Subspecialty News

VEGF Trap shows a positive response; Virtual indirect ophthalmoscopy as a teaching tool; Bascom Palmer rejects Lucentis rebates


VEGF Trap Shows a Positive Response

Drug effective in wet AMD, CRVO and DME.

Jerry Helzner, Senior Editor

■ A flurry of clinical data released late in 2010 indicates that the investigational therapy VEGF Trap-Eye could be a safe, highly effective and durable therapy for such diseases as wet AMD, central retinal vein occlusion and diabetic macular edema.

The data released were from two phase 3 VIEW trials in wet AMD, the phase 3 COPERNICUS study for macular edema associated with CRVO, and the phase 2 DA VINCI trial for DME.

► Data from two large-scale phase 3 trials for wet AMD indicates that a 2 mg injection of VEGF Trap-Eye from Regeneron Pharmaceuticals dosed every two months provided almost the same improvement in visual acuity as Genentech's 0.5 mg approved dose of ranibizumab given monthly.

In a North American study, called VIEW 1, both of these dosing schedules improved visual acuity by approximately eight letters, with one-month ranibizumab 0.5 mg dosing providing an average 8.1-letter improvement against VEGF Trap's 7.9-letter gain with every two-month 2 mg dosing. In the international VIEW 2 trial, conducted by Bayer Healthcare, the comparisons were similar.

Additionally, in the VIEW 1 study, 2 mg of VEGF Trap injected monthly provided an even greater 10.9-letter gain in visual acuity. There was no 2 mg ranibizumab arm in these trials but Genentechs ongoing HARBOR study does include 2 mg monthly and PRN dosing.

► In Regeneron's phase 3 COPERNICUS study for CRVO, 56.1% of patients receiving VEGF Trap-Eye 2 mg monthly gained at least 15 letters of vision from baseline, compared to 12.3% of patients receiving sham injections at six months, the primary endpoint of the study. Patients receiving VEGF Trap-Eye 2 mg monthly gained, on average, 17.3 letters of vision compared to a mean loss of 4.0 letters with sham injections at six months, a secondary endpoint. A second phase 3 CRVO study, GALILEO, is being conducted by Bayer, with data expected in the second quarter of 2011.

Ranibizumab was approved in June 2010 for treatment of macular edema associated with CRVO and BRVO However, the COPERNICUS trial compared VEGF Trap-Eye to sham, so there is as yet no head-to-head comparison between VEGF Trap-Eye and Lucentis in either CRVO or BRVO.

► Regeneron and Bayer Healthcare also reported 52-week follow-up results from the phase 2 DA VINCI study in patients with DME. In this study, the previously reported visual acuity gains achieved with VEGF Trap-Eye treatment over 24 weeks (the primary endpoint of the study) were maintained or numerically improved up to completion of the study at week 52 in all VEGF Trap-Eye study groups, including 2 mg dosed every other month. Mean 52-week gains in visual acuity from four VEGF Trap dosing schedules ranged from 9.7 letters to 13.1 letters, while the mean loss in 52-week VA in the laser-treated group was 1.3 letters. Based on these positive results, Regeneron and Bayer are discussing plans to initiate phase 3 studies.

More detailed results for both the COPERNICUS and DA VINCI studies will be presented at the Bascom Palmer Angiogenesis Conference in Miami in February 2011.

Bayer Healthcare and Regeneron are planning to submit regulatory applications for marketing approval of VEGF Trap-Eye for wet AMD in Europe and the US in the first half of 2011 based on the positive results of the VIEW 1 and VIEW 2 trials.

“A critical goal of these studies was to demonstrate that VEGF Trap-Eye could achieve robust improvements in vision and maintain them over time with a more convenient every-other-month dose,” said Jeffrey Heier, MD, chair of the Steering Committee for the VIEW 1 trial. “Achievement of this goal could be important for patients, caregivers and physicians.”

A generally favorable safety profile was observed for both VEGF Trap-Eye and ranibizumab. The incidence of ocular adverse events was balanced across all four treatment groups in both studies, with the most frequent events associated with the injection procedure, the underlying disease and/or the aging process. The most frequent ocular adverse events were conjunctival hemorrhage, macular degeneration, eye pain, retinal hemorrhage and vitreous floaters.

In the second year of the studies, patients in VIEW 1 and VIEW 2 will continue to be treated with the same dose per injection as in the first year but administered only every three months, or more often (PRN) for any worsening of AMD, based on protocol-defined criteria.

Teaching Tool: Virtual Indirect Ophthalmoscopy

Case-based training provides realistic simulations.

■ Mrs. H., a 27-year-old, presents with visual acuity loss. Five days ago, she had been referred to an ophthalmic hospital with acute onset visual acuity loss with metamorphopsia in the right eye. Before examining the patient's eyes, the resident refers to her patient history. Mrs. H. suffers from atopic dermatitis and uses cortisone ointment for treatment if required. Apart from that, she has no known allergies and has had no relevant previous diseases, trauma or surgery. She regularly takes oral contraceptive pills and vitamin B12 substitution.

But Mrs. H. is not a real person. She is a virtual patient. Her case is one of a range of clinically relevant cases presented in a new training system for indirect ophthalmoscopy named Eyesi Ophthalmoscope.

With the Eyesi simulator, residents can learn how to properly handle the diagnostic lens and light source of the ophthalmoscope in order to examine the patient's retina without ever touching a real patient. Furthermore, they can develop diagnostic skills by examining and comparing a range of pathologies independent from patient flow.

The case database of the Eyesi Ophthalmoscope covers typical retina and vitreous pathologies. As opposed to studying two-dimensional images, the high-end technology employed in the Eyesi instrument offers residents a realistic, interactive simulation experience. The system also provides results of other examination methods, such as angiography, OCT and diagnostic data from other clinics.

In the case of Mrs. H., residents can consult an OCT image and a fluorescein angiograph. The process of evolving a clinical diagnosis is guided by multiple-choice questions. Initially, the resident is asked to specify possible side effects for the eye from long-term systemic cortisone treatment or which blood parameters would clarify a possible infection cause, for example. A case summary and post-diagnostic discussion as well as a detailed evaluation both of the resident's procedural skills and the diagnostic outcome is instantaneously provided by the training system.

Resident at the Eye Clinic of the J.W. Goethe University Hospital training with the Eyesi Ophthalmoscope. The highly realistic simulator consists of a head-mounted display and a patient model head, as well as freely movable diagnostic lenses.

“The cases in the simulator's database are based on actual retina cases, which have previously been didactically adapted. Going hand in hand with examining real patients, the simulation system helps to find pathologic characteristics more easily and to make medical decisions accordingly more dependable,” explains Prof. Dr. Frank Koch, head of the Department for Vitreous and Retinal Surgery at the Eye Clinic of the J.W. Goethe University Hospital in Frankfurt, Germany.

Dr. Koch has been involved in the development of the training system from its beginnings in 2007. The idea of indirect ophthalmoscopy simulation has its roots in a cooperative effort between the Eye Clinic of the J.W. Goethe University Hospital, the Department of Computer Science at the University of Heidelberg, and the VRmagic company of Mannheim, Germany. The database of the simulator has been designed as an open platform: medical schools can submit their own cases to VRmagic to be added to the existing database. So far, cases have been contributed by the German University Eye Clinics of Gießen and Tübingen as well as the University of Toronto.

Bascom Palmer Rejects Lucentis Rebates

■ A recent New York Times article detailed a new program initiated by Genentech in which retina practices that perform a significant number of Lucentis injections can receive rebates on the drug. Genentech has explained that the rebates are specifically tied to promoting use of the drug for a newly approved indication in retinal vein occlusion and not to discourage the use of its much cheaper drug, Avastin, to treat wet AMD.

Questioning the purpose of the rebates was Bascom Palmer Eye Institute in Miami, where Philip Rosenfeld, MD, PhD, pioneered the use of Avastin injections for the treatment of wet AMD. In rejecting the rebates, Bascom Palmer released the following statement:

“On Thursday, Nov. 4, 2010, Andrew Pollack of the New York Times wrote an article describing a secret rebate program between the pharmaceutical company Genentech and select eye doctors throughout the country. In this program, eye doctors are offered a financial kickback if they increase their use of an expensive eye drug known as Lucentis to treat patients who have the wet form of AMD. Lucentis was approved by the FDA in 2006 to treat this blinding disease. Some patients with this condition require repeated injections of this drug for many years at a cost of approximately $2,000 per injection.

“The ophthalmologists at the University of Miami's Bascom Palmer Eye Institute have not participated in this program and will never accept any type of financial kickback designed to influence patient care.

“Bascom Palmer … is committed to providing its patients the best possible, most cost-effective, advanced eye care. When treating eye disease, the decision to select one treatment therapy over another rests with the physician and the patient who together consider the patient's medical condition, financial resources, and medical insurance. Bascom Palmer will continue to use both Avastin and Lucentis appropriately in the care of its AMD patients.”

In addition, the AAO has said it will join with the major retina-related organizations to soon publish an educational article discussing the ethical ramifications of the rebate program.

Stem cell trial approved. Advanced Cell Technology said the FDA has cleared the company's Investigational New Drug application to initiate a 12-patient phase 1/2 multicenter clinical trial using retinal cells derived from human embryonic stem cells to treat patients with Stargardt's macular dystrophy (SMD).
“There is currently no treatment for Stargardt's disease,” said Robert Lanza, MD, ACT's chief scientific officer. “Using stem cells, we can generate a virtually unlimited supply of healthy RPE cells, which are the first cells to die off in SMD and other forms of macular degeneration. We've tested these cells in animal models of eye disease. In rats, we've seen 100% improvement in visual performance over untreated animals without any adverse effects.
The company also filed an IND application for a 12-patient phase 1/2 trial using human embryonic-derived RPE stem cells to treat dry AMD.
FDA requests more Iluvien data. Alimera Sciences experienced a setback at year-end when the FDA failed to approve its Iluvien implant for the treatment of DME and in stead requested a third year of clinical data on the drug, plus additional manufacturing specifics. Alimera had submitted two-year data for Iluvien but has now completed the third-year. No new trials were requested.
Lpath targets lipids. Lpath has been awarded a $3 million grant by the National Eye Institute to support phase 2 clinical development of Lpath's iSONEP in treating wet AMD and possibly other ocular disorders.
Lpath is involved in lipidomics-based therapeutics, an emerging field of medicine that targets bioactive signaling lipids for treating a wide range of human disease. It is partnering with Pfizer on developing iSONEP.
iSONEP binds to and inhibits the function of S1P (sphingosine-1-phosphate). Lpath says growing evidence suggests that the bioactive lipid S1P could contribute to both the early and late stages of maladaptive retinal remodeling associated with wet AMD. Lpath believes that inhibiting the action of S1P could be a novel and effective therapeutic treatment for wet AMD that may offer significant advantages over exclusively anti-VEGF approaches (or could act synergistically with them) to address the complex processes and multiple steps that ultimately lead to serious vision loss. RP