CATT Study Data: An Evaluation
Jerry Helzner, Senior Editor
■ The much-anticipated one-year results from the 1185-patient Comparison of Age-Related Macular Degeneration Treatment Trials study are now available for evaluation and interpretation. The data indicate that Lucentis and Avastin are about equally effective in improving vision in patients with wet AMD. Gain in visual acuity at one year was 8.5 letters for Lucentis monthly, 6.8 for Lucentis PRN, 8.0 for Avastin monthly and 5.9 for Avastin PRN. However, Lucentis monthly demonstrated a slightly greater ability to decrease central retinal thickness.
While the results answer many questions regarding the comparative effectiveness of Lucentis and Avastin in the treatment of wet AMD, they also raise other questions. These mainly concern possible systemic side effects and the option of using PRN dosing as a way to reduce the number of injections at a small sacrifice in visual improvement. PRN dosing resulted in four to five fewer injections over the first year, but an average of about two fewer letters of visual gain compared to monthly injections.
A major issue that remains unresolved is possible systemic side effects with Avastin. Patients given Avastin had a 24% overall incidence of adverse events, while Lucentis patients had a 19% incidence. But the most serious adverse events, such as stroke, were about equal for both drugs.
Genentech, the developer of both drugs, said the CATT study added to safety concerns regarding Avastin use in the eye, while the AAO said in a statement that both drugs should be available to treat wet AMD.
“This important study provides critical information that further empowers ophthalmologists to make evidenced-based decisions and select the treatment option that provides the best care for their patients,” said Academy CEO David Parke, II, MD.
SAFETY ISSUES RAISED
Genentech has long contended that Lucentis was formulated and tested as an eye drug, while Avastin was formulated as a cancer therapy and has never been tested in clinical studies or proven its safety as an eye drug.
“Avastin and Lucentis are different medicines,” Genentech said in a statement after the CATT data was released. “We specifically designed Lucentis to be cleared more quickly from the bloodstream to minimize side effects.” Noting the higher rate of serious adverse events (primarily hospitalizations) among Avastin patients, Genentech said that “these findings from CATT add to an emerging body of evidence from much larger analyses that suggest the risk of systemic adverse events may be higher when injecting Avastin into a person's eye compared to Lucentis.”
The difference in systemic adverse events may be due to a slight imbalance in baseline health between the Lucentis and Avastin patients. More of the latter had diabetes, hypertension, congestive heart failure and other medical conditions, noted Dan Martin, MD, principal investigator of CATT, in his presentation at ARVO.
Genentech has also been pointing to another study presented at ARVO that links Avastin to a higher incidence of stroke and in creased mortality than with Lucentis — a finding that is contrary to the almost equal incidence of stroke found in the CATT study. The study presented at ARVO was conducted by university-affiliated researchers, with support from Genentech.
IMPACT ON PRACTICE
“On an efficacy level, the drugs appear equal,” noted David Boyer, MD. “We will have to see the second-year data to see if the OCT fluid that seems to persist with Avastin will amount to anything. It also showed that if patients are followed monthly, the results of PRN vs monthly are close.
“I think the differences in adverse events were probably background noise and not significant. The lack of APTC events was important.”
Dr. Boyer said “the big unknown” is the Medicare database analysis used in the ARVO study to indicate increased stroke risk with Avastin. “If safety is a problem, efficacy is not going to matter, he said.” Dr. Boyer said an independent group of retina specialists should look into the safety issues. He also noted that efficacy findings for wet AMD may not translate to RVO and DME.
CATT study patients will be followed for a second year, looking at questions such as duration of VA gain, impact of switching from monthly to PRN dosing, and the role of SDOCT in clinical decision-making.
In his ARVO presentation, Dr. Martin noted that CATT offers copious detail on visual acuity among the four groups at multiple time points, and likened it to “a very high-power microscope.” Some of the smaller distinctions in letter gains to be found by parsing the data may not be noticeable to patients and should not overshadow the significant improvement made possible by any of the four regimens documented in the study, he concluded.
Antibiotic After Intravitreal Injection?
Bascom Palmer study finds no added benefit.
■ Researchers at Bascom Palmer Eye Institute found that applying topical antibiotics before and after intravitreal injections provides no added benefit in reducing the risk for endophthalmitis as long as a rigorous prophylactic protocol that emphasizes the use of povidone-iodine is followed. Their data was reported at the recent ARVO meeting.
The incidence of endophthalmitis was assessed following intravitreal injections performed by one physician who stopped the use of daily postinjection topical antibiotics following intravitreal injections on April 1, 2008.
The following protocol was used for all intravitreal injections:
Topical proparacaine was applied followed by a povidone-iodine (10%) scrub of the lids and lashes. A sterile lid speculum was placed, and povidone-iodine (5%) drops were applied over the ocular surface three times several minutes apart. Between povidone-iodine drops, a sterile cotton swab soaked in sterile 4% lidocaine was applied to the area designated for injection in the infero-temporal quadrant. Povidone-iodine 5% solution was applied to the site just prior to injection. Immediately after the injection, one drop of topical 0.5% moxifloxacin was placed into the inferior fornix in all patients injected between April 1, 2008 and June 30, 2009. Thereafter, the one drop of antibiotic was replaced with one drop of povidoneiodine 5%. Following the injection, none of the patients received any additional topical antibiotics.
From April 2008 through June 2009, a total of 3,928 injections were performed using one drop of postinjection moxifloxacin. From July 2009 through October 2010, a total of 4,515 injections were performed with the post-injection drop of povidone-iodine Overall, 8,443 injections were performed without the use of daily post-injection topical antibiotics.
Researchers reported that the injected medications included ranibizumab, bevacizumab and triamcinolone acetonide. The clinical indi cations for injections included wet AMD, choroidal neovascularization from other causes, RVO, proliferative diabetic retinopathy, DME, CME and neovascular glaucoma. No cases of endophthalmitis were identified.
The researchers concluded that “the absence of daily post-injection topical antibiotics did not result in any cases of endophthalmitis. It seems as though topical povidone-iodine is adequate to prevent endophthalmitis, and the use of topical antibiotics may not be justified based on their cost and the growing epidemic of antibiotic resistant organisms.”
New Concepts in Sustained-Release Drugs
Utah researchers offer a novel implant design.
Jerry Helzner, Senior Editor
■ Enthusiasm about the proven effectiveness of intravitreal injections of anti-VEGF drugs to treat a range of retinal diseases has been tempered by the hardships imposed on patients and retinal practices by the need for repeated injections.
Major benefits to society and a substantial financial payoff are the potential rewards for whoever comes up with a more patient-friendly way to administer anti-VEGF drugs. Thus, it is no surprise that Eugene de Juan, MD, MA, who co-founded the ForSight incubator in Menlo Park, CA to encourage innovation in eye care, estimates that there are “about 20 serious initiatives” now underway around the world to develop new ways to administer ophthalmic drugs. ForSight itself is working on such an initiative.
While most retinal specialists are familiar with companies such as pSivida, SurModics and Neurotech, which have been developing advanced drug delivery systems for years, presentations from the recent ARVO meeting indicate that highly innovative concepts are also coming from academia.
For example, a multi-departmental effort by the University of Utah and Johns Hopkins University is in the process of developing a refillable, sustained-release drug-delivery system called the capsule drug ring (CDR) that has the potential to deliver a drug to the front or back of the eye for up to a year.
Designed to be implanted in the capsular bag, the CDR is intended to maximize the volume available in the capsular bag without interfering with or impairing vision. The device is designed as a circular ring shape with a drug reservoir of 40 µL. Prototype CDR designs have been manufactured and testing in rabbit eyes has begun. Each component of the device is made from established medical grade biomaterials so it expected that the CDR will be within acceptable biocompatibility limits.
Balamurali Ambati, MD, of the University of Utah Moran Eye Center, says the CDR should have several advantages over competing sustained-release delivery systems because of the following factors:
► The CDR is the only system that takes an anterior approach rather than the usual method of intravitreal implantation.
► CDR implantation can be done by a general ophthalmologist, thereby greatly enlarging the market for the device.
► The CDR can be designed to deliver a combination of drugs.
► The CDR can deliver drugs to the front or back of the eye.
► The CDR can be placed prophylactically for future use, as part of cataract surgery, for example.
The researchers have used Avastin and dexamethasone as drugs of interest through in vitro testing to show that the device works as designed and delivers the drug in the desired way. The in vitro biocompatibility of the completed CDR and of the component materials was also assessed through a variety of tests and evaluation.
Dr. Ambati says the current timetable calls for duration of release and efficacy studies in the next year, with the possibility of a phase 1 human trial beginning late next year. Dr. Ambati and his brother Jayakrishna Ambati, MD, a noted retinal specialist from the University of Kentucky, have formed a company, Ivena, that will license the intellectual property from the University of Utah. A Dutch company, DSM Biomedical, is also expected to participate in the development and commercialization effort.
Another ARVO presentation featuring a sustained-release concept focused on a minimally invasive, controllable device being developed by researchers at McMaster University in Ontario. The device combines photogels and microneedles to control the release of therapeutic molecules into the back of the eye for a prolonged period.
Still another presentation highlighted a drug-delivery system being developed by French and Swiss researchers. This system is based on copolymer micelles, which have been tested in rabbit and rat eyes using cyclosporine A delivered into corneas and corneal cells via the micelles.
Predicting Macular Hole Surgical Outcomes
Two factors that can determine success.
■ Researchers representing the ophthalmology departments of several universities in Scotland combined to conduct a study to determine if any patient data available to them preoperatively could serve as predictors for the outcomes of idiopathic full-thickness macular hole (FTMH) surgery.
The researchers initiated a prospective randomized clinical trial, enrolling 141 patients. Patients with stage 2-3 FTMH were randomized 1:1 to receive internal limiting membrane peeling or no peeling. Baseline measurements included in the evaluation of outcomes included duration of symptoms, distance and near BCVA, size of the hole, and surgical procedure carried out. Results were measured on both functional and anatomical outcomes, including distance visual acuity at six months and macular hole closure with a single surgery. The outcomes were investigated using step-wise regression analysis.
The researchers found that distance and near BCVA at baseline had the most significant p-values for association with postoperative vision, with the best vision following surgery in those patients with higher levels of vision preoperatively. The most statistically significant factor predicting macular hole closure was the type of surgery received—ILM peel versus no peel—with a statistically significantly higher chance of hole closure in patients receiving ILM peeling at initial surgery. Another lesser, but statistically significant, factor contributing to outcomes was the size of the hole.
The researchers concluded that visual acuity and peeling of the internal limiting membrane were the best predictors for functional and anatomical success following macular hole surgery in patients with idiopathic FTMH.
The research was presented at the recent ARVO meeting.
RP Patients Benefit from Retinal Prosthesis
Some functional sight restored.
■ The largest study yet on the effectiveness of Second Sight's Argus II retinal prosthesis in restoring some sight to retinitis pigmentosa patients was recently reported at ARVO. The study, encompassing 30 patients and an average of more than two years of follow-up, showed significant visual benefits for the great majority of the patients.
Researchers led by Mark S. Humayun, MD, of the Doheny Eye Institute reported that all subjects had bare light perception or worse vision due to retinitis pigmentosa. All subjects were implanted with an Argus II implant. Visual function was evaluated by a grating visual acuity test as well as by assessing the ability to determine the direction of motion of a line and the location of a square on an LCD screen. Orientation and mobility (O&M) tests were also given, which involved following a line and finding a door.
As of December of last year, 30 subjects had been implanted for an average of 28 months. The rate of adverse events, which was moderate to begin with, was significantly reduced in the last 15 patients.
In terms of implant retention, 28 out of 30 devices remain intact and functioning. One device was explanted at approximately 14 months post-implant; a second remains implanted but functions intermittently due to partial loss of the radio frequency link that provides power and data to the array.
Results on visual function tests with high-contrast stimuli showed a hierarchy of function, progressing from the ability to locate an object, through the ability to detect the direction of motion, and finally to the ability to distinguish the orientation of black and white gratings. To date, the best grating visual acuity measurement obtained by the researchers was 1.8 logMAR (20/1260). Functional vision O&M tests demonstrate that subjects are significantly better at performing visual tasks with the system “on” vs. “off ” and that this effect is maintained during long-term follow-up of more than two years.
Researchers concluded that “the results confirm previous reports on the ability of the Argus II prosthesis to provide visual function and functional vision over the long-term. Higher resolution devices are in development.”
Dry AMD Drug Effective in Trial
Neurotech implant stabilizes vision.
■ It was recently reported in the Proceedings of the National Academy of Sciences that Neurotech Pharmaceuticals' product candidate NT-501 slowed progression of vision loss in patients with geographic atrophy associated with dry AMD in a phase 2 study. NT-501 is an intraocular implant that consists of human cells genetically modified to secrete ciliary neurotrophic factor (CNTF)—a nerve growth factor capable of rescuing and protecting dying photoreceptors.
The phase 2 study was a multi-center, double-masked, sham-controlled, dose-ranging study in 51 subjects with geographic atrophy. Subjects were randomly assigned to receive either a high- or low-dose NT-501 implant or sham surgery. The primary study endpoint was change in BCVA at 12 months. The study results demonstrated a dose-dependent increase in retinal thickness suggesting increased photoreceptor metabolic activity. This increase was followed by visual acuity stabilization (loss of fewer than three lines of vision, or 15 letters) of 96.3% in the high-dose group compared to 83.3% in the low-dose group and 75.0% in the sham group. In a sub-group analysis of subjects with better vision at baseline (20/63 or better), 100% of the high-dose group (n=10) maintained visual acuity stabilization compared to 55.6% in the combined low- and sham-treated groups (n=9). In this sub-group analysis, there was a 0.8 mean letter gain in the high-dose group compared to a 9.7 mean letter loss in the combined low- and sham-treated groups.
Overall, there were no serious adverse events reported and the surgical procedures were well tolerated.
The study's lead author and one of its clinical investigators, Kang Zhang, MD, PhD, professor of ophthalmology and human genetics at Shiley Eye Center of San Diego, commented, “The study findings are very promising since both structural and functional improvements were demonstrated in a disease that is currently untreatable. These results support the initiation of larger confirmatory studies of NT-501 in patients with GA.”
In another small study of NT-501, the drug demonstrated statistically significant cone photoreceptor preservation in patients with retinitis pigmentosa, a disease characterized by the progressive degeneration of photoreceptor cells. This data was recently reported in the journal Investigative Ophthalmology & Visual Science.
|■ Anti-VEGF and delayed ocular hypertension. With some small-scale studies indicating that anti-VEGF injections can cause significant delayed increases in IOP, researchers at the University of Pennsylvania set out to conduct a large-scale study to either prove or disprove the earlier findings.|
After studying 347 treated eyes and 200 control eyes for up to two years, the researchers found that only four of the treated eyes and three of the control eyes experienced significant delayed IOP increases to greater than 30 mm Hg at a single visit. These patients had IOPs of less than 21 mm Hg at baseline.
The researchers, who presented their findings at the recent ARVO meeting, concluded that there is no significant increased risk of delayed ocular hypertension following anti-VEGF injections.
■ Phase 3 DME trial for VEGF Trap. Regeneron Pharmaceuticals and Bayer HealthCare said they have initiated the first of two phase 3 clinical trials evaluating the efficacy and safety of investigational VEGF Trap-Eye in the treatment of DME. The companies are extending their development program for VEGF Trap-Eye in DME after promising results in the phase 2 DaVinci DME program.
The first phase 3 trial in DME, named VIVID-DME, is being led by Bayer HealthCare and has started in Australia. The trial will also be conducted in Europe and Japan. A second study led by Regeneron, named VISTA-DME, is expected to begin later in 2011 in the United States, Canada and other countries.
In related news, Regeneron said the FDA has accepted for priority review the company's Biologics License Application for VEGF Trap-Eye for the treatment of wet AMD. Under priority review, the target date for an FDA decision on VEGF Trap-Eye is August 20, 2011.
■ IOP spikes following vitrectomy. Japanese researchers found a number of variables that govern the incidence of short-term IOP spikes following vitrectomy. Their findings were presented at the recent ARVO meeting.
A prospective study was performed in 231 consecutive patients with various vitreoretinal disorders. IOP was measured before surgery, at the end of surgery, and at five hours and one day after surgery. Clinical data were collected, including age, sex, performance of combined cataract surgery, vitrectomy cutter size (20-G or 25-G), operation time, use of expanding gas tamponade, number of laser photocoagulations, occurrence of postoperative fibrin formation, and severity of postoperative vitreous hemorrhage, to determine risk factors for IOP elevation.
IOP elevation (>25mm Hg) was found in 23.8% and 23.4% of patients at five hours and one day postop, respectively. IOP at five hours in macular hole was significantly lower than in DME, PDR, PVR and RD. The IOP at one day in PDR and RD was significantly higher than in macular hole and epiretinal membrane. Step-wise multiple regression analysis revealed that IOP at five hours postoperatively had a significant correlation with number of laser photocoagulations, preoperative IOP, combined cataract surgery and 20-g vitrectomy. IOP at one-day postoperatively was also significantly associated with these four parameters as well as severity of postoperative vitreous hemorrhage and use of expanding gas tamponade.
■ Lidocaine gel doesn't prevent endophthalmitis. A 10-year study of all intravitreal injections given by ophthalmologists at the Stanford University School of Medicine and presented at ARVO found no statistical benefit for administering 2% lidocaine gel prior to the application of povidone iodine.
More than 8,800 cases were studied, with 4,120 patients receiving no lidocaine and 4,682 receiving lidocaine. The researchers, led by Theodore Leng, MD, found that each group had four cases of endophthalmitis.