Retinal Degenerations: Imaging, Research, and Trials

Angiogenesis, Exudation, and Degeneration 2008

RYAN M. RICH, MD

The Bascom Palmer Eye Institute's Angiogenesis, Exudation, and Degeneration 2008 meeting was held on February 22 and 23 in Key Biscayne, FL. This conference was codirected by Philip J. Rosenfeld, MD, and Carmen A. Puliafito, MD. The following discussion provides an overview of the presentations during the 2-day conference.

IMAGING

Brandon Lujan, MD, and Giovanni Gregori, MD, discussed the use of spectral-domain optical coherence tomography (SD-OCT) in analyzing and monitoring dry agerelated macular degeneration (AMD). The high-speed, high-resolution 3D mapping of the macula enables visualization of pathologic alterations in the retina and retinal pigment epithelium (RPE), such as drusen and geographic atrophy (GA), and monitor the progression in a reproducible and quantitative manner. This holds significant potential for use in clinical trials and patient management.

GENETICS AND PHARMACEUTICALS

Margaret Pericak-Vance, MD, Kang Zhang, MD, and Scott Cousins, MD, examined the role of inflammation via complement factor H (CFH) and oxidative stress via gene HTRA1 as important contributors to advanced AMD. These pathways seem to be exacerbated by smoking. Gregory Hageman, PhD, added that drusen contain complement-related byproducts and RPE cells express many complement proteins. Genetic dysfunction is associated with development of AMD. There is 1 "risk" haplotype and 2 "protective" haplotypes of the CFH gene. Victor Perez, MD, said that drusen products may result by oxidative damage through antibody- and cellular-mediated immunologic mechanisms. Genetic analysis may identify high-risk patients and inspire pharmaceutical intervention.

Several presenters then discussed developments in complement inhibition. Lloyd Klickstein, MD, summarized the use of complement inhibitors in humans for many non-ophthalmic diseases. Complement targets discussed included C5 inhibitors (Alexion Pharmaceuticals, Cheshire, CT; and Jerini Ophthalmic, New York), C3 inhibitors (Potentia Pharmaceuticals, Louisville, KY), and complement factor D (Genentech, South San Francisco, CA). Several of these drugs are currently in phase 1 studies.

Other potential treatments for AMD that were discussed included subcutaneous glatiramer acetate (Copaxone, Teva Neuroscience), which is approved by the Food and Drug Administration for the treatment of multiple sclerosis; fenretinide (Sirion Therapeutics, San Diego), which competes with vitamin A metabolism and theoretically should reduce the deposition of these toxic fluorophores in dry AMD; and OT-551 (Othera Pharmaceuticals, Exton, PA), a topical antioxidant and anti-inflammatory that can achieve presumed therapeutic levels in the retina and choroid in animal eyes, was discussed as a treatment for GA in AMD (in phase 2 studies) and retinitis pigmentosa (RP). NT-501 (Neurotech, Lincoln, RI), an encapsulated delivery form of ciliary neurotrophic factor, is being studied in phase 2 trials as a neuroprotectant in dry AMD and RP. Byron Lam, MD, presented the current therapies for retinal degenerations, including stem-cell treatment for Leber congenital amaurosis and RP (CNTO trial), RPE cell transplantation, gene therapy, nutritional supplementation, and antioxidants.

NEW APPROACHES IN DRUG DELIVERY

Barry Kuppermann, MD, and Patrick Hughes, MD, provided an overview of topical therapies for retino-choroidal diseases. Topical administration seems to access the retina and choroid through transconjunctival and scleral routes, rather than through the cornea and vitreous. Topical ocular drugs for treatment of choroidal neovascularization (CNV) were discussed. Peter Campochiaro, MD, spoke of such a drug, mecamylamine, which appears to block nicotinic acid receptor-induced stimulation of CNV. The guest panel remarked that the imaging of drug delivery to the appropriate target tissue is important in understanding the pharmacokinetics of these drugs.

EXUDATION AND NEOVASCULARIZATION

Stanley Wiegand, MD, of Regeneron Pharmaceuticals (Tarrytown, NY) presented the role of angiopoietins (protein angiogenic growth factors) in CNV and inflammation. Systemic administration of Ang2 blockers has been shown to attenuate angiogenesis in rodent models of wet AMD.

Lois Smith, MD, shared data showing that erythropoietin (Epo) mRNA was substantially up regulated in periods of hypoxia and neovascularization and that exogenous Epo protected against hypoxia-induced neovascularization and vessel dropout in a mouse model of retinopathy of prematurity (ROP). She stated that understanding the role of Epo in angiogenesis is critical to timing intervention in patients with retinopathy or other angiogenic diseases.

Tim Murray, MD, stated that tumor vascular maturation is unique compared to the normal ocular vasculature and contains qualitatively and quantitatively different proteins that may allow for targeted therapy. Robert D'Amato, MD, described how anthrax toxin binds to a specific receptor on neovascular membranes and leads to destruction of new vessels. Studies are under way to test the efficacy of a modified anthrax toxin.

Jeffrey Edelman, MD, from Allergan (Irvine, CA) explained efforts to modulate glucocorticoids to preserve beneficial effects of steroids (including neuroprotection of the RPE) while eliminating side effects of ocular hypertension and cataractogenesis. Other therapies for wet AMD included the possible applications of the anti-tumor necrosis factor α drug infliximab (Remicade, Centocor), doxycycline, and an anti-platelet derived growth factor drug E10030 (Ophthotec, Princeton, NJ) in therapy for CNV.

Anat Loewenstein, MD, discussed models used to study retinal toxicity of intravitreal administration of antiangiogenic and antipermeability drugs. Based on electrophysiological, histological, and immunocytochemical studies, she concluded that intravitreal bevacizumab (Avastin, Genentech) and ranibizumab (Lucentis, Genentech) did not induce retinal toxicity even after frequent injections in rabbits. Ketorolac and infliximab need to be further studied.

HEALTHCARE ECONOMICS

George Williams, MD, explained that Medicare Part B includes physician-administered outpatient drugs and detailed how the expenditures of Part B are controlled through the Sustainable Growth Rate conversion factor. There is consensus that this formula is fatally flawed due to the always growing utilization of physician services and a shift of procedures from hospital-based services (Part A) to the office or outpatient area (Part B). Additionally, the increasing number of office visits and treatment for wet AMD has accounted for a tremendous increase in ophthalmology. The sales of ranibizumab alone accounted for $850 million in 2007. The current situation is untenable and Dr. Williams argued that the cost of physician-administered drugs should be removed from the equation.

William Smiddy, MD, updated last year's calculations of the cost of a line of vision. He compared the high cost of ranibizumab protocols used in the MARINA, PrONTO, and PIER studies with that of bevacizumab, photodynamic therapy, and combination therapies. He noted the problem of escalating costs at the expense of physician reimbursement. The use of less expensive drugs and combination therapies may provide solutions to cost containment without loss of quality. Stephan Michels, MD, reported that similar controversies are playing out in Europe.

MEDICARE AND AVASTIN CLINICAL TRIALS

Dan Martin, MD, provided an update of the CATT trial. Important developments that occurred before actual patient enrollment included: verification of a 6-month shelf life in a glass vial; the elimination of a mandatory 1-week follow-up visit; and a clarification of payment by the Centers for Medicare and Medicaid services of drugs used in clinical trials sponsored by the National Institutes of Health. Enrollment for CATT has already begun and is anticipated to continue for 1 year. Audina Berrocal, MD, reviewed aggressive posterior ROP and the role of vascular endothelial growth factor (VEGF) in ROP. She reported on bevacizumab in ROP as salvage and primary therapy. BLOCK-ROP is a study that will evaluate the safety of 1 intravitreal dose (0.75 mg) in a phase 1 trial.

UVEITIS, DIABETES, AND MORE

Lawrence Yannuzzi, MD, reviewed the pathogenesis of aneurysmal and perifoveal telangiectasia. Preliminary pilot studies suggest that anecortave acetate may be effective in the treatment of some patients with this condition. Current studies are exploring a possible genetic link between perifoveal telangiectasia and spastic paraplegia and Louis-Bar disease.

Janet Davis, MD, stated that CNV in uveitis occurs through inflammatory and ischemic pathways and seems to have a different profile than that of AMD. Inflammatory CNV appears to be responsive to bevacizumab, but treatment of underlying inflammation with immunosuppressives and immunomodulatory medications should also be used.

Harry Flynn, Jr., MD, provided an update of the Diabetic Retinopathy Clinical Research Network (DRCRN) and SCORE trial. The DRCRN has 118 active sites employing 322 investigators with 11 studies under way. Some results included the following: modified Early Treatment of Diabetic Retinopathy Study grid laser was superior to mild macular grid for diabetic macular edema (DME); diurnal variation of central retinal thickness (CRT) by OCT is <10%; peribulbar TA for DME was ineffective; bevacizumab and laser for DME were not statistically different at 12 weeks and a phase 3 trial is under way. Information regarding other SCORE trial is forthcoming.

Diana Do, MD, updated the READ-2 study for patients with DME. Treatment with ranibizumab vs. focal laser vs. ranibizumab followed by focal laser is being evaluated. A unique Web-based data entry and follow-up system has been employed in this study. Between 116 and 126 patients have completed the endpoint 6-month follow-up. Results will be published later this year.

Mark Blumenkranz, MD, detailed the clinical experience with rapamycin in DME. Phase 1 trials showed safety in both subconjunctival and intravitreal administration routes with no evident toxicity or adverse events. The majority of patients did have a benefit, although the phase 1 study was not powered to determine efficacy. A subconjunctival administration of rapamycin is moving into phase 2 studies.

Ninel Gregori, MD, presented the final data of the safety and efficacy of bevacizumab for cystoid macular edema (CME) secondary to central retinal vein occlusion (CRVO) and branch retinal vein occlusion. Significant improvements in visual acuity (VA) and CRT measured by OCT were observed through 1 year with an average of 3 injections. No systemic or ocular complications were noted. The authors concluded that a prospective trial for bevacizumab for this indication is warranted based on results of this study.

Richard Spaide, MD, discussed ranibizumab in treating CRVO. The severity of CRVO correlates with the amount of VEGF that is produced. Vision loss is from CME, optic nerve edema, and vitreous hemorrhage. Twenty patients with CRVO were studied prospectively. He reported a significant improvement in VA and OCT thus far but reserved conclusions, as the data are incomplete.

Bob Avery, MD, continued the discussion as he presented data from an ongoing prospective study of 10 patients with non-ischemic CRVO treated with ranibizumab. Patients were given 3 consecutive injections followed by interval treatments, similar to the PIER study. Although VA and OCT improved initially, by 1 year the effect was lost. Transient improvements were seen after each injection, and he concluded that interval PIER-style treatment might be inferior to "prn" PrONTO-style treatment.

AGE-RELATED MACULAR DEGENERATION

Emily Chew, MD, summarized conflicting studies reporting a potential increase in wet AMD following cataract surgery. The AREDS study analyzed this relationship in a prospective fashion and showed no clear effect of cataract surgery on the risk of progression to advanced AMD. She stated that patients should be aware of the risk of worsening disease as part of the natural course of AMD.

Mike Trese, MD, discussed the altered microenvironment at the macula following a posterior vitreous detachment (PVD), such as a decreased concentration of VEGF and increased oxygen concentration. In 1 study, only 34% of patients with wet AMD and 72% of patients with dry AMD had a PVD. Additionally, the area of posterior vitreous attachment may correlate with the area of CNV.

Sandy Brucker, MD, reported that OCT findings are highly predictive of the results of fluorescein angiogram (FA) in wet AMD patients. FA offers the ability to assess CNV, but the number of patients in whom active CNV by detected by FA is missed by OCT alone is very small. The clinical significance of this difference needs further analysis. SD-OCT could significantly lower this discordance.

Bailey Freund, MD, reviewed retinal angiomatous proliferation (RAP) as a distinct form of neovascularization in wet AMD. The origin of RAP remains controversial, but the ultimate location of the neovascular complex appears to be located in the substance of the retina. This type of neovascularization responds well to anti-VEGF therapy.

Progress of early clinical trials was then discussed. Pravin Dugel, MD, conveyed intermediate results of phase 1 studies for rapamycin in wet AMD. The trial design was identical to that of rapamycin for DME and was administered subconjunctivally and intravitreally. There were no toxicities or serious adverse events and 1 ocular adverse event. Both administration routes resulted in improved vision and OCT measurements in most patients. Final results will be presented later this year.

Jeff Heier, MD, stated that the inhibition of integrins (transmembrane proteins present in developing and pathologic proliferating vessels) such as alpha(1)beta(1), may provide a target to disrupt neovascularization. Promising results in animal models of CNV led to a phase 1 trial to evaluate an intravitreal integrin antagonist. DavidBrown, MD, described the use of tyrosine kinase inhibitors (TargeGen, San Diego; GlaxoSmithKline, Philadelphia) to target VEGF receptors. Early data indicate some anatomic validation of TargeGen's drug, but difficulties have been encountered in its formulation.

Larry Singerman, MD, provided an update on bevasiranib (OPKO Health, Miami). This small interfering RNA interferes with VEGF production, suggesting a complementary role to anti-VEGF therapies currently available. The CARE study, a phase 2 study, showed improved VA and decreased CRT by OCT with stabilization after 6 weeks (a period of residual VEGF after administered therapy). COBALT is a phase 3 trial that will assess whether bevasiranib administered every 8 or 12 weeks is safe and has equivalent efficacy in preventing vision loss as ranibizumab administered every 4 weeks.

Quan Dong Nguyen, MD, discussed the results of VEGF Trap-Eye (Regeneron) for wet AMD and DME. This high-affinity VEGF binder is smaller than an antibody and penetrates all layers of the retina. Preliminary results from the CLEAR-IT 1 and 2 studies showed good safety and efficacy in both AMD and DME with the possibility of longer duration of action than current VEGF therapies. The phase 3 VIEW results are expected in 2010.

Sander Dubovy, MD, presented a clinicopathologic case of a patient from the PrONTO study who achieved a dry retina after 3 consecutive injections with no further treatment for 2 years. The CNV was located in both subretinal and sub-RPE locations with adjacent fibrosis and RPE atrophy. Despite significant retinal structural damage, the patient's vision was 20/50 prior to death.

Robert Murphy, MD, postulated that quiescent neovascular vessels remain after anti-VEGF therapy. While not active, they may still leak due to hydrostatic pressures or development of "polypoidal" lesions, perhaps explaining why VEGF therapy can fail. Indo cyanine green angiography may reveal these vessels, which might be amenable to laser therapy. Anne Fung, MD, reported on a study looking at Medicare patients that compared age-matched controls without retinal pathology with patients coded with a diagnosis for wet AMD. There was no increased rate of myocardial infarction or stroke in patients with wet AMD.

David Boyer, MD, presented SAILOR 1-year results. The interim data led to concern that there was a significantly increased stroke rate in the 0.5-mg group compared to the 0.3-mg group. However, at 1 year, Dr. Boyer stated that patient demographics, retreatments, and adverse events were similar between the 0.3-mg and 0.5-mg groups. Stroke rates and nonvascular deaths were higher in the 0.5-mg group but not statistically significant and not attributable to anti-VEGF therapy. Prior stroke was the most significant risk factor. SAILOR results compared favorably with MARINA and ANCHOR results across all safety parameters.

The efficacy 0.5 mg was slightly increased compared to 0.3 mg but was not statistically significant. Also, Dr. Boyer noted that the efficacy seen in the SAILOR trial was less than that seen in MARINA and ANCHOR, but retreatment was performed less frequently than in clinical practice because of outdated retreatment criteria.

CONCLUSION

While wet AMD treatments continue to expand, research efforts are under way to understand and develop treatments for dry AMD. Advances in imaging may elucidate the pathogenesis and course of macular disease and provide qualitative and quantitative data for clinical trials. Newer treatments have been revolutionary in some cases. However, as the financial burden is increasingly a concern, clinicians search for more cost-effective solutions. Finally, innovative drug delivery devices and gene therapies appear to hold promise for treatment of various retinal diseases. RP