EyeNet Magazine

News in Review

Drug Finds New Use in Treatment of Uveitis

Cancer Drug Is First VEGF Blocker to Market

Types, Levels of VEGF Are Key

Cataract More Prevalent in Blacks Than Whites 

A Simple Solution

Drug Finds New Use in Treatment of Uveitis

Wherever it is in the body, chronic inflammation causes damage to living tissue. But when the site is the eye, the outcome can be particularly catastrophic.

So there was excitement at the National Eye Institute, after publication several months ago of results of a small NEI clinical trial showing that a powerful immunosuppressant, normally used after organ transplants, can control chronic uveitis with fewer side effects than standard therapy.1

That news came not long before an epidemiological study, done with the help of Kaiser Permanente’s extensive database in California, delivered some surprises about who gets uveitis and at what age.2

The drug, daclizumab (Zenapax), is a humanized monoclonal antibody to the interleukin-2 alpha receptor. In recent years, it has been tested against a variety of autoimmune diseases, including psoriasis, ulcerative colitis and the subepidermal blistering disease epidermolysis bullosa acquisita.

“Daclizumab offers the promise of a safe, well-tolerated and effective long-term therapy for uveitis. We are now in the planning stages to begin a larger clinical trial to compare standard therapies with daclizumab,” said Paul A. Sieving, MD, PhD, director of the NEI.

The director of NEI’s immunology lab, Robert B. Nussenblatt, MD, was the lead author on the paper. He is widely known as an expert in uveitis and its possible therapies. In addition to comparing daclizumab to corticosteroids and methotrexate, Dr. Nussenblatt said the NEI Clinical Research Center also will do further studies of administering the drug via subcutaneous injections.

In the recently reported study, seven patients received 1 milligram/kilogram of daclizumab intravenously every two to six weeks for up to four years. (Three other patients dropped out of the study, two because of uveitic flare-up about a year after beginning, and one because of progression of a choroidal neovascular membrane.) After four years, five of the remaining patients entered a Phase 1 safety trial for receiving the drug via subcutaneous injection.

“Patients who were receiving the infusions converted over to the subcutaneous injections, tolerating this very well,” Dr. Nussenblatt said. “This is important since it simplifies administration quite a bit and is cheaper, and long-term patients then could administer [it] themselves at home.”

In a few cases, a patient’s disease flared when the dosing intervals were stretched to six weeks. When that happened, a short course of corticosteroid therapy was used to end the flare-up, then the daclizumab was substituted again. The researchers speculated that the inflammation flared because with six-week dosing the IL-2 alpha receptors were no longer saturated with the antibody.

No patient had to discontinue therapy because of side effects, and participants experienced no increase in infections. That contrasts with an early trial of cyclosporine for uveitis two decades ago, in which a third of patients had to drop out because of side effects and only 63 percent of the remainder were considered a therapeutic success.3

As Dr. Nussenblatt’s group demonstrated this new therapy, epidemiological research that was published in Ophthalmology concluded that uveitis is three times more prevalent than previously thought, and that both incidence and prevalence increase with age, with the highest ongoing prevalence in women.

The study concluded that incidence of uveitis was 52.4 per 100,000 person-years, and the prevalence over the one-year study period was 115.3 per 100,000 persons. If applied nationwide, this would yield an annual incidence of 280,000 uveitis cases in the United States. Rates were highest in people over 65 years of age—compared with the 25-to-44-year- old age group that until now had been thought to be most at risk.

“Their analysis raises very important issues that all of us have missed before,” said Ivan R. Schwab, MD, director of the cornea and external disease service at the University of California, Davis. “This is a surprise to all of us who work in the field and is important information.”

1 Nussenblatt, R. B. et al. J Autoimmun 2003;21:283–293.
2 Gritz, D. C. and I. G. Wong. Ophthalmol 2004;111:491–500.
3 Nussenblatt, R. B. et al. J Ocul Pharmaco 1985;1(4):369–382.

Retina Update
Cancer Drug Is First VEGF Blocker to Market
The recent approval of a VEGF-blocking drug to treat cancer is a milestone not just for oncology but also for ophthalmology. The reason: the new cancer-fighter is a very close cousin to a drug in the pipeline to become a therapy for AMD, Lucentis.

The FDA approved Genentech’s Avastin (bevacizumab) in March for metastatic colon cancer, bringing to market the first medication based on the burgeoning science of halting disease by shutting down blood vessel growth. Based on the same principle, Lucentis (ranibizumab) currently is in Phase 3 trials for treatment of AMD.

“Lucentis is a humanized, affinity-matured—that is, improved—fragment of Avastin,” said Peter K. Kaiser, MD, a retinal specialist and director of the clinical research center at the Cleveland Clinic’s Cole Eye Institute. “Since it is a fragment, it is small enough to be injected into the eye and to cross the retina to the subretinal space where the choroidal neovascularization occurs.”

Phase 1b/2 results with Lucentis showed patients gaining an average of 12.8 to 15 letters of visual acuity at 210 days, compared with a loss of 5.1 letters at day 98 in control patients who received only photodynamic therapy. When the latter patients were switched to Lucentis, they regained an average of 7.3 or 3.2 letters from the original baseline, depending on the dosage.

Macugen (pegaptanib sodium) also blocks VEGF, the growth factor that has been the “hot” target of AMD researchers for several years. The drug’s Phase 3 results, reported at the Academy meeting last fall, could lead to FDA approval late this year.1

Still unsettled is whether a shotgun (Lucentis) or targeted (Macugen) approach to blocking VEGF is better, Dr. Kaiser said.

“Lucentis binds all isoforms of VEGF. Macugen is an aptamer against VEGF-165 only,” he said. “It is felt that the most pathologic form is VEGF-165, but the other forms play an unclear role in the pathology of AMD and diabetic retinopathy.”

However the details turn out, this approach is exciting to CNV researchers like Dr. Kaiser. “I think this approach is excellent and holds great promise for neovascular conditions,” he said.

1 See April 2004’s “Macugen Ups the Anti-AMD Ante” at www.eyenetmagazine.org.

Angiogenesis Report
Types, Levels of VEGF Are Key
The results of a Stanford University study suggest that it won’t be necessary to block every molecule of VEGF to stop aberrant angiogenesis. The group of researchers has found that tissues can be swimming in some types of VEGF without problems, but just a little bit of another type will trigger problem angiogenesis.

The discovery came from manipulating the amounts and types of VEGF being expressed by myoblasts implanted into transgenic mice. Hemangiomas formed when even just a few cells in a localized cell population were overexpressing VEGF. However, large populations of cells could be expressing low to medium levels of VEGF—for a large total production—with no untoward effect.1

“Long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal angiogenesis without other exogenous growth factors,” conclude the researchers, who want to find ways to repair damaged heart muscle with VEGF.

Senior author Helen M. Blau, PhD, an expert on angiogenesis who directs the Baxter Laboratory for Genetic Pharmacology at Stanford, said the research contains good news for stopping CNV with anti-VEGF drugs.

“It overcomes some of the problems of VEGF dosage, because the dosage of the antidote is not so critical,” said Dr. Blau. “You’re much less likely to have to worry about dosage at microenvironmental levels. It would affect the vessels that are immature but not the mature vessels, so you would still have the vessels that you need.”

1 Ozawa, C. R. et al. J Clin Invest 2004;113:516–527.

Eye on Research
Cataract More Prevalent in Blacks Than Whites
Over nine years of follow-up in the Barbados Eye Studies, blacks were twice as likely to develop lens changes of any type than were whites, according to the latest report from the long-running study.1

Cortical cataract was the most common to develop among the 2,008 black participants, occurring at 300 percent the rate seen among whites, the research found.

“This high risk may be related to the higher prevalence of diabetes, abdominal obesity and hypertension in black than white populations. Modifying these conditions could perhaps modify the risk of cortical cataracts, but that is not proven,” said the study’s senior author, M. Cristina Leske, MD, MPH, professor of preventive medicine at Stony Brook School of Medicine.

In addition, the occurrence of nuclear cataracts was higher over nine years than researchers had expected, based on how low the incidence had been at the four-year data point (40 percent at nine years, vs. 9 percent at four).

The high rates have significant implications for the ophthalmic community, Dr. Leske said. “Since cataracts are the main cause of blindness throughout the world, the public health implication is that we need to address this major problem, which particularly affects black populations, by providing adequate surgical treatment.”

1 Leske, M. C. et al. Ophthalmol 2004;111:483–490.

Additional citations are as follows:
Berson, D. M. et al. Science 2002;295(5557):1070–1073.
Brainard, G. C. et al. J Neurosci 2001;21(16):6405–6412.
Gooley, J. J. et al. Nat Neurosci 2001;4(12):1165
Hannibal, J. et al. J Neurosci 2002;22(1):RC191(1–7)
Hattar, S. et al. Science 2002;295(557):1065–1070.

Glaucoma Compliance
A Simple Solution
The phenomenon of poor patient compliance might have met its match: the simple idea of coloring bottle tips black.

That news comes from a study in which clinicians at a New Zealand hospital wrapped black, sterile tape around the tips of glaucoma medication bottles (timolol maleate) and gave them to 40 patients.1 A month later, Malcolm J. McKellar, FRANZCO, and Rebecca R. Stack, MB, ChB, asked the study participants to rate their experiences.

Patient preference was overwhelmingly in favor of the black tip, compared with the standard white or clear tip.

Survey results were as follows:

  • 38 (95 percent) found the black tip easier to see.
  • 35 (87.5 percent) were more likely to use their drops as often as their ophthalmologist had prescribed.
  • 27 (67.5 percent) experienced fewer instances of having to instill a second or third drop because the first one missed its target.
  • 12 (30 percent) touched their eye or eyelid less often with the bottle tip.
  • 6 (15 percent) volunteered that their medication lasted longer when they were using the black tip.

The Christchurch Hospital researchers suggest that the contrast between a black tip and a white bottle overcame the poor contrast sensitivity that occurs in aging patients.

They urged manufacturers to take note. They write: “A change to dark coloured tips should lead to an increase in patient compliance, less wastage of eye drops and less contamination of both eye drop bottles and the patient’s eye.”

1 Clin Exper Ophthal 2004;32: 39–41. 

News compiled by Linda Roach.

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