Can Anti-VEGF Trigger GA?
The issue is spurring a lively debate.
JERRY HELZNER, SENIOR EDITOR
■ One of the most puzzling and controversial findings to come out of the two-year CATT study data is the presence of geographic atrophy (GA) in 30% of the patients who received monthly doses of ranibizumab (Lucentis, Genentech) during the trial. Some patients who received bevacizumab (Avastin, Genentech) monthly or ranibizumab or bevacizumab PRN also showed signs of GA but not at the high levels seen in the Lucentis monthly arm of the trial.
The association of GA with the most potent dosing regimen of CATT has led at least two highly respected retina specialists, Philip Rosenfeld, MD, PhD, of Miami and Lawrence Singerman, MD, FACS, of Cleveland, to express concern that repeated anti-VEGF injections can serve as a trigger mechanism for GA. Dr. Rosenfeld has called the GA findings “one of the most interesting outcomes” from the entire CATT trial. But other equally highly respected retina specialists are reserving their opinion pending further corroborative data.
A SUSPECTED LINK
Dr. Rosenfeld told Retinal Physician he had suspected a possible anti-VEGF/GA association while following patients in the ranibizumab trials, including his own PRONTO study. In his retrospective review of all patients who participated in the pivotal ANCHOR and MARINA trials for ranibizumab and published last year in the journal Ophthalmology (2011;118:523-30), Dr. Rosenfeld explored the causes of vision loss among the 10% of the patients in these trials who lost at least 3 lines of vision at the 24-month mark. He found that retinal pigment epithelium (RPE) abnormalities indicative of GA were associated with this vision loss. At the time, Dr. Rosenfeld says he thought the changes were most likely signs of normal disease progression once the CNV was controlled; however, he says in light of the CATT results, the other possibility is that too much VEGF inhibition might promote the formation and growth of geographic atrophy.
DR P. MARAZZI/SCIENCE PHOTO LIBRARY
In his 2011 article, Dr. Rosenfeld concluded that “vision loss after two years of monthly ranibizumab therapy was associated with lesion characteristics commonly associated with suppressed CNV, such as pigmentary abnormalities, atrophic scar, and the absence of leakage.” He added that “future VA improvements in patients receiving ranibizumab therapy may require preservation of photoreceptor and RPE function rather than strategies that target CNV.”
‘TREAT AND EXTEND’
As a result of his analysis of the three studies, Dr. Rosenfeld concludes that, given the current lack of an effective treatment for GA, anti-VEGF therapy should be used judiciously following a “treat-and-extend” protocol. In this way, he says the significant and immediate visual benefits of anti-VEGF can still be achieved. He sees treat-and-extend dosing as possibly a necessary real-world trade-off to reduce the possible risk of GA until researchers have better knowledge of whether the GA results of the CATT trial can be reproduced.
“While blockage of VEGF can stop the growth of blood vessels and improve vision in the short-term, too much VEGF inhibition may cause the dry AMD to progress,” Dr. Rosenfeld states.
“I refer to treat-and-extend dosing as the Goldilocks approach; we don’t want too much VEGF inhibition and we don’t want too little,” Dr. Rosenfeld says. “We want just the right amount.”
Though almost all retina specialists tend to support the “treat-and-extend” protocol as an effective and patient-sparing regimen, the possible role of anti-VEGF injections in triggering GA remains controversial.
David Boyer, MD, of Los Angeles calls the theory “speculation.” He notes that “we should be aware that GA was not diagnosed by autoflourescence and may be related to the difference of drying that Lucentis was shown to do more frequently than Avastin. GA can also be measured by OCT but is very difficult to measure when you have glial scarring.”
Others have gone so far as to say the GA images are meaningless artifacts that carry no real indications of new disease. However, mouse studies conducted by Patricia D’Amore, PhD, of Schepens Eye Institute, and Martin Friedlander, MD, PhD, of the Scripps Research Institute, were early in indicating that attacking VEGF aggressively could produce the unintended consequence of producing GA.
Asked by Retinal Physician to comment on meaning of the CATT findings, a spokesperson for Genentech e-mailed that “we believe the GA finding in CATT needs to be corroborated with other phase 3 wet AMD studies. We are in the process of analyzing our own data to determine whether we see the same GA finding or not.” The spokesperson also added, “the finding is not definitive and requires further research.”
A spokesperson for Regeneron told Retinal Physician that the incidence of GA was not evaluated during the pivotal VIEW trials but that the company is open to further evaluation of the VIEW trials, assuming that any relevant information could be gleaned from the fundus photography and angiography used in that trial.
If anti-VEGF therapy is proven to be associated with the formation and progression of GA, it could be a boost to those companies pursuing alternatives to anti-VEGF or effective treatments for GA.
Ocriplasmin Approved for Symptomatic VMA
A key role is played by Drs. Trese and Williams.
■ The FDA has approved ThromboGenics’ drug ocriplasmin (brand name Jetrea) as a therapy for symptomatic vitreomacular adhesion (VMA). Approval was widely expected after an FDA advisory committee earlier voted 10-0 to recommend ocriplasmin.
Ocriplasmin is administered as a one-time intravitreal injection and will be the first pharmacologic treatment for VMA, which encompasses such conditions as macular hole. Until now, VMA has been treated only with vitrectomy or observed through what is termed “watchful waiting.”
Two multicenter, randomized, double-blind phase 3 trials with ocriplasmin were conducted in the United States and Europe, involving 652 patients with VMA. Both studies met the primary endpoint of pharmacological resolution of VMA at day 28. Secondary endpoints were nonsurgical closure of a macular hole at day 28, avoidance of vitrectomy and improvement in visual acuity.
ThromboGenics developed a form of recombinant truncated ocriplasmin after partnering with Drs. Michael T. Trese and George A. Williams of Royal Oak, MI, who had for many years conducted successful human studies of their own autologous plasmin formulation. Alcon is now an international partner on Jetrea, having purchased the non-US rights to the therapy earlier this year.
ThromboGenics says it expects to make Jetrea available in January with 30 US sales representatives and a 15-member reimbursement team.
ThromboGenics is now exploring the potential use of Jetrea in other retinal diseases, including macular degeneration with traction, where a 100-patient study is under way, and diabetes-related eye disease.
A Pill to Treat Wet AMD?
Xcovery Vision will soon begin a trial.
■ Xcovery Holdings, the parent company of Xcovery Vision, a privately held biopharmaceutical company focused on creating novel eye therapeutics, said it will begin its phase 1/2 clinical trial of its oral angiogenesis inhibitor, X-82, for the treatment of wet AMD.
Xcovery Holdings also announced it has raised a total of $6 million in Series B financing.
“This round of financing demonstrates recognition of Xcovery’s progress in the advancement of our pipeline and the company’s long-term opportunities developing next-generation targeted therapeutics for cancer and ophthalmology,” says Xcovery Holdings CEO Sheridan G. Snyder.
The initial phase 1/2 trial will assess the preliminary safety and tolerability of X-82, a unique tyrosine kinase inhibitor (TKI) in an oral formulation that acts by blocking pathologic blood vessel growth. The trial will enroll a maximum of 20 patients and will be conducted at three US ophthalmology centers.
“The potential for an oral treatment for wet AMD is considered the ultimate therapeutic option for these patients,” Mr. Snyder says.
X-82 inhibits both VEGF and platelet-derived growth factor (PDGF), two important targets implicated in wet AMD. The compound has been designed to have a favorable toxicity profile and better tolerability as an oral medication than previous injectable drugs in this class.
“There is growing evidence that combined inhibition of VEGF and PDGF may have advantages over existing anti-VEGF therapies,” says Jeffrey S. Heier, MD, of Massachusetts General Hospital and head of Xcovery Vision’s advisory board “The prospect of an oral therapy for wet AMD is appealing to patients who may prefer taking a pill instead of an eye injection.”
Kenneth Mandell, MD, PhD, president and COO of Xcovery Vision adds, “Unlike current anti-VEGF injections that only treat the affected eye, our oral pill has the potential to prevent development of wet AMD in the opposite eye before disease progression.”
FDA Panel Endorses Argus II for RP
Retinal prosthesis provides functional vision.
■ An FDA advisory panel has voted unanimously to recommend approval of the Argus II retinal prosthesis developed over two decades of research by Second Sight Medical Products and its government and venture capital partners.
The device, which has been proven in clinical trials to offer some limited functional vision to patients living in darkness due to profound retinitis pigmentosa, has three components, encompassing a video camera attached to special eyeglasses, a processing unit worn on a belt and an implanted retinal prosthesis that receives signals from the processing unit.
In a 30-patient trial, most patients were able to gain enough functional vision to walk straight on a sidewalk and also determine if a person was walking toward them or away from them. Half of the patients could read very large letters from a foot away.
The FDA panel did express concerns about the number of both serious and minor adverse events that occurred with the Argus II but decided that the benefits to blind or nearly blind patients outweighed the risks.
The panel, comprised of 19 voting members with expertise in ophthalmology, retinal disease, low vision, electrophysiology and other specialties, heard testimony from the sponsor, FDA, and several doctors and participants involved in the most recent clinical trial that began in 2007.
“We are looking forward to working with the FDA now to quickly get the product approved,” states Anne-Marie Ripley, vice president of clinical and regulatory affairs at Second Sight. “There is no therapy available currently for these patients and we would like to make Argus II available to American doctors and their patients as soon as possible.”
The panel recommendation came after more than 20 years of work in the field, three clinical trials, more than $100 million in public investment by the National Eye Institute, the Department of Energy, and the National Science Foundation, and an additional $100 million in private investment.
“Modest gains in vision can make a big difference to a person blinded by retinitis pigmentosa,” says Paul Sieving, MD, PhD, director of the National Eye Institute. “The Argus II retinal prosthesis allows users to reclaim their independence and improve their lives.”
The panel’s unanimous vote is not binding but is expected to carry some weight in the FDA’s final decision.
Lucentis Preserves … Drivers’ Licenses?
Study shows improvement in driver-related outcomes.
BY RENÉ LUTHE, SENIOR ASSOCIATE EDITOR
■ Monthly injections of ranibizumab for patients afflicted with wet AMD improved outcomes relevant to driving, and thus may enable AMD patients to retain their licenses longer, according to a study led by Neil M. Bressler, MD, of Wilmer Eye Institute, Baltimore.
The phase 3, multi-site, randomized clinical trial examined 1,126 patients over a two-year period. Researchers used a 25-item National Eye Institute Visual Function Questionnaire to measure participants’ driving ability, perception and self-reported driving status in two studies. They also conducted monthly assessments of the best-corrected vision in each eye of the participants to evaluate the efficacy treatments for AMD.
One group looked at ranibizumab vs sham injections; the second compared results for ranibizumab injections to those for photodynamic therapy (PDT). The reports predictably showed that ranibizumab was more effective in avoiding vision loss than both sham and PDT.
The most recent analysis of the trials, however, focused on the impacts of the treatments that were relevant to driving.
Investigators looked at treatment vs no treatment in participants who said they were driving or not driving at the beginning and end of the study; treatment vs no treatment in those who had vision at the beginning and end of the study that would qualify them for an unrestricted driver’s license in at least 45 states; and a standardized questionnaire assessing the patient’s own perception about the level of difficulty driving in conditions such as rain, fog or at night.
In the ranibizumab vs sham group, 85% of those receiving ranibizumab achieved the level of vision required for an unrestricted license. In the ranibizumab vs PDT group, 88% of those receiving ranibizumab achieved the necessary level of vision.
In addition, both groups reported higher confidence while driving. However, the investigators concluded that more research was needed to determine whether individuals actually improve or maintain their level of driving skills or driving safety while using the medication.
“Our study has limitations because these two studies were not designed to assess directly the impact of ranibizumab on driving, and because there was just a small number of patients in the groups that were analyzed relative to the hundreds of thousands of patients affected by the wet form of AMD each year around the world,” Dr. Bressler says.
Bressler NM, Chang TS, Varma R, Suñer I, et al. Driving Ability Reported by Neovascular Age-Related Macular Degeneration Patients after Treatment with Ranibizumab. Ophthalmology. published online 24 September 2012.
■ EVRS Macular Edema Study results A major highlight of the recent European VitreoRetinal Society annual Congress in Dresden, Germany, was the release of preliminary data from the EVRS Macular Edema Study encompassing 2,603 cases from 85 retina specialists in 29 countries. All patients were treated between 2008 and the end of 2011 and all were followed for at least six months.
The study covers nine different disease etiologies, with by far the greatest focus on (in descending order of cases) DME, idiopathic epiretinal membrane, BRVO and CRVO. These four diseases represent approximately 80% of all the cases in the study.
The study is best viewed as a snapshot of the treatment choices European retina specialists were making within these four categories during the time period under study and the overall results achieved with the various treatment options. The study notes a number of difficulties in acquiring meaningful results, such as the large number of disease categories, the use of combination treatments and changes of treatments during the follow-up period.
However, some insights can be drawn from the data, including that anti-VEGF is shown to be the primary single therapy used in treating RVO, pars plana vitrectomy (PPV) combined with ILM peeling is by far the most favored and effective treatment for epiretinal membrane, and PPV/ILM demonstrated better results than anti-VEGF in treating DME despite anti-VEGF being used more often as monotherapy. RP