Article Date: 5/1/2009

FDA Advisory Panel Recommends IMT
SUBSPECIALTY NEWS

FDA Advisory Panel Recommends IMT

Device a Step Closer to Approval.

JERRY HELZNER, SENIOR EDITOR

■ The Implantable Miniature Telescope (IMT), an investigational device designed to improve the vision of patients with end-stage macular degeneration, has cleared a major hurdle with the recent unanimous vote recommending approval of the IMT by the FDA Advisory Committee for Ophthalmic Devices. The panel endorsed the device with conditions, including post-approval surveillance and labeling suggestions.

Though the FDA is not required to accept the recommendation of the Advisory Committee, the 8 to 0 vote represents a favorable reversal of fortune for the IMT, which was rejected for safety reasons by a 10 to 3 Advisory Committee vote in July 2006. The IMT, already approved in much of Europe, is implanted in a complex anterior segment procedure that requires the participation of an anterior segment surgeon, retina specialist, and low-vision specialist for comprehensive patient management.

What made the 2006 vote somewhat of a surprise was an encouraging phase 2/3 clinical study, the IMT002 trial, that enrolled 217 patients at 28 US investigational sites. Patients entering the trial had severe vision loss due to the characteristic central blind spot caused by end-stage macular degeneration. The 1-year results available in 2006 indicated that 90% of patients met or exceeded the protocol-specified primary efficacy endpoint of visual improvement, defined as a 2-line gain in either distance or near vision on the study eye chart. The protocol stated the endpoint would be achieved if at least 50% of patients met this target.

A rendering of the Implantable Miniature Telescope (IMT) as it would appear when implanted into the eye. The IMT, developed by VisionCare Ophthalmic Technologies, won the unanimous approval of an FDA Advisory Committee.

Two-year trial results were published in the American Journal of Ophthalmology (AJO) last November.

"The (new) published data show improved visual acuity in end-stage AMD patients that was maintained over 2 years — a 3-line improvement that we have previously shown makes a real impact on our patients' independence and quality of life," said Henry L. Hudson, MD, lead author for the IMT002 study and retina specialist at Retina Centers, P.C. in Tucson, AZ. "These findings are important because vision loss from end-stage AMD profoundly affects both the daily activities and social well-being of many older Americans."

"The data presented in AJO confirm the effectiveness of the AMD telescope prosthesis and the long-term safety profile of the device," stated R. Doyle Stulting, MD, PhD., professor of ophthalmology at Emory University in Atlanta and study coauthor. "Key indicators of corneal health and diagnostic verification of device placement substantiate earlier findings that risks of surgery are outweighed by the benefits the improved vision brings to these patients' lives."

"We are pleased with the panel's recommendation for approval and will work closely with FDA to address the approval conditions," said Allen Hill, president and CEO of VisionCare Ophthalmic Technologies, the Saratoga, CA company that developed the IMT. "We look forward to providing the ophthalmic community a new treatment option to improve vision and quality of life for patients with untreatable, end-stage age-related macular degeneration."

Goal: Identify All Leber's Cases

Project 3000 Seeks Physician Participation.

■ It is estimated that there are approximately 3000 persons in the United States who have Leber Congenital Amaurosis (LCA). The John and Marcia Carver Nonprofit Genetic Testing Center at the University of Iowa is on a mission — called Project 3000 — to attempt to identify all of them.

The Center has already identified approximately 1000 Leber's patients who have the vision-robbing and often blinding disease, but they need the help of the nation's retina specialists to achieve their aim.

The major goal of Project 3000 is to be able to get im touch with all of the individuals affected with LCA and offer them state-of-the-art genetic testing to try to identify the specific genetic cause of their disease. This effort is also designed to provide hope to these individuals and to assure them that steps are being taken to combat this disease.

By collecting some basic clinical information from thousands of people affected with LCA, doctors will be able to learn how each genetic subtype of LCA behaves over time and will be able to use this information to give newly diagnosed individuals and their families more accurate information about what to expect.

The genes responsible for about one third of LCA cases remain to be discovered. Scientists believe that by gathering samples from the hundreds of individuals affected by LCA whose genes have not yet been discovered, they will be much more likely to find all of the remaining ones, which will help in the quest to develop cures.

If Carver is to succeed in this ambitious undertaking, it believes strongly that it will be important for the doctors who currently care for these patients to be involved at every level of the effort.

The Project 3000 team says it is ready to support the patients' doctors in any way necessary to achieve the goals of the project, but, the Carver team believes that the patients' doctors must remain at the center of each patient's medical care. Thus, all individuals interested in participating in the project will be encouraged to do so through their existing physicians.

When ordering the test, a patient may express interest in learning about LCA research projects by checking a box on the order form. If this box is checked, members of the Project 3000 team will contact the patient after the genetic test is complete and the report is sent. The team will offer the patient the opportunity to participate in an appropriate research project. For example, patients with negative results will have the opportunity to participate in projects designed to find the remaining LCA genes while patients with positive results will have the opportunity to participate in projects designed to correlate clinical findings with specific genetic changes.

One of the fundamental goals of Project 3000 is to make clinical genetic testing of LCA a standard of care. Events are moving in that direction but since insurance companies cannot be billed directly, it is important for patients and physicians to work together to provide payment for genetic testing. There are several options available:

► Patients (or physicians) may go to the Project 3000 Web site at www.carverlab.org/project-3000-instructions to download a letter to assist them in obtaining insurance coverage for the LCA test.

► Patients and physicians may also use the same Web site to download a form to use in requesting Project 3000 financial assistance for the LCA test and to learn how to submit a sample for genetic testing.

Chicago Cubs' star Derrek Lee, the Boston Celtics, the Foundation for Retina Research and the Foundation Fighting Blindness are also partners in Project 3000.

CORRECTION
An article in the March 2009 issue, "Putting the Brakes on Geographic Atrophy," incorrectly referred to the FAME (Fluocinolone Acetonide in Diabetic Macular Edema) and FAMOUS studies from Alimera Sciences. The comment should have read, "If the results [in FAME] are anything like what has been observed in the FAMOUS study thus far, Alimera has reason to be hopeful."

Common Drugs Linked to High DME Risk

■ Drugs that are commonly used to reduce insulin resistance for patients with type 2 diabetes have now been associated with a much higher incidence of DME in patients who take those drugs.

The findings are the result of a 5-year study by Kaiser Permanente of Southern California that involved more than 170,000 diabetes patients. The data was reported in a recent issue of the American Journal of Ophthalmology.

Drugs classified as glitazones have been identified with more than twice the risk of DME development for those diabetics taking them, even after factors such as age, insulin use, and glycemic control have been taken into account. Commonly used glitazones include Actos (pioglitazone) and Avandia (rosiglitazone).

Other drugs also demonstrated an increased risk of DME in the study group. Insulin itself and meglitinide also appeared to increase the risk of DME, researchers noted. However, metformin and acarbose use were not associated with DME.

Donald S. Fong, MD, and Richard Contreras, MD, the researchers who led the study, cautioned that "the current larger study of over 17,000 users of glitazone confirms an association between glitazone use and macular edema. When treating patients with DME, ophthalmologists should consider the role of the glitazone class of drugs."

Retina Researchers Win ARI Grants

Four Are Based in the United States.

■ Of the 6 doctors who were recently awarded unrestricted $200,000 grants from the Alcon Research Institute (ARI), 5 are involved in retina research, and 4 of those doctors are based in the United States.

The 4 US researchers receiving the awards are:

► Gregory S. Hageman, PhD, for his significant contributions to the study of age-related macular degeneration. Dr. Hageman graduated from the University of Southern California and has been a professor at the University of Iowa in Iowa City, Iowa for the past 12 years.

► Mark S. Humayan, MD, PhD, for his groundbreaking research in the development of a retinal prosthetic device. Dr. Humayan has degrees from both Duke University and the University of North Carolina. Currently, he is a professor and researcher at the Doheny Eye Institute, University of Southern California Medical School in Los Angeles, California.

► Robert W. Massof, PhD, and Eli Peli, MSc, OD, who will share an award for their impressive research on low-vision rehabilitation. Dr. Massof is a graduate of Indiana University and is now a professor and director of the Lions Vision Research & Rehabilitation Center at the Johns Hopkins Wilmer Eye Institute in Baltimore, Maryland.

Dr. Peli is a graduate of the Technion, Israel Institute of Technology and the New England College of Optometry. He currently serves as a professor of ophthalmology at Harvard Medical School and as the Moakley Scholar in Aging Eye Research at the Schepens Eye Research Institute in Boston, Massachusetts.

In addition, Brenda L. Gallie, MD, of Canada, won for her distinguished career and research into the genetic causes of retinoblastoma. Dr. Gallie is a graduate of Queen's University in Kingston, Canada and is now the Head of the Retinoblastoma Program at the Hospital for Sick Children and a senior scientist at the Ontario Cancer Institute, University Health Network, in Toronto.

"The Alcon Research Institute has a goal of recognizing the world's leading researchers in ophthalmology," said Stanley Chang, MD, chairman of the Alcon Research Institute, and Edward Harkness professor and chair of Ophthalmology, Columbia University. "The research these brilliant minds are undertaking will have profound effects on our ability as doctors to preserve, restore and enhance sight in the future."

The ARI grant program has been ongoing for the past 29 years.

Lux Uveitis Drug Shows Positive Results

■ Lux Biosciences has reported encouraging results from the three phase 3 LUMINATE trials of its LX211 (Luveniq, voclosporin oral capsule) drug candidate for the treatment of uveitis. The data show a positive effect on ocular inflammation and safety consistent with the expected use of LX211 in this indication.

Of the 3 studies, only the LX211-01 trial involved patients with active, noninfectious posterior manifestation of the disease.

"The available results from the LUMINATE program demonstrate that Luveniq, if approved, can play a significant role in the treatment of inflammation in certain forms of sight-threatening uveitis," said Eddy Anglade, MD, Lux Biosciences' chief medical officer. "A significant unmet therapeutic need exists for an ap proved agent which is not a corticosteroid and allows sparing of those drugs to reduce their associated, serious side effects."

The 3 randomized, double-masked, dose-ranging and placebo-controlled trials comprising the LUMINATE program, the largest ever conducted in uveitis, enrolled 558 patients at 56 sites in 7 countries. The trials included 218 patients with active noninfectious uveitis with posterior manifestation of the disease (LX211-01), 232 patients with clinically quiescent disease (LX211-02), and 108 with active uveitis with anterior manifestation of the disease (LX211-03).

In study LX211-01, Lux says the 0.4 mg/kg BID dose fully met the primary endpoint of superiority to placebo at both week 16 (p=0.008) and week 24 (p=0.04) for mean change from baseline in vitreous haze, a validated measure of posterior segment inflammation. The magnitude of the effect was >1-step change, which Lux says demonstrates a clinically relevant benefit.

Lux notes that the integrated safety profile of 0.4 mg/kg BID LX211 in the LUMINATE trials suggests that it would be suitable for chronic use in this indication. Of particular interest were the relatively small effects of LX211 0.4 mg/kg BID on renal function, an area of concern for first-generation calcineurin inhibitors. Patients experienced a mean increase in systolic blood pressure over baseline of 6 mm Hg. However, Lux says most of these patients were successfully controlled with medication and only 1.3% discontinued therapy due to hypertension.

Other adverse events typical of the calcineurin inhibitor class, in particular diabetes, elevation of lipids, hypomagnesemia, and tremor, were not observed in the LUMINATE studies. Additional adverse events included headache, diarrhea, and infections, which were similar in incidence to placebo. There was no apparent effect on IOP, cataract formation, or endothelial cell density.

Ulrich Grau, PhD, Lux Biosciences' president and chief executive officer, said, "Based on the available data from the LUMINATE pivotal trial program, we plan to engage in discussions with several regulatory agencies and plan regulatory filings of Luveniq in the near future."

IN BRIEF
Fenretinide study is encouraging. Sirion Therapeutics announced positive results from an interim analysis of its phase 2 trial evaluating fenretinide to treat geo graphic atrophy (GA) associated with AMD. This interim analysis was triggered when all patients had reached the 12-month visit.
The analysis compared the growth rate of GA lesions, measured by retinal photography, in patients treated with daily doses of placebo or 100 mg or 300 mg of oral fenretinide. These data showed slower growth of the lesions for the 300 mg dose for all lesion sizes at entry. According to Sirion, this trend was evident as early as 6 months and increased over time. Among the sub-population of 78 patients who reached the 18-month study visit, the median growth rate of the lesions in the 300 mg group was 22.7% vs 41.6% in the placebo group, representing a 45% reduction in median lesion growth rate at month 18. The current study is powered to detect a 50% reduction in lesion growth rate at the 24-month mark.
Slower lesion growth was also observed in the 100 mg group among subjects who had lesions smaller than the median baseline at entry approximately 3 disc areas). These data suggest that early intervention may improve outcomes.
Based on the results of this interim analysis, Sirion plans to continue the current study to its conclusion, and will meet with its scientific advisers and the FDA to design an appropriate phase 3 program for fenretinide. RP


Retinal Physician, Issue: May 2009