SUBSPECIALTY NEWS

Better Home Tests for AMD

Web-based Checkup Offers Greater Convenience.

JERRY HELZNER, SENIOR EDITOR

■ Richard Trevino, OD, thinks that a home test for macular degeneration can be "engaging, interesting, informative, and perhaps even fun. The traditional Amsler grid is none of those."

Dr. Trevino, who is employed by the Veterans Administration in Evansville, IN, is among those who have recently been working on new home tests for macular degeneration that can either replace or be used as a supplement to the Amsler grid.

Dr. Trevino has put two new tests that he has created on a free Web site whose address is MyVisionTest.com. On the site, he provides a tutorial with complete instructions on how to take both tests, plus an automatic scoring system that immediately delivers the results. Ophthalmologists may want to check out the site before recommending it to their patients.

In addition to Dr. Trevino's efforts at creating new home-based tests, the Foresee Home AMD Monitor, developed by Notal Vision and being distributed by Sightpath Medical, will soon be introduced. The Foresee Home test lasts 3 to 5 minutes per eye, measuring 500 retinal data points covering the central 14 degrees of the macular visual field. The patient's response patterns are automatically recorded, analyzed, and compared to the patient's previously established baseline, producing a visual field map and report revealing the relative location and intensity of defects in the macular area.

Moreover, citing a high incidence of negative results using the classic Amsler grid, Lars Frisén, MD, PhD, of the University of Gothenburg, Sweden, has created a new version of the grid using computer technology, dubbed "MacuFlow." Although further assessment is needed, initial evaluations of simulated scotomata and metamorphopsia using the updated grid showed promising results.

Dr. Trevino welcomes the other innovators, whom he views as complementary rather than competition.

"I encourage my users to test their vision in a variety of ways," he says. "It is possible that, for a given patient, certain vision defects may be detected earlier on one test or another. By checking their vision in a variety of ways they will be more likely to detect a change, should it occur."

In comparing his test to the Amsler, Dr. Trevino says one of the key differences is that MyVisionTest provides a permanent record of each test session, making it easier to detect change over time. Each time a user takes a test on the Web site, the results are saved. If an apparent worsening occurs, the patient is alerted to this fact. In addition, the results can be easily downloaded to their computer as a PDF file then e-mailed to their doctor, or printed out.

In describing his two Web-based tests, Dr. Trevino notes that one of the tests is more difficult for home use than the other.

"I developed an entoptic perimetry test that was based upon the original research of Plummer, Crossland and others," he notes. "The research on this technology is very encouraging. Essentially, the patient is asked to stare at a field of video static and then attempts to perceive any scotomas that may be present. The perception of the scotomas can be enhanced using the ‘twinkle after-effect.’ Unfortunately, the subjective appreciation of scotomas is completely foreign to most patients, making it difficult for many patients to understand and perform the test in an unsupervised home setting."

As an alternative, for patients who have difficulty performing entoptic perimetry, Dr. Trevino has adapted the Macular Mapping Test, originally developed by MacKeben, for self-assessment of vision over the Internet. This test is essentially traditional supra-threshold perimetry of the central visual field.

"Research by Bartlett and Trauzettel-Klosinski indicated the potential suitability of this test for macular function self-assessment," he says. "My users seem to prefer it to my original entoptic perimetry vision test, apparently because it is easier to understand and use."

Dr. Trevino says he will continue to work on his online tests, which are "complete departures" from grid-based tests, to improve them and make them more user friendly.

A siRNA Pioneer Looks Ahead

Dr. Tolentino Seeks "Next Big Thing."

JERRY HELZNER, SENIOR EDITOR

■ If anyone has the pedigree to conduct advanced research in retinal therapies, it's Michael Tolentino, MD.

His father, Felipe Tolentino, MD, is a leading vitreoretinal surgeon who played a key role in developing the vitrector. The younger Dr. Tolentino spent five years studying in Dr. Judah Folkman's research lab at Harvard Medical School, enabling him to be present at the creation of the first generation of anti-VEGF drugs. Moving on to the University of Pennsylvania, Dr. Tolentino co-developed bevasiranib for wet AMD, the first siRNA drug to reach a phase 3 clinical trial, and helped found Acuity Pharmaceutical.

These days Dr. Tolentino, 42, can be found in practice at the Center for Retinal and Macular Disease, based in Winter Haven, FL. He has easily made the transition from research scientist to practitioner. But he is also designing and participating in clinical trials for potential retinal therapies, waiting to commit his full energies to what he calls "the next big thing."

"I chose a career in medicine because I wanted to help people," says Dr. Tolentino. "In research, I was making a contribution at the macro level. By taking drugs from the bench to the bedside, I can now see them work on a day-to-day basis while advancing the clinical end of the process. It's really rewarding."

Dr. Tolentino speaks with a tinge of disappointment about the current limbo status of bevasiranib, which had a stellar phase 2 study before Acuity was sold to newly formed Opko Health. Opko recently terminated the phase 3 study of bevasiranib, alluding to a failure to meet efficacy hurdles.

"Opko gave us a good deal when it bought the drug," he notes. "I had no say in designing the phase 3 study. I can only say that Opko's phase 3 was not designed to optimize the benefits of bevasiranib."

Michael Tolentino, MD

Dr. Tolentino asserts that VEGF "is a very hardy molecule" and says the key to a successful bevasiranib trial would have involved eliminating all of the pre-existing VEGF, which persists for a minimum of 6 to 8 weeks.

"Designing clinical trials is an art," he says. "I would have designed it differently. I have to say that I was shocked when they stopped the study. It's almost unprecedented. There were no safety issues and the study was completely enrolled."

Dr. Tolentino says that the future of bevasiranib "is all in Dr. [Philip] Frost's hands." (Dr. Frost is the Opko CEO). "It's all up to him, but I'd be happy to help out."

Asked about the skeptical views of Jayakrishna Ambati, MD, PhD, of the University of Kentucky Medical School, regarding 21-nucleotide siRNAs such as bevasiranib, Dr. Tolentino chooses his words carefully.

"Jay is a good friend," he begins. "He's designing his own siRNAs. We did studies at Acuity and Opko that contradict a lot of what he's been saying."

Dr. Tolentino views Dr. Ambati as being "very good at targeted big science. He tries to break dogma and is comfortable with controversy."

Dr. Tolentino has spent the past few years expanding his skillset. In addition to his already strong credentials as a scientist, he is now comfortable with such key areas as patents and financing. He is putting himself in a position to start a company if the opportunity arises.

"I would love to commit to one therapy if I believe it is outstanding," he says. Having taken both VEGF and siRNAs from invention to advanced clinical trials, he feels he'll be able to recognize and help develop the next big thing. "I've seen some therapies that are promising, but nothing that I would say is the next category killer like Lucentis has been."

Dr. Tolentino is convinced that VEGF is the right target for potential therapies for retinal disease.

"The next big drug may be a maintenance treatment," he says, "an enhancer, or a therapy that will reduce the number of treatments. It may involve a new method of delivery, such as an eye drop."

Whatever it is, you can be sure that Dr. Tolentino will know it when he sees it.

The Latest on Lucentis

Vision Gains Reduced With PRN Treatment.

RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

■ Recently released ranibizumab study results, including the longest-term data to date, continued to validate the safety and effectiveness of the drug. However, the key HORIZON study indicated that much of the gain in visual acuity (VA) achieved over 2 years following a monthly dosing regimen was lost in the following 2 years with a PRN dosing regimen.

Another study, conducted by Ivan Suner, MD, focused on functional vision and ranibizumab treatment. Data from this study demonstrated that patients receiving monthly Lucentis injections over 2 years reported improvement in reading ordinary and small print while patients receiving sham injections or PDT did not report a change in reading ability.

The HORIZON IIIB study consisted of 548 patients divided into three groups. The largest group, 388 patients, had previously received 2 years of monthly ranibizumab as part of the MARINA, ANCHOR, or FOCUS trials. However, when switched to PRN ranibizumab, their average VA gain dropped from 10.2 letters to 2.0 letters. A second group of 127 patients received PDT or sham for all or most of the first 2 years and PRN ranibizumab for the remainder of the 4-year period. Patients in this group on average went from an 11-letter loss over the first 2 years to a 13-letter loss over the next 2 years. A third group of 33 untreated patients originally randomized to sham or PDT never received Lucentis over the entire 4-year period. They went from a 3.2-letter loss over the first 2 years to a 6.9-letter loss over the next 2 years.

"Sixty-five percent of the people in all groups got less than 3 shots in the second 2 years," says lead investigator Michael A. Singer, MD, of San Antonio, TX, who presented the findings at the recent ARVO meeting. "So you're not looking at a lot of therapy. If you remeasure patients' vision when they start rolling over into PRN therapy, it turns out that the people who actually do the best are those who crossed over. The way I interpret the data is that these lesions were basically anti-VEGF naive. They had never been exposed to Lucentis before. Once they've been exposed to Lucentis, they have a pretty good response."

"The research underscores the importance of ongoing vigilance with follow-up and treatment for optimal control of the condition," says Carl D. Regillo, MD, of Wills Eye Institute in Philadelphia. "The mean 2-line visual acuity gain that was seen after 2 years of monthly ranibizumab treatments was nearly completely lost over the next 2 years in the HORIZON extension trial with a mean of only 3.6 treatments over that time frame. This suggests relative undertreatment and the need for ongoing anti-VEGF treatment and continued close followup for most patients with neovascular AMD."

In the Suner study, patients who participated in the MARINA or ANCHOR trials completed the NEI Visual Function Questionnaire (VFQ)-25 at baseline and months 1, 2, 3, 6, 9, 12, 18, and 24. Patient-reported reading ability was assessed at baseline, 12 months, and 24 months.

While baseline patient-reported reading ability was similar in ranibizumab- and control-treated patients in both trials, the ranibizumab-treated patients were (on average) quick to show improvement. Specifically, ranibizumab-treated patients in both trials had significantly more patients reporting "no difficulty" or "a little difficulty" in response to a question about their ability to read ordinary-sized print and fewer reporting "extreme difficulty" or "stopped activity due to eyesight" compared with sham- or PDT-treated patients. The greatest improvement occurred during the first month of ranibizumab therapy and was maintained for the second year of treatment.

"The [ARVO] poster presentation by Suner et al. on VFQ-25 test results in the MARINA and ANCHOR studies shows clear evidence of functional benefit with reading in patients that received ranibizumab for neovascular AMD," says Dr. Regillo. "What makes this particularly significant is that reading represents an important daily activity associated with improved quality of life and that a monocular intervention has a positive impact on a binocular function."

Ozurdex Implant Wins FDA Approval.

An Extended-release Drug for RVO.

■ The FDA has approved Allergan's Ozurdex dexamethasone 0.7 mg intravitreal implant as the first drug therapy indicated for the treatment of macular edema following branch or central retinal vein occlusion (RVO).

Ozurdex (formerly Posurdex) employs a solid-polymer drug-delivery system that gradually releases dexamethasone over a period of several months while the carrier matrix slowly degrades into carbon dioxide and water, eventually dissolving completely. "Ozurdex has an apparent effect of 3 to 6 months so it has a potential advantage over other pharmacotherapeutic options for RVO based on efficacy, safety, and durability," says Baruch Kuppermann, MD, chief of Retina Service and vice chair of Clinical Research in the Department of Ophthalmology at the University of California at Irvine. Dexamethasone levels in the retina were observed for at least 4 months following intravitreal placement of the Ozurdex implant, according to Allergan.

Studies have shown that dexamethasone exerts its multiple physiological effects by binding to glucocorti coid receptors followed by genomic and nongenomic intracellular signaling. Like other steroids, dexamethasone appears to inhibit the inflammatory processes involved in retinal vascular disease. Because it is water soluble and has a very short half-life in the vitreous, sustained-release delivery via an implant is a preferred method to provide continuous treatment for an extended period.

"The safety data suggest that there may be less IOP and cataract issues than what we are used to seeing with other steroid-based options," notes Dr. Kuppermann.

Ozurdex is placed in the vitreous cavity during an in-office procedure, with the slowly released dexamethasone treating the macular edema associated with RVO, thereby improving a patient's visual acuity. In clinical studies, 20% to 30% of patients experienced a 3-line improvement in BCVA with an onset of effect within the first 2 months following therapy. The treatment is expected to be available in the United States in the third quarter of 2009.

Though some retinal specialists may be tempted to consider off-label use of Ozurdex for indications that go beyond RVO, such as uveitis and DME, Dr. Kuppermann anticipates that the bulk of use will be on label, at least initially.

"Off label use may be expanded as other nonpivotal clinical trial data become available, though ultimately there is a fully-enrolled pivotal trial for DME in follow up phase that will determine expansion of the label."