March/April 2007 News
CLINICAL NEWS

ANCHOR: 2-Year Results Show Ranibizumab Superior to PDT in AMD
The 2-year results of a phase 3 trial of ranibizumab (Lucentis; Genentech, San Francisco) showed that the agent helped patients with neovascular age-related macular degeneration (AMD) maintain vision better than photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis, Basel Switzerland).

Peter K. Kaiser, MD, from the Division of Ophthalmology at the Cole Eye Institute presented results of the ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) trial at Retina 2007, held in conjunction with Hawaiian Eye 2007.

Patients in ANCHOR had predominantly classic, subfoveal choroidal neovascularization secondary to AMD and had not received prior PDT treatment. The 423 patients in the trial were randomized to 0.3-mg or 0.5-mg ranibizumab intravitreal injections plus sham PDT or sham injections plus active PDT. Dr. Kaiser said that injections (sham or active) were performed monthly, and PDT (sham or active) was performed every 3 months as needed for 2 years.

The 2-year data mirrored results from the first year, in terms of primary outcome, Dr. Kaiser said, with 90% of ranibizumab patients losing <15 letters of vision compared with 65.7% of PDT-treated patients. Visual acuity improved a mean of 11 letters compared with baseline in the ranibizumab group, and 34% to 41% of patients improved >15 letters. Additionally, 9% to 14% of patients gained >30 letters.

Close to 80% of ranibizumab-assigned patients maintained baseline visual acuity or gained some letters versus <30% in the PDT-assigned group, he said.

The low rate of serious adverse events also mirrored that reported in the 1-year ANCHOR results, Dr. Kaiser said. There was nothing out of the ordinary about the 2% incidence of endophthalmitis—as the injections are given intravitreally.

“There were cases of endophthalmitis, 2.1% overall, but the per injection endophthalmitis rate was 0.05%, which is similar to other intravitreal injection studies,” Dr. Kaiser said.

Seven patients experienced nonocular hemorrhages which Dr. Kaiser said could have been related to the injections. He is not concerned about potential vascular complications with ranibizumab, however. Neither ANCHOR nor MARINA excluded patients based on vascular conditions, although other studies of VEGF agents have. The trial was not designed to find all safety issues, he added.

Surgeons should report any adverse events to Med Watch—www.fda.gov/medwatch/report/hcp.htm—Dr. Kaiser and others emphasized from the podium. Dr. Kaiser is a member of the Retina Today Editorial Board.

Elevated White Blood Cell Level Predicts AMD Later
Findings from the Blue Mountains Eye Study suggest that an increased white blood cell count predicts individuals who are at an increaed risk of developing AMD.

Reporting in the American Journal of Epidemiology, Anoop Shankar, MD, and colleagues from the National University of Singapore, found that an elevated white blood cell count was predictive of early AMD independent of confounding variables, including smoking. The investigators said that few studies have looked at the association between systemic markers of inflammation and the development of eye disease, although inflammation is thought to play a major role in the pathogenesis of AMD.

The Blue Mountains Eye Study included 3,654 patients aged 49 years to 97 years who were followed for up to 10 years. Those individuals in the highest tertile of white blood cell count, >6.7 billion cells/L, were 85% more likely to develop AMD than those in the lowest tertile. This association was true for all types of early AMD lesions.

Mycophenolate Mofetil Effective for Pediatric Uveitis
Mycophenolate mofetil is an effective agent in the treatment of uveitis in children, according to a report in the British Journal of Ophthalmology. The agent has “marked steroid-sparing potential and an acceptable side effect profile,” wrote the researchers from the University Eye Hospital Tuebingen, Germany.

They reviewed the outcomes of 17 children who received a minimum of 6 months of treatment with the new immunosuppressive agent for noninfectious uveitis. A steroid-sparing effect was achieved in 88% of the patients; oral prednisolone was successfully discontinued in 41% children and reduced to a daily dose of 5 mg in 47% of the children, according to the report. A total of 24% of the patients remained relapse-free during the treatment, but a reduction in the relapse rate was observed in all other patients except one. Visual acuity was increased or maintained in 13 children (76%).

Research Examines Risk Factors for Cystoid Macular Edema
Iris trauma and severe postoperative inflammation are risk factors for cystoid macular edema (CME), researchers from SSK Vakif Gureba Education Hospital in Turkey, concluded.

A prospective study of 98 eyes of 98 patients examined patients who underwent phacoemulsification with temporal clear-corneal incision and implantation of foldable hydrophilic acrylic IOL in the bag. In this study, 25 patients were found to have the disease. Patients were examined on day 1, week 1, and at 1, 3 and 6 months for the presence of CME, according to the report in the Canadian Journal of Ophthalmology.

Of those diagnosed, CME occurred in 70% of patients with iris trauma versus only 20.5% of patients with no iris trauma. CME was also more common in patients who had postoperative anterior chamber inflammation (43.2% vs 11.5%), and may be associated with decreased visual acuity, researchers found.

Additionally, complete posterior vitreous detachment had some apparent protective effect against CME development, the authors wrote.

Pegaptanib Sodium May Trigger Allergic Reaction
In an observational case study reported in the American Journal of Ophthalmology, Andrew C. G. Steffensmeier, MD, and colleagues reported two cases of systemic allergic reactions associated with vitreous administration of pegaptanib sodium (Macugen; OSI/Eyetech and Pfizer, New York, NY).

One patient developed a delayed and prolonged anaphylactoid reaction following administration of his first dose. The second patient received four injections of pegaptanib over the course of 6 months and developed mild lip swelling and prolonged urticarial rash following the first injection. This subsided when pegaptanib was suspended.

Researchers caution that severe hypersensitivity reactions may occur with vitreous administration of pegaptanib sodium and may be associated with prolonged urticaria and angioedema. “Elderly individuals with comorbidities are at a higher risk for fatality from severe hypersensitivity reactions in the ambulatory setting,” researchers wrote.

Researchers Uncover Why Graves’ Disease Attacks the Eyes
Scientists at UCLA’s Jules Stein Eye Institute and Harbor-UCLA Medical Center discovered defects in the infection-fighting T-cells of Graves’ Disease immune systems. Reported in the Journal of Immunology, the study may deepen understanding of how the autoimmune disorder damages the body and offer a new target for treating the disfiguring disease.

Earlier research found that Graves’ Disease patients’ immune systems produce an antibody that other people do not, according to a UCLA news release. The antibody mistakenly mounts an attack against the organ, causing inflammation and damage to the thyroid, including eye tissue.

In the current study, UCLA researchers discovered that T-cells taken from Graves’ Disease patients contain an abnormal surplus of the receptor targeted by this antibody. An antibody must latch to a specific receptor in order to elicit a cellular response. The receptors mobbed the patients’ immune systems, even on T-cells that normally would not produce them.

“We didn’t know why [Graves’ Disease] patients’ cells created a new antibody, but had a hunch that it sprang from an immune abnormality,” said Raymond Douglas, MD, first author and assistant professor of ophthalmology at the Jules Stein Eye Institute. “Because T-cells are the generals of the immune system and lead the attack in any immune response, we assumed that they played a key role in this antibody’s development.”

The team tested Graves’ Disease patients’ blood for the antibody and compared their findings to samples from healthy people, with about 100 subjects in each group. The new antibody was found in almost all of the Graves’ Disease patients’ blood.

The new antibody binds to the excess receptors on the T-cells, mimicking the actions of insulin-like growth factor 1 (IGF-1). Similar to insulin, IGF-1 stimulates cell growth while suppressing normal cell death. The team suspects that this mechanism prolongs the survival of older T-cells, causing a cascade of autoimmune problems that spur the body to attack its own tissue.

“We think that the extra receptors allow the new antibody and IGF-1 to disrupt the programming of the T-cells,” said principal investigator Terry Smith, MD, professor of medicine at the David Geffen School of Medicine and chief of molecular medicine at Harbor-UCLA Medical Center.

“The antibody provokes the receptor to signal the T-cell to grow and multiply—long after the cell was programmed to die,” he said. “After two or three generations of this process, we suspect that the high-jacked T-cells mutiny over the normal T-cells, sparking the body’s immune reaction against itself.”

The next step is to identify what the T-cells are reacting to and how the receptor enables the cells to survive beyond their normal lifespan. The team plans to develop an antibody drug to block the receptor from interacting with the T-cells and slow disease progression.

In Graves’ Disease, the thyroid gland goes into overdrive, producing excess levels of hormone that attack the tissue behind the eye, causing them to protrude. In extreme cases, patients experience trouble closing their eyelids, severe double vision, corneal scarring, optic nerve damage, and even blindness.

Eye Cancer Treatment Looks at Tree Bark
Researchers from the University of California, San Francisco are examining the bark of a South American tree to find a treatment for retinoblastoma, a childhood eye cancer.

The study, lead by Joan O’Brien, MD, and published in the journal Eye, examined a tree bark extract called beta-lapachone. Their research found a proapoptotic effect of beta-lapachone and the compound also induces significant dose-dependent growth inhibitory effects in retinoblastoma cell lines, according to the authors.

“Beta-lapachone induced potent cyotoxic effects in retinoblastoma cell lines at low micromolar concentration, suggesting that this agent could be useful in the clinical management of the disease,” the authors concluded.

INDUSTRY AND BUSINESS NEWS

TargeGen Completes Phase I Clinical Trial for Topical AMD Drug
TargeGen, Inc. (San Diego) announced that the company has completed a single-center phase 1 clinical trial of TG100801 in 42 healthy patients. TG100801 is a small-molecule, topically applied, multitarget kinase inhibitor that is being developed for the treatment of AMD and other debilitating eye diseases. Preliminary results from this phase 1 study suggest that TG100801 is well-tolerated in humans at the low and high doses tested when applied topically twice daily for 14 days. Final study results are expected by the end of April 2007, according to a company news release.

TargeGen currently plans to initiate phase 2 clinical trials in neovascular AMD patients in mid-2007.

TG100801, applied daily in eye drop form, is designed to suppress disease-related edema, angiogenesis, and inflammation simultaneously—all pathological hallmarks of AMD, diabetic macular edema, and proliferative diabetic retinopathy.

“The successful completion of this first in human safety study with TG100801 represents a meaningful milestone for TargeGen and sets the state for the near initiation of human efficacy trials. We remain very optimistic about the potential for demonstrating efficacy in humans in the near future,” said Peter G. Ulrich, President, CEO and cofounder of TargeGen, in a company news release.

Phase 2 Trial Begins for Microplasmin in Vitrectomy
ThomboGenics NV (Leuven, Belguim), a biotechnology company focused on vascular disease, initiated a phase 2b clinical trial of microplasmin in vitrectomy in the United States.

Microplasmin is a truncated form of natural human protein plasmin; ThromboGenics has developed on a proprietary basis for use in the treatment of vitreoretinal disorders, according to a company news release. In addition to its potential benefits in the setting of the vitrectomy, microplasmin may also allow for nonsurgical treatment of macular edema and diabetic retinopathy.

The Microplasmin for Vitreous Injection III (MIVI III) trial is a phase 2b multicenter, randomized, placebo-controlled, double-masked, dose-ranging clinical trial evaluating the safety and efficacy of microplasmin intravitreal injection prior to vitrectomy. It is estimated 120 patients will be treated in this trial. The results are expected to allow dose selection for subsequent phase 3 clinical development.

In parallel with this trial, ThrombGenics will proceed with phase 2 development in Europe to evaluate microplasmin injection for the nonsurgical treatment of diabetic macular edema and other back of the eye conditions. These conditions may benefit from microplasmin without the need for vitrectomy. The first of these studies, the MIVI II trial, evaluating patients with diabetic macular edema, has started patient enrollment.

In current clinical practice, the induction of posterior vitreous detachment (PVD) is achieved via surgical vitrectomy, however given the complications inherent to detaching the vitreous by surgical vitrectomy; there is a great desire for an improved approach to achieving PVD in a minimally invasive way. The approached is being studied in the MIVI III trial (US phase 2b trial) is to administer microplasmin prior to surgical vitrectomy, as this may result in a more rapid surgery with fewer complications.

Approximately 600,000 surgical vitrectomies are performed annually, worldwide. The United States accounts for >40% of these treatments.

Bausch & Lomb Initiates Second Recall
Bausch & Lomb (Rochester, NY) initiated a limited voluntary recall from distribution centers and retail shelves in the United States, and specific other countries, of 12 lots of ReNu MultiPlus lens care solution made at its plant in Greeneville, SC, because it contained an elevated level of trace iron. This may result in discoloration of the solution in some bottles, and the shelf life may be shortened to less than the 2-year expiration date, due to potential loss of effectiveness over time. About 1 million bottles of the solution from these lots were originally distributed in the United States, according to the company.

Bausch & Lomb has received no reports of serious adverse events associated with these lots and believes virtually all of the affected products have already been used by consumers. The US Food and Drug Administration (FDA) was alerted of this voluntary action.

“We are confident we have identified the source of the problem and we are taking appropriate measures designed to avoid a recurrence,” said Angela J. Panzarella, Vice President and Head of Bausch & Lomb’s Global Vision Care Business, in a news release.

The company said it does not expect the costs associated with the limited recall to have a significant impact on its financial results.

Optical Coherence Tomography Comes to US
The Eye Care Center at the Southern California College of Optometry, in Fullerton, Calif., introduced the first-ever optical coherence tomography (OCT) slit-lamp combined imaging system (SL-OCT; Heidelberg Engineering, Heidelberg, Germany) in the United States. This technology allows for clearer and more detailed views of the cornea and anterior eye tissues than with other eye-imaging technologies, and is completely noninvasive.

“This technology will revolutionize the way the medical community diagnoses, treat, and evaluate multiple eye health issues,” said David Sendrowski, OD, Chief of Ophthalmology Consultation and Special Testing Services at the Eye Care Cente, in a news release. “Practitioners at the Eye Care Center are among the first in the United States able to view the eye in this completely new way, using noncontact ultrasound-like technology. The accuracy and detail of the image it produces will give doctors a more precise understanding of the eye, and will lead to early detection and diagnosis, more defined treatment, and ultimately better patient outcomes.”

Much like a risk-free, noncontact MRI or CAT scan for the eye, OCT technology is 40 times faster, and more sensitive, according to the manufacturer. Its clinical applications range from more accuracy in LASIK procedures and other eye surgeries, to anterior segment tumor detection, pre- and postop corneal evaluations, early detection of sudden onset glaucoma, and the more effective management of other common vision and eye health issues.

“While it will likely be years before this revolutionary technology is fully-integrated into general practice, one of the great things about it is how consumer-friendly it is. Patients do not like having a doctor’s finger or equipment touching their eyes. This technology gives doctors more accurate and detailed images than ever before and nothing ever touches the patient’s eye or makes them uncomfortable,” Dr. Sendrowski said in a news release.

The Eye Care Center worked closely with Heidelberg Engineering to support the development of the SL-OCT. Through this partnership, it was able to purchase an early version of the device before its general market release, which is anticipated later this month. While the FDA has approved the device, its automatic image analysis software was pending approval at press time.

New Device Creates Eye Maps to Diagnose Disease
A new digital ophthalmoscope, devised by a research team led by the University of Warwick (Coventry, UK) can provide both doctors and high street optometrists with a hand held eye disease diagnosis device equal to the power of bulky hospital based eye diagnosis cameras. It will also give optometrists the ability to e-mail detailed eye maps of patients to specialist eye doctors, according to a news release issued by Warwick University.

Ophthalmoscopes have changed little in design in the last century. As a result the effective operation of the device is constrained by the skill, expertise and eyesight of the eye specialist. The new digital ophthalmoscope (developed from a 3-year research partnership with the University of Warwick; ophthalmoscope manufacturer Keeler Optics, Windsor, UK; City University, London; and University College London) uses a combination of specialist lens digital imaging and lighting technology, which for the first time allows a high quality digital image to be captured and recorded by an ophthalmoscope.

University of Warwick research Professor Peter Bryanston-Cross has also been able to apply software used to stitch together detailed map images to assemble the captured images from the digital ophthalmoscope. This produces a highly detailed single picture of medical significance and usefulness. It provides a map of the eye equal to the field of view and resolution of the large fundus cameras typically used in hospital settings to examine eyes. The new digital ophthalmoscope would also be around 10 times cheaper than a fundus camera. This technology will be a powerful tool in the hands of ophthalmologists, but it will also revolutionize eye care on the high street, according to the university release.

Warwick Hospital consultant eye surgeon Gary Misson has been working with Professor Bryanston-Cross’s digital ophthalmoscope research digital program for several years. “This is an exciting development as it makes an instrument that is traditionally difficult to use much easier to handle and therefore available for use to a wider range of health care workers. It will allow digital images of disease such as the potentially blinding complications of diabetes and glaucoma to be accurately and quickly sent to specialists who will then be able to arrange appropriate treatment. I foresee a relatively inexpensive instrument that is about the size of a mobile phone in common use in the near future,” Mr. Misson said.

Deformable Mirror Enhances Retinal Imaging Systems
Boston Micromachines Corp., (Watertown, MA) has manufactured an enhanced deformable mirror (DM) capable of meeting the criteria for ultra-high resolution retinal imaging, which is necessary for early detection of ocular diseases. The new mirror meets the requirements of both retinal imaging systems, as well as vision science and microscopy researchers who use adaptive optics for biological imaging, according to a news release.

“This deformable mirror represents a significant scientific advancement in the field of biological imaging; specifically vision science. Until now, doctors were limited in their ability to gain a clear view of the human retina due to image distortion caused by tissue-induced wavefront aberration. Our deformable mirror corrects for that wavefront aberration,” said Paul Bierden, president of Boston Micromachines, in the news release. “This marked improvement in retinal imaging will provide doctors with the technology necessary to detach the leading diseases of the eye: glaucoma, diabetic retinopathy, and AMD years earlier than previously possible.”

The new mirror, which is an enhanced version of Multi-DM (Boston Micromachines) delivers increased stroke while maintaining the high resolution afforded by its 140 independently controlled actuators. The mirror’s 3 kHz frequency allow for high-speed real-time imaging, with a 6-mm aperture suited for a dilated pupil. Additionally, the new Multi-DM provides the wavefront amplitude correction needed for older eyes by offering 6 µm of stroke. This translates to 12 µm of wavefront correction.

The improved Multi-DM will also enable enhancements in other biological imaging areas. Biological imaging instruments often suffer from resolution limitations, constraining the ability of researches and clinicians to detect critical detail, the company release said.

The new Multi-DM is available immediately.

Research to Prevent Blindness Awards $9 Million
Research to Prevent Blindness (RPB), a New-York based foundation, awarded 90 grants, totalling more than $9 million in 2006, according to a news release. The grants benefited 55 medical schools and 176 ophthalmic scientists.

Researchers supported by RPB highlighted restoration of sight signaling in mice through stem cell transplantation, development of side-effect-free treatment for retinoblastoma and identification of the mechanism by which the cornea remains clear and free of vasculature, as research highlights, according to an organization news release.

Since it was founded in 1960, RPB has channeled more than $240 million to medical institutions throughout the United States. As a result, RPB has been identified with nearly every major breakthrough in eye research in that time—including the development of laser surgery now used to treat diabetic retinopathy, glaucoma, AMD, myopia, retinal detachment, and astigmatism.

FDA Rejected Lilly’s Appeal to Reverse Ruboxistaurin Decision on Additional 3-Year Study
The FDA said it stands by the approvable letter it sent to Eli Lilly and Company (Indianapolis) in September 2006 informing the drugmaker that an additional study would be needed before ruboxistaurin (Arxxant) could be approved. Steven Paul, Lilly’s Executive Vice President for Science and Technology, said that the company is disappointed in the ruling, however it will not seek further appeal. Lilly is considering its options for the product.

Preliminary Safety Information From a Planned Interim Analysis in SAILOR
Genentech (San Francisco) informed health care professionals of preliminary safety information from a planned interim analysis in an ongoing study, according to the FDA.

The Safety Assessment of Intravitreal Lucentis for AMD trial (SAILOR) confirmed the higher incidence of stroke in the 0.5-mg dose group compared to the 0.3-mg dose group (1.2% vs 0.3%, respectively; P=.02) of patients with neovascular AMD who received intravitreal ranibizumab (Lucentis). The rates of stroke for both dose groups are lower than the rates seen in the controlled clinical trials and included in the approved labeling. The planned frequency of dosing was not the same as that described in the approved labeling. This comparison was one of many made during this interim analysis.