VEGF Trap Extension Study Encouraging
…And A New Trap Trial for CRVO.
JERRY HELZNER, SENIOR EDITOR
■ Regeneron Pharmaceuticals said that 117 patients of the 157 individuals who participated in the phase 2 CLEAR-IT 2 study for wet AMD elected to enter an extension stage of the study after receiving VEGF Trap-Eye for 1 year. The company said 6-month data from the extension study confirmed a durable response from VEGF Trap-Eye.
VEGF Trap Eye is currently in 2 phase 3 trials (VIEW 1 and VIEW 2), with enrollment continuing and initial results expected next year.
Patients in the extension study have been dosed on a 2.0 mg PRN basis. On a combined basis, for these 117 patients, the mean gain in visual acuity was 7.3 letters at the 3-month primary endpoint of the original phase 2 study, 8.4 letters at 1 year, and 7.1 letters at month 6 of the extension stage. Thus, after 18 months of dosing with VEGF Trap-Eye in the phase 2 study, Regeneron said that patients continued to maintain a highly significant improvement in visual acuity vs baseline, while receiving, on average, only 3.5 injections over the 15-month PRN dosing phase that extended from month 3 to month 18. Patients continue to be dosed in the extension stage of the phase 2 study.
In addition, Bayer HealthCare AG and Regeneron Pharmaceuticals, Inc. said that the companies are extending their global development program for VEGF Trap-Eye to include Central Retinal Vein Occlusion (CRVO). The companies plan to initiate a phase 3 program evaluating the efficacy and safety of VEGF Trap-Eye in the treatment of CRVO in the second half of this year.
The phase 3 program in CRVO will consist of 2 multinational, 1-year clinical studies, which have been reviewed with regulatory authorities. These studies will expand the companies' global development collaboration for VEGF Trap-Eye, which already includes 2 ongoing phase 3 studies in patients with wet AMD and a phase 2 study in patients with Diabetic Macular Edema (DME).
Enrollment in the wet AMD and DME studies is expected to be completed later this year.
In the phase 3 CRVO program, Regeneron and Bayer HealthCare will conduct 2 identical multinational clinical studies: COPERNICUS (COntrolled Phase 3 Evaluation of Repeated iNtravitreal administration of VEGF Trap-Eye In Central retinal vein occlusion: Utility and Safety) will be led by Regeneron and GALILEO (General Assessment Limiting InfiLtration of Exudates in central retinal vein Occlusion with VEGF Trap-Eye) will be led by Bayer HealthCare.
Patients in both studies will receive 6 monthly intravitreal injections of either VEGF Trap-Eye at a dose of 2 mg or sham control injections. The primary endpoint of both studies is improvement in visual acuity vs baseline after 6 months of treatment. At the end of the initial 6 months, all patients will be dosed on an as-needed basis for another 6 months. All patients will be eligible for rescue laser treatment.
|■ Reading center expands OCT capabilities. The Digital Angiography Reading Center (DARC), New York, NY and its affiliate, the Digital Optical Coherence Tomography Reading Center (DOCTR), Cleveland, OH, the largest international reading center for standardized assessment of ophthalmic images for clinical trials, announced the integration of the newest spectral domain optical coherence tomography devices into their interpretation capabilities. DARC/DOCTR says it is the first reading center to offer sponsors the capability to choose from several spectral domain OCT devices for their clinical trials.|
The Cirrus HD-OCT from Carl Zeiss Meditec, Spectralis from Heidelberg Engineering, 3D OCT-1000 Optical Coherence Tomography System from Topcon Medical Systems, and the Spectral OCT SLO from Opko Health are currently accepted SD-OCT devices. Other systems are under review and validation. As the only reading center that can perform image interpretation using multiple SD-OCT imaging instruments, DARC/DOCTR offers sponsors a choice when it comes to spectral domain-OCT.
■ Ophthotech drug in wet AMD trial. Ophthotech Corp. said a small phase 1 clinical study evaluating E10030, its novel anti-platelet derived growth factor (anti-PDGF) used in conjunction with anti-VEGF therapy, produced encouraging results in treating wet AMD. The company said the addition of its anti-PDGF therapy resulted in enhanced visual outcome and was associated with significant neovascular regression.
Ophthotech said 59% percent of patients treated with anti-PDGF and anti-VEGF gained significant vision (3-line gain) at week 12 after therapy while 100% of treated patients demonstrated neovascular regression. E10030 was well tolerated with no evidence of drug-related adverse events. Current standard of care treatment utilizing monotherapy anti-VEGF results in 3-line visual gain in approximately one third of patients and without significant neovascular regression, according to Ophthotech.
■ Potentia completes phase 1 trial. Potentia Pharmaceuticals said that it successfully completed its phase 1 clinical trial for the company's leading drug candidate, POT-4 for AMD. The company now expects to move forward with a phase 2 program for the treatment of both dry and wet AMD.
The phase 1 trial was an open label, first-in-man, multicenter, single escalating-dose study. Potentia said the primary safety endpoint of this trial was achieved and the drug was well tolerated by all subjects at all doses tested, based on clinical signs, ophthalmic examinations, and laboratory results. No drug-related serious adverse events and no identifiable intraocular inflammation were reported. Additionally, significant sustained levels of POT-4 were consistently measured via serum analysis in subjects receiving the highest dose studied.
Potentia says the current POT-4 formulation is expected to provide sustained therapeutic ocular levels of the drug for several months following a single injection.
■ As-needed bevacizumab seen as cost-effective. A cost/benefit analysis performed by William Smiddy, MD, of Bascom Palmer Eye Institute, compared the costs per benefit of current widely used AMD treatments as well as modifications in regimens. He wrote in a recent article in Ophthalmology that, based on clinical data on the efficacy of various therapies, the cost per line of vision saved for 1 year of treatment ranged from a low of $84 with as-needed bevacizumab to $766 for protocolstyle use of ranibizumab.
Combination treatment yielded a range of $71 to $269. He found that the pharmaceutical portion of treatment cost can range as high as 83% for protocol-style ranibizumab compared to professional and facility costs. The author concludes that as-needed dosing, use of alternate medications, and combination therapy may preserve benefit for substantially lower costs.
■ Eye bank expands into research. The Tampa Lions Eye Institute for Transplant and Research (LEITR) plans to open a new 12,000-square-foot eye bank and advanced research facility to add to its existing 35,000-square-foot eye bank.
LEITR believes that expansion of its activities into advanced research is now necessary because of the "exponential growth" of such vision-robbing diseases as macular degeneration and glaucoma.
LEITR researchers will study diseased tissue as well as providing healthy tissue for transplant procedures. The goal will be to have a full spectrum of tissue available for study as a means to get to the underlying causes of blinding diseases while improving the quality of life for those already afflicted.
■ Leber's gene identified. Researchers with McGill Ocular Genetics Laboratory at the Montreal Children's Hospital of McGill University Health Centre, Canada, and elsewhere have identified a link between the retinal gene SPATA7 and Leber congenital amaurosis (LCA) and retinitis pigmentosa. Earlier research had identified 14 genes involved in LCA, but SPATA7 is the first gene with a mutation that disrupts the protein transport between 2 important compartments of the cell – the endoplasmic reticulum and the Golgi apparatus.
■ Home AMD detector. Researchers have confirmed the accuracy of a new in-home preferential hyperacuity perimetry (PHP) device, designed to detect the conversion of dry to wet AMD.
The device, the ForeseeHome AMD Monitor, will soon be introduced as an in-home complement to Foresee PHP, which currently helps clinicians to detect neovascular AMD at an early stage. The Foresee PHP and ForeseeHome were developed by Notal Vision and are being distributed by Sightpath Medical.
According to Sightpath Medical, a recent study conducted by a team of researchers led by Anat Loewenstein, MD, of the Tel-Aviv Medical Center, found that the ForeseeHome has a specificity of 84% and a sensitivity of 85% in detecting CNV. The sensitivity is independent of location or type of CNV lesion. Researchers say the device, which can be used frequently at home, will allow earlier detection of CNV and better visual outcomes following treatment.
Earlier research showed that the ForeseeHome demonstrated 30% greater sensitivity than the Amsler grid when used to test patients previously diagnosed with CNV. By combining patient interactive software with an innovative algorithm that measures relative photoreceptor field location, the ForeseeHome is designed to identify CNV lesions when they are very small and often before the patient notices symptoms. The ForeseeHome 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. RP
Our Men in Palau
Two US Doctors Battle Rampant DR.
■ A chance remark at a professional meeting in the early 1990s led to a long-term commitment by 2 retina specialists to bring better eyecare to the tiny Pacific island nation of Palau. It was at the meeting that Mark Wieland, MD, of San Jose, CA, mentioned that the technology for the diode lasers to treat diabetic retinopathy had improved to the point that the lasers were "now small enough to take anywhere in the world."
Hearing that comment, a US Public Health Service doctor approached Dr. Wieland and asked if him if he could bring such a laser to the island of Palau, where the incidence of diabetic retinopathy was almost 10 times the incidence in the United States.
Dr. Wieland, an avid scuba diver, knew that Palau, a tourist paradise, offered some of the best scuba diving in the world. With an opportunity to both help people in need of eyecare and get in some scuba diving, Dr. Wieland quickly accepted the offer.
After his first trip, Dr. Wieland asked his friend, James Handa, MD, also a retina specialist and diving enthusiast, to join him on subsequent missions to Palau. Dr. Handa, the Robert Bond and James Bond Welch professor of ophthalmology at the Wilmer Eye Institute of Johns Hopkins University Medical School in Baltimore, picks up the story:
"Diabetic retinopathy and obesity on the island is basically the result of a terrible diet," says Dr. Handa. "It's a shame because the islanders used to have a healthy diet consisting of fish and taro, which is a locally grown vegetable similar to a potato."
Dr. Handa says that after World War II, the approximately 20,000 residents of Palau got access to packaged foods and many of them wound up eating mainly potato chips and Spam. "There are some local efforts going on now to reverse that trend, including getting the island doctors to set a better example for their patients by cutting the potato chips and Spam from their own diets."
Dr. Wieland examines a patient on the Pacific island of Palau.
Making his first trip to Palau in 1994, Dr. Handa found that the island had a newly built hospital.
"We brought our own equipment and, through the years, have received a number of donations from US eyecare companies, including a slit lamp from Zeiss and IOLs from Alcon."
Drs. Handa and Wieland go back to Palau each year, usually in February. Local physicians, who have been trained by Drs. Handa and Wieland in basic eye care, pre-screen patients so that the visiting ophthalmologists can treat the patients most in need of care. The pre-screening has been helped by the addition of a Digiscope nonmydriatic fundus camera that is now used to send images from Palau to the Johns Hopkins reading center. This technology allows the highest-risk patients to be identified in advance.
"We can see about 300 patients on each trip, with about 50 receiving laser treatment," notes Dr. Handa. "We also do cataract surgery and handle other eye problems." For their efforts, Drs. Handa and Wieland receive only free air fare. Their time is donated. "We probably save the Palau health authorities about $100,000 to $500,000 on each trip," says Dr. Handa. "But our real reward comes from the patients. When I walk down the street, people laugh and say things like "look up now." They mimic the instructions we give them during their exams."
One further achievement: Drs. Handa and Wieland were able to get an autorefractor that stays on the island.
"Now, the local doctors can do a basic eye exam and get eyeglasses made for people throughout the year," says Dr. Handa.
Dr. Handa says his commitment to Palau pays off in continuity of care.
"We're able to better manage cases," he says. "We see some of these people every year."
|■ Plasmapheresis for dry AMD takes a hit. The lead-off editorial in the May 2009 issue of Retina concludes that plasmapheresis lacks evidence at this point to merit anything other than further clinical trials in treating dry AMD. Furthermore, the authors — a team of retinal physicians from the University of Bonn — write that, unlike AREDS or anti-VEGF treatments, plasmapheresis is also not cost-effective, since most insurance companies will not cover the complicated blood-filtration process. Five studies have been undertaken to look at the possible efficacy of plasmapheresis for treating dry AMD. Of the studies, only a single Austrian trial, which combines plasmapheresis with lutein supplementation, is still recruiting. Occulogix's RHEO-AMD trial was suspended in late 2007.|
■ Stem cells offer promise for retinal disease. With President Obama removing restrictions on stem-cell research, researchers expect a host of stem-cell-based medical therapies to emerge in the coming year, including for retinal disorders. Doctors at Wills Eye Institute have published a literature review in the May 2009 Current Opinions in Ophthalmology on stem-cell research in retina, describing 5 donor sources (including embryonic) and then transplantation methods under investigation, including direct transplantation to the RPE. While there is much work to be done, the authors see stem-cell research as a very promising horizon for new therapies.
■ TGF-beta key to healthy retina. Scientists at Schepens Eye Research Institute have found that the growth factor known as TGF-beta is essential to the health of blood vessels in the retina and that blocking it can cause retinal dysfunction. These findings, published in a recent issue of PLoS ONE, may have an important impact on the prevention and treatment of diseases such as diabetic retinopathy and macular degeneration, according to Schepens.
"These results are significant because they add to our understanding of the molecules that help to maintain blood vessels in a healthy state," says Patricia D'Amore, PhD, senior scientist at Schepens and principal investigator of the study, who adds that this information may be useful in understanding the changes that occur in the retinal microvasculature prior to the development of proliferative diabetic retinopathy.
"Insight into the role of this growth factor may also help clinicians monitor the use of systemic drugs targeting TGF-beta, which is elevated in a number of conditions (such as cancer and fibrotic diseases) to limit any vision problems that might occur as a side effects," adds Tony Walshe, PhD, the first author of the study.
■ Macular translocation vs patch graft. A retrospective review of the first 12 wet AMD patients who underwent macular translocation (MT) and the first 12 patients who underwent patch graft (PG) at Moorfields Hospital, London, was reported in the April 2009 issue of Investigative Ophthalmology and Visual Science. Researchers recorded visual acuity (VA), contrast sensitivity (CS), clinical findings, and complications. Microperimetry and fundus imaging were reviewed. Outcome measures were the change in VA and CS over 3 years in each group and rates of complication.
The two groups were matched for age and VA. Median follow-up durations were 41 (MT) and 38 (PG) months. Median VA (logMAR) was maintained in the MT group but declined significantly in the PG group after 3 years. Both modalities had high rates of detachment and macular edema. Although more extensive RPE damage occurred with PG, the graft resisted growth of recurrent choroidal neovascularization toward the fovea. Near normal VA was achievable by each technique but macular sensitivity and fixation stability were superior in the MT group.
In the cohorts studied, MT maintained VA for 3 years but PG did not. Researchers postulated this outcome may be related to the differences in surgical approach, source of RPE, and choroidal perfusion. The authors recommend MT in preference to PG for treatment of patients with the second eye affected by neovascular AMD unsuitable for other treatment.
■ Viagra and Cialis safe for retina. Researchers using electroretinogram, as well as other tests, to measure ocular anatomy and vision found no toxicity related to use of sildenafil (Viagra) or tadalafil (Cialis) by men with erectile dysfunction.
In a study published in the April 2009 Archives of Ophthalmology, the ERG Testing During Chronic PDE5 Inhibitor Administration (ERG-PDE5i) Consortium saw no abnormalities in ERGs taken from 102 men taking either 5 mg Cialis or 50 mg Viagra daily, and no statistically significant difference between the test and the placebo arms in visual function or intraocular pressure. The ERG-PDE5i consortium concludes that there is no retinal damage caused by either of their test doses for the 6-month study period, although they acknowledge the study is limited by the fact that only otherwise healthy men with erectile dysfuction were recruited for the study.
Intraoperative Retina Navigation Debuts
■ Surgeons may soon have the ability to apply laser pulses during retinal photocoagulation procedures more precisely if done with real-time guidance from a new laser, called Navilas, that provides a fluorescein angiographic overlay onto the surgical field.
The surgeon first captures retinal images and fluorescein angiography results, then uses a computer interface to mark areas to treat — and those not to treat, such as near the fovea and optic nerve. The plan is then displayed over top of the live fundus image to provide a roadmap for the surgeon to follow. Manufacturer OD-OS, located in Teltow, Germany, summarizes this process as "image, plan, treat" and the concept itself as "retina navigation."
OD-OS (www.od-os.com) was recently created as a spin-off from SensoMotoric Instruments, a company with a long history of providing eye tracking and registration solutions in many refractive lasers.
Imaging takes place via scanning slit digital ophthalmoscope rather than a slit-lamp. Three fields of view are possible (10°, 30°, and 50°). The system uses a 532 nm diode laser. For safety, the laser is inoperable in areas marked by the surgeon to be blocked from treatment. Proponents of the concept stress that it is not an automated process. Surgeons can make adjustments on the fly.
After pre-planning the treatment strategy on diagnostic images such as fluorescein angiography, "this graphic plan may then be subsequently overlaid onto the live image of the retina during treatment to assist the doctor in localizing his treatment," said Winfried Teiwes, CEO of OD-OS. "However, the doctor — and not the device — makes the final treatment decision, as he does now during photocoagulation with the slit lamp."
The Navilas interface allows the surgeon to mark areas for treatment using spots or grids, and to block certain areas from receiving laser energy.
The initial results of image registration and tracking accuracy were presented at the recent ARVO and Euretina conferences by William Freeman, MD and Aljoscha Neubauer, MD, respectively. In the study, 98 eyes were evaluated by 5 specialists at 2 centers. Dr. Neubauer mentions the following highlights of the study:
- Tracking robustness (the ratio between images correctly tracked and total images) was 95%.
- Image overlay accuracy is within 60 microns.
- Manual positioning of an individual laser pulse is accurate within an average 21 microns at a 50-micron laser spot size.
- When using a rectangular grid pattern, the average positioning error is less than 6%.
The main advantage to the surgeon is greater precision. "You now have a one-to-one relationship between your treatment target and the location treated," Dr. Neubauer said. "There may also be safety advantages from blocking certain zones from treatment." Future studies will attempt to show this in the clinic.
Although the primary use at the outset will be photocoagulation in diabetic macular edema, the device may find a role for other retinal diseases such as venous occlusions or treatments in AMD such as for feeder vessels, Dr. Neubauer says.
Navilas is pending CE certification and not yet for sale.
Euretina Attendees Enjoy a Diverse Program
■ A record-setting 1700 members of the retina community converged on the Mediterranean seaside town of Nice, France last month for the 9th annual Euretina Congress, hosted by the European Society of Retina Specialists.
The diverse educational program updated attendees on state-of-the-art care in AMD, uveitis, diabetic retinopathy, intraocular tumors and much more. The format varied from brief presentations of scientific papers to lengthier instructional courses and surgical workshops, plus two point-counterpoint debates on timely issues: the future of small-gauge surgery, and whether to treat all peripheral retinal lesions prophylactically.
The keynote lecture, "Can We Overcome the Fragmented European Space in Ophthalmology?" by Eberhart Zrenner, MD, of Tübingen, Germany, broke from the usual slate of scientific and clinical topics to offer a sobering look at the challenges stemming from a lack of coordination among the dozens of national and European ophthalmic societies operating largely independent of each other.
"No other field in medicine [in Europe] is more fragmented than ophthalmology," Dr. Zrenner observed. The consequences for practicing ophthalmologists and researchers, he said, are lower visibility and hence lower impact on research policy making and fundraising efforts. This dampens the pace of innovation and makes it more difficult to recruit promising new researchers to the field.
Dr. Zrenner chairs the European Vision Institute, founded in 2005 to overcome these impediments by forming an alliance of all organizations. Its goals are to coordinate collaborative efforts among societies, improve the visibility of European vision research on the world stage, encourage the free exchange of ideas between the basic science and clinical research worlds, and to build a pan-European platform for conducting clinical trials.
Next year's Euretina meeting will take place September 2-5 in Paris, to be immediately followed by the ESCRS annual meeting.