), which in November was recommended for approval by the EU’s Committee for Medicinal Products for Human Use. Final approval typically follows a few months after the recommendation, according to a press release from Novartis Pharma AG, which will market the drug in Europe. “It should be expected that Lucentis may face similar reimbursement challenges to Macugen across Europe,” the Pfizer representative said.

For more information:

• Carl D. Regillo, MD, can be reached at the Retina Service, Wills Eye Hospital, 840 Walnut St., Suite 1020, Philadelphia, PA 19107; 856-755-1278; fax: 856-667-9082; e-mail: cregillo@aol.com. Dr. Regillo has received research funds from, and consulted for, Genentech, OSI, Novartis and QLT.
• Victor H. Gonzalez, MD, can be reached at 1309 East Ridge Road, Suite 1, McAllen, TX 78503; 956-631-8875. Dr. Gonzalez is a consultant for (OSI)Eyetech. He has no direct financial interest in the products mentioned in this article.
• John A. Wells III, MD, FACS, can be reached at Palmetto Retina Center, 2750 Laurel St., Suite 101, Columbia, SC 29204; 803-931-0077; fax: 803-931-0076; e-mail: jackwells@palmettoretina.com. Dr. Wells has served as a consultant and on the speaker’s bureau for OSI and Pfizer and has been paid honoraria and travel expenses by both. He has no direct financial interest in the drugs discussed in this article.
• Neil M. Bressler, MD, is the James P. Gills Professor of Ophthalmology at the Wilmer Eye Institute of Johns Hopkins University. He can be reached at 550 North Broadway, Suite 115, Baltimore, MD 21205; e-mail: nmboffice@jhmi.edu. Johns Hopkins University, but not Dr. Bressler, receives funding from Genentech, Novartis, OSI, and other companies for sponsored projects. Under the university’s policy, support for the costs of research, administered by the institution, do not constitute a conflict of interest.

• (OSI)Eyetech, the maker of Macugen, can be reached at 3 Times Square, 12th Floor, New York, NY 10036; 212-824-3100; fax: 212-824-3101; Web site: www.macugen.com.

References:

• Adamis AP, Altaweel M, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology. 2006;113:23-28.
• Gonzalez VH, Macugen Diabetic Retinopathy Study Group. Pegaptanib in diabetic retinopathy: Improvements in diabetic macular edema, retinal neovascularization and diabetic retinopathy severity. Paper presented at: American Academy of Ophthalmology annual meeting; November 12, 2006, Las Vegas.
• Wells JA III, Pegaptanib in Central Retinal Vein Occlusion Study Group. Safety and efficacy of pegaptanib sodium in treating macular edema secondary to central retinal vein occlusion. Poster presented at: American Academy of Ophthalmology annual meeting; November 11-14, 2006, Las Vegas.

• Katrina Altersitz is an OSN Staff Writer who covers all aspects of ophthalmology.