Peter E. Liggett, M.D Whitney Avenue-Suite 300 Hamden, CT Tel: (203) Fax: (203)

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1 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 1 N E R A New England Retina Associates N E R A New England Retina Associates 2200 Whitney Avenue-Suite 300 Hamden, CT Tel: (203) Fax: (203) Peter E. Liggett, M.D. 400 Bayonet Street-Suite 206 New London, CT Tel: (860) Fax: (860) David Tom, M.D., F.A.C.S. Guilford Glen 5 Durham Road, Bldg. 2 Guilford, CT Tel: (203) Fax: (860) Kings Highway No. Westport, CT Tel: (203) Fax: (203) Valleywood Medical Bldg. 40 East Putnam Avenue Greenwich, CT Tel: (203) Fax: (203) Nauman A. Chaudhry, M.D., F.A.C.S. 10th Anniversary Edition

2 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 2 NERA is celebrating its 10th Anniversary this year! We at New England Retina Associates thank all of you for your kind support during the past 10 years. Without you, we could never be. At NERA, we constantly strive to provide the best quality of care for your patients. We continue to have a very active clinical trials program which offers you and your patients cutting edge technologies for the treatment of various retinal diseases. This Anniversary Issue will give you a review of what s new in the treatment of age-related macular degeneration (AMD). We will also update you on our upcoming clinical trials and give you the results of some past clinical trials NERA participated in. Thank you all again for your support! Greg Haffner, who completed his ophthalmology residency at Yale, has joined us as a retinal fellow. According to Yale Department of Ophthalmology Chairman Bruce Shields, Greg is one of the finest residents he has seen come through the GREG HAFFNER, MD program at Yale or Duke. In recognition of his achievements, Greg was awarded the Marvin Sears Award for Excellence in Clinical Ophthalmology given to Yale s best resident. Apparently, Greg scored so high on his OKAP exams that they used his answer sheet to score everybody else! Please join us in welcoming Dr. Greg Haffner aboard. Dr. David Tom will be the Principal Investigator on the Genentech Lucentis Sailor trial which allows for the use of Lucentis on all new subfoveal CNV from AMD. (See inside for details.) Nauman Chaudhry, MD was voted into membership in the Macula Society. The Macula Society is one of the most prestigious invitation-only societies in the field of retina and vitreous. As you may recall, he was also recently accepted as a member of the invitation-only Retina Society. Please join us in congratulating Dr. Chaudhry on his membership. Dr. Chaudhry has also been named Chairman of Ophthalmology at Backus Hospital in Norwich. SPONSOR EYETECH/PFIZER ELI LILLY ACUITY PHASE II EYETECH/PFIZER STARTING FALL 2005 NOVARTIS B STARTING FALL 2005 EYETECH/PFIZER Clinical Trials (Just Starting) INDICATION CRVO WITH MACULAR EDEMA NPDR WITH NON CSME WET AMD DME WET AMD CRVO WITH MACULAR EDEMA ENROLLMENT CRITERIA (OPEN ENROLLMENT) >18 Y.O. BCVA 20/50-20/400, FELLOW EYE 20/200OR BETTER, RECENT CRVO W/IN 6MOS, NO PRIOR TX FOR CRVO, NO PRP OR SCATTER, NO STEROIDS >18 Y.O BCVA 20/32 OR BETTER NON CSME BCVA: 20/50-20/320 ALL SUBFOVEAL CLASSIC TYPES HEME >50%, 2 OR LESS MACUGEN, 1 PDT AND/OR 1 KENALOG ALLOWED >18 Y.O. IOP >21, NO PRP, YAG, CRYO, FOCAL, GRID W/IN 16WKS, >1 FOCAL, GRID, NO INJECTED OCULAR STEROIDS SUBFOV. CNVM CRITERIA NOT YET AVAILABLE >18 Y.O. BCVA 20/50-20/400, FELLOW EYE 20/200OR BETTER, RECENT CRVO W/IN 6MOS, NO PRIOR TX FOR CRVO, NO PRP OR SCATTER, NO STEROIDS DRUG MACUGEN RUBOXISTAURIN PLACEBO RNA INTRAVIT. INJ NO MACUGEN PDT W/ MACUGEN PDT W/ KENALOG MACUGEN DRUG DELIVERY INTRAVIT INJ Q 6 WEEKS FOR 30 WKS ORAL PILL 2 VISITS/YR FOR 4 YRS 2 INTRAVIT. INJ 6 WEEKS APART INTRAVIT INJ Q 6 WEEKS FOR 3 YRS 24 MONTH STUDY INFO NOT AVAILABLE INTRAVIT INJ Q 6 WEEKS FOR 30 WKS Dr. Liggett s new book, Age-Related Macular Degeneration: A Comprehensive Textbook, is due out at the American Academy of Ophthalmology in October of Dr. Liggett was recently appointed Clinical Professor of Ophthalmology & Visual Science at Yale School of Medicine. He continues as Clinical Professor of Ophthalmology at Cornell Medical Center in New York. Please welcome Dr. Juner Colina, who has completed her retinal fellowship with Professor Hugo Quiroz in Mexico City. Dr. Colina is replacing Dr. Alejandro Lavaque, who has returned to Argentina. Dr. Colina joins us before DR. JUNER COLINA becoming one of the 16 retina surgeons to serve all of Venezuela, a country of 19 million people. ELI LILLY ACUITY PHASE II EYETECH/PFIZER STARTING FALL 2005 NOVARTIS B STARTING FALL 2005 NPDR WITH NON CSME WET AMD DME WET AMD >18 Y.O BCVA 20/32 OR BETTER NON CSME BCVA: 20/50-20/320 ALL SUBFOVEAL CLASSIC TYPES HEME >50%, 2 OR LESS MACUGEN, 1 PDT AND/OR 1 KENALOG ALLOWED >18 Y.O. IOP >21, NO PRP, YAG, CRYO, FOCAL, GRID W/IN 16WKS, >1 FOCAL, GRID, NO INJECTED OCULAR STEROIDS SUBFOV. CNVM CRITERIA NOT YET AVAILABLE RUBOXISTAURIN PLACEBO RNA INTRAVIT. INJ NO MACUGEN PDT W/ MACUGEN PDT W/ KENALOG ORAL PILL 2 VISITS/YR FOR 4 YRS 2 INTRAVIT. INJ 6 WEEKS APART INTRAVIT INJ Q 6 WEEKS FOR 3 YRS 24 MONTH STUDY INFO NOT AVAILABLE

3 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 3 Clinical Trials (Completed) SPONSOR INDICATION STUDY DRUG VAM STUDY NOVARTIS CLASSIC WET AGE-RELATED MACULAR DEGENERATION VISUDYNE PDT MIRAVANT DRY AGE-RELATED MACULAR DEGENERATION SNET2 FIGURE 7 EYETECH PHARMACEUTICALS ALCON PHARMACEUTICALS PTAMD ISTA PHARMACEUTICALS ELI LILLY & CO. CLASSIC AND OCCULT WET AGE-RELATED MACULAR DEGENERATION CLASSIC WET AGE-RELATED MACULAR DEGENERATION DRY AGE-RELATED MACULAR DEGENERATION VITREOUS HEMORRHAGE MACULAR EDEMA RESULTING FROM BACKGROUND DIABETIC RETINOPATHY MACUGEN ANECORTAVE ACETATE (RETAANE) DIODE LASER TO DRUSEN VITRASE INTRAVITREAL INJECTION RUBOXISTAURIN MESYLATE ORAL PILL ANGIOGENESIS (FIGURES 7, 8, 9) Angiogenesis is the growth of new capillaries from pre-existing vessels. Leakage of fluid and blood from these abnormal blood vessels is the main cause for visual loss in AMD. Interestingly, it is not the development of the abnormal blood vessels, but rather the presence of fluid and/or blood distorting the anatomy of the photoreceptors which causes visual loss. Molecular processes involved in angiogenesis include stimulation of endothelial growth by cytokine production (i.e., vascular endothelial growth factor, (VEGF); fibroblast growth factor-2, (FGF-2)), degradation of extracellular matrix proteins by matrix metalloproteinases and migration of endothelial cells mediated by integrins (cell membrane adhesion molecules). Among these, VEGF serves as a "master switch" controlling angiogenesis leading to CURRENT THERAPIES FOR CNV IN AMD FOCAL LASER. This is still the gold standard for the treatment of extrafoveal CNV due to AMD. As you can imagine, these represent less than 4% of active AMD treatment. The recurrence rate is high (59%) because the laser does nothing to change the underlying pathophysiology of the choriocapillaris-bruch s Molecular All the Way! membrane-rpe complex which leads to the development of CNV. There is no difference in what wavelength is used in this procedure, be it argon green or krypton red or orange dye. (FIGURE 10) endothelial growth factor technologies were still being developed and tested. SUB-MACULAR SURGERY. We still use submacular surgery to intervene in very large sub-retinal hemorrhages (greater than 2mm in elevation). In this surgery, we remove the blood using tpa assisted technique. The technique is useful in this select group of patients. (FIGURE 11) PHOTODYNAMIC THERAPY (PDT) WITH VERTEPORFIN (VISUDYNE). Launched in 2000, Visudyne was the first approved photodynamic therapy for CNV from age-related macular degeneration (AMD). NERA participated in the clinical trials which showed its effectiveness in CNV from AMD. Verteporfin is infused intravenously, accumulates preferentially in proliferating cells such as CNV, and generates short-lived reactive oxygen species when activated by choroidal neovascularization ( CNV) in AMD TRANSLOCATION. This procedure has been laser light at a wavelength of 689 nm. The OCULEX MACULAR EDEMA RESULTING FROM DIABETIC RETINOPATHY, BRVO, CRVO, IRVINE-GASS SYNDROME OR UVEITIS DEXAMETHASONE BIODEGRADEABLE OCULAR IMPLANT and complications of diabetic retinopathy. VEGF s mechanism of action is through (1) promotion of endothelial cell proliferation, (2) survival vascular permeability, and largely abandoned due to the very high complication rate (25%) and the development of alternative molecular strategies. As you recall, this procedure was developed during reactive oxygen species cause highly localized damage leading to rapid and selective occlusion of the CNV without damaging the overlying retina. The present recommendation for (3) ocular inflammation. a time when photodynamic and anti-vascular Visudyne-based PDT is for subfoveal lesions

4 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 4 NEW ENGLAND RETINA RESEARCH AND EDUCATION FOUNDATION FIGURE 8 This Foundation supports research projects, including research on stem cells, gene transfer, molecular and surgical treatments for macular degeneration, diabetes, inflammation of the eye, and choroidal tumors on a selected basis. You may see the scientific presentations listed below which the Foundation has helped support just in the past year. The Foundation is also active in retina specialty training at the Yale, Harvard, and Cornell ophthalmology teaching programs. The Foundation supports international programs for the teaching of students, residents, fellows and ophthalmologists in advanced retinal diagnosis and treatments. Dr. Alejandro Lavaque has returned to Argentina where he will head one of the largest retina teaching programs in the city of Tecuman. We are welcoming Dr. Juner Colina from Venezuela. Additionally, the Foundation provides funds for projects which serve our community involving retinal diseases, including continuing education programs for patients, students, and physicians. The Foundation also provides support for patients in need of low vision devices, support groups, and counseling. We have appreciated your calls regarding patients who have been interested in contributing to ongoing clinical and molecular research. The Foundation thanks you.

5 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 5 NERA Research Presentations NERA Research Publications Chaudhry NA, Lavaque AJ, Jablon EP, Flynn HW Jr, Liggett PE, Tom DE. Management of Submacular Perfluorocarbon Liquid. Annual Meeting, The Retina Society, Chicago, 2003, and Annual Meeting, The Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Liggett PE, Lavaque AJ, Chaudhry NA, Tom D, Quiroz-Mercado H, Jablon E. Combined Transpupillary Thermotherapy Enhanced with Indocyanine Green and Intravitreal Triamcinolone Acetonide for Occult Choroidal Neovascularization in Age-related Macular Degeneration. Annual Meeting, The Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Liggett PE, Lavaque AJ, Jablon EP, Quiroz-Mercado H. Indocyanine Green-enhanced Transpupillary Thermotherapy of Small and Medium Size Suspected Choroidal Melanoma: A Preliminary Study. Annual Meeting, The Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Chaudhry NA, Lavaque AJ, Liggett PE, Tom DE. Optical Coherence Tomography (OCT) findings of Waldenstorm s Macroglobunemia associated Maculopathy. Presented at the Atlantic Flourescein Club Conference, Philadelphia, PA, Chaudhry NA, Lavaque AJ, Flynn Jr. HW, Liggett EP. Anterior Macular Prolapse Associated With Epiretinal Membrane; An Optical Coherence Tomography (OCT) Study. Presented at the American Research in Vision and Ophthalmology Fort Lauderdale, FL. 1. Chaudhry NA, Lavaque AJ, Scott IU, Flynn HW Jr, Liggett PE. A cluster of patients with acute-onset endophthalmitis following cataract surgery. Ophthalmic Surg Lasers Imaging 2005;36: FIGURE 9 PRE OP = HM POST OP = 20/80 FIGURE 10 FIGURE 11 composed of predominantly classic CNV (regardless of lesion size) and for those with small lesions containing occult with no classic or minimally classic CNV and having evidence of recent disease progression. The main objective of the treatment is to stabilize vision. Only 4% of patients may see a visual improvement of 2 lines or more in vision despite morphologic regression of the lesion on fluorescein angiography. Visual stabilization after treatment with verteporfin therapy correlates with a significant reduction in CNV growth and a progressive resolution of leakage. Recanalization of the neovascular complex can occur after initial closure following therapy. Patients may therefore require additional treatments, on average three the first year and two the second year. The reason for lack of visual improvement is related to toxicity of the subretinal blood and fluid on the photoreceptors and distortion of the microanatomy due to fibrous proliferation component. We and others have reported occasional complications of this procedure in patients who are on anticoagulants such as ASA or Coumadin with massive hemorrhage probably occurring due to rapid necrosis of the endothelial cells from treatment in some patients. A few patients experience choriocapillaris closure, which is usually temporary but in a very few patients may be permanent and lead to further loss of vision. (FIGURE 12) 2. Chaudhry NA, Lavaque AJ, Shah A, Liggett PE. Photodynamic therapy for choroidal neovascular membrane secondary to optic nerve drusen. Ophthalmic Surg Lasers Imaging 2005;36: Lavaque AJ, Yilmaz T, Liggett PE, Chaudhry NA. Pharmacological Inhibition of the Vascular Endothelial Growth Factor (VEGF) in Patients with Exudative Age-related Macular Degeneration. The Highlights of Ophthalmology 2005;33:9-16. STEP 2 STEP 1 FIGURE 12 INTRAVITREAL TRIAMCINOLONE (IVTA). Corticosteroids have complex, multi-faceted, and integrated mechanisms of action, including 1) stabilization of the blood retinal barrier, 2) resorption of exudation, and 3) down-regulation of inflammatory stimuli. Steroids have both direct and indirect

6 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 6 angiostatic effects. Corticosteroids exert direct angiostatic effects through downregulation of extracellular matrix metalloproteinases, reduction in vascular endothelial growth factor (VEGF) expression, dissolution of basement membrane, and down-regulation of intracellular adhesion molecule (ICAM)-1 expression. Experimental models have shown that triamcinolone acetonide acts on ICAM-1 and the major histocompatibility complex-1, thus reducing cell permeability to blood retinal barrier. Reducing the permeability of the tight junction of the blood retinal barrier might be expected to reduce the risk of developing CNV by inhibition of migration and activation 8 9 months. VA increased significantly after first and second injections in this study (Jonas et. al). Peak in VA and intraocular pressure elevation occurred 2 5 months after each injection. IVTA has its own risks, including the development of cataract in 50% of patients, elevated intraocular pressure (IOP) in 30% of patients, and rarely, endophthalmitis and retinal detachment. In rare cases, the increased IOP is not transient, not amenable to topical therapy and requires SLT or trabeculectomy. We have markedly decreased the occurrence of endophthalmitis by the pre-injection prep, the removal of most of the preservative, and post- injection Combination Trials MACUGEN : PEGAPTANIB (FIGURE 14) Two anti-vegf agents are now available: pegaptanib sodium Macugen from Eye Tech (approved since January) and ranibizumab Lucentis from Genentech, expected for clinical use by December Macugen binds to extracellular VEGF165 (one of 7 VEGF isoforms). Experimental studies have shown that inhibition of a similar VEGF isoform suppressed pathological neovascularization. Our Staff...Led by our wonderful Donna Connerton. Donna has been with us for almost all of the 10 years. Without Donna, I don t know if we would be here...a special thanks to her in our 10th year. COOKIE AND LINDA of inflammatory cells (monocytes, leukocytes, and macrophages) that secrete angiogenic growth factors (VEGF and FGF). The angiostatic effect of steroids is minimal compared with their anti-inflammatory effect. Steroids inhibit the synthesis and release of various inflammatory mediators, including prostaglandins and leukotrienes in addition to their actions on inflammatory cells. Neuroprotection is also seen from the action of corticosteroids, independent from the angiostatic and anti-inflammatory effect, through the formation of 7-hydroxy metabolites of the steroid molecule induced from the cytochrome P450 enzyme termed cyp7b. Machemer, Ryan and others first suggested the use of intravitreal injection of triamcinolone acetonide (IVTA), which as a crystalline steroid has a considerably longer absorption time than an injection of soluble cortisone (6 weeks vs. 24 hours). Pilot studies have also reported beneficial effects of 4 or 25 mg doses of IVTA on visual acuity, for eyes considered unsuitable for laser photocoagulation (subfoveal or juxtafoveal CNV) recurrent extrafoveal CNV, and subfoveal CNV. In a prospective clinical interventional case series study of 44 eyes in 42 patients with neovascular AMD, the effects of IVTA mg lasted approximately antibiotics. (FIGURE 13) IVTA + PDT Continued angiogenic stimuli from cellular damage at the choriocapillaris-bruch s membrane-rpe complex contribute to regrowth of the retinal neovascularization. These stiumuli from the microenvironment include vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) derived from retinal pigment epithelium (RPE) cells and recruited macrophages, leading to further CNV development and growth. Surprisingly, verteporfin therapy may result in the release of angiogenic factors such as VEGF and PEDF, as demonstrated in a study of four patients scheduled for enucleation as a result of untreatable malignancy. Thus supression of cytokines and cellular inflammatory responses in the microenvironment counteracts both AMDrelated and PDT-induced inflammatory reactions and angiogenesis. This combination of treatment (IVTA + PDT) may lead to much improved morphologic and visual results in patients with subfoveal CNV from AMD. Currently we are using such combined treatment on most of our patients who are eligible for PDT. NERA participated in the clinical trials which have shown Macugen to be effective. Seventy percent of patients lost fewer than 15 letters of visual acuity, as compared with 55 percent among the controls (P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their visual acuity or gained acuity (33 percent vs. 23 percent; P=0.003). The benefit was similar in all subtypes of lesions choroidal neovascularization. This new molecular compound requires intravitreal injections every six weeks for two years according to the initial trials. The drug, while being paid for by Medicare, is extremely expensive at about $1000 (our cost) for the drug per injection. COMBINATION TREATMENT TRIAL- IVTA + PDT + MACUGEN We have enrolled 20 eyes of 18 patients with subfoveal CNV from AMD. The rationale of this trial is to examine the hypothesis that initial suppression of the microenvironment allows for an earlier and more complete resolution of CNV. We also believe that this combination treatment will require fewer retreatments long term. The trial gives one DONNA CHRISTEL, KATHLEEN, PAULA, DR. HAFFNER AND ROBERT LIZ MEG, DR. COLINA AND BASIL JUSTINE, DEBBIE, MICHELLE AND ANNA SUE

7 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 7 FIGURE 25 Mystery Case FIGURE year-old male with known Waldenström s macroglobulinemia who had no problems for more than 4 years presents with gradual vision loss of left eye. See answer at bottom of last page. Anti-Angiogenic Agents: Mechanism of Action (FIGURES 25, 26, 27, 28) FIGURE 26 Genentech EyeTech Signaling Pathways Lilly PKCi Basement Membrane VEGF Proliferation bfgf Migration Others Proteolysis Angiogenic Factors Receptors Steroids (Anecortave Acetate) Vascular Endothelium FIGURE 14 FIGURE 27 FIGURE 28 FIGURE 15 FIGURE 16

8 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 8 initial treatment of IVTA + PDT + Macugen. Macugen then is continued every six weeks up to six months, as distinguished from monotherapy with Macugen which requires two years of intravitreal injections. LUCENTIS (Genentech): ranibizumab = rhufab V2 (FIGURE 15, 16, 17) is a humanized monoclonal antibody fragment designed to bind all forms of VEGF (VEGF-A, VEGF(121), VEGF(165), VEGF(189), VEGF-B, C and D), thereby blocking vessel permeability and angiogenesis in neovascular age-related macular degeneration. The drug in trials was injected every month for 12 months. The drug has a terminal half-life of approximately three days. NERA participated in clinical trials of Lucentis in a Phase III study. The study included 716 patients in the United States with minimally classic or occult CNV. Results showed that 25 34% had improved vision, compared to 5% in the placebo group. Approximately 95% of patients maintained or improved vision (defined as a loss of fewer than 15 letters in visual acuity) at one year when compared to approximately 62% of those treated in the control arm (p=0.0001). Lucentis met its primary efficacy endpoint of maintaining vision in patients with wet age-related macular degeneration (AMD) when used in combination with verteporfin (Visudyne ) photodynamic therapy (PDT). In combination with Visudyne, Lucentis showed 24% of patients with improved vision compared to 5% of the group that received Visudyne alone. Macugen results as monotherapy are approximately the same as Visudyne alone. Lucentis intravitreal causes mild transient intraocular inflammation in some patients. Cost of the drug is not known, but expect $1500 (our cost) per injection. The Lucentis molecule will be available to all patients with subfoveal AMD immediately as part of the Genentech trial called Sailor. FIGURE 22 COMBINED SIMULTANEOUS TRANSPUPILLARY THERMOTHERAPY AND INDOCYANINE GREEN-BASED PHOTODYNAMIC THERAPY (CSTIP) OF SMALL AND MEDIUM SIZE SUSPECTED CHOROIDAL MELANOMA As we discussed in our last newsletter this is our current approach to treating choroidal melanomas up to 5 mm in height. Lesions larger than than 5 mm require a combined approach using either I125 or palladium episcleral plaques in a sandwich approach. The advantage to ICG-based PDT + TTT is we get equally good tumor erradication while preserving more vision and fewer radiation-associated complications. Notice in figures 22 and 23 a pre- and posttreatment choroidal melanoma treated at the edge of the macula 5 years ago. The patient maintains 20/60 vision. This would be a difficult result to achieve using any other current technique including charged particle irradiation or laser alone. Please see our coming article on this subject in Ophthalmic Surgery, Lasers and Imaging. (FIGURE 22, 23) POSURDEX IMPLANT FOR UVEITIS The biodegradable sustained-release implant that delivers dexamethasone directly to macular edema and inflammatory targeted tissue is now being studied for its use in uveitis. This implant may have implications for not only sustained release of corticosteroids but for other medications as well. (FIGURE 24) FIGURE 17 Avastin, from which Lucentis is derived, is approved for cancer chemotherapy. The drug FIGURE 24

9 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 9 FIGURE 23 given IV has been used in some preliminary studies and found to be effective in treating subfoveal CNV from AMD. This molecule is 3x larger than Lucentis and does not have as strong an affinity to the VEGF receptor, but preliminary reports are that Avastin, when given intravitreally at 1/400 the dose of the IV drug, is as effective as Lucentis. Many centers, including ours, are now using Avastin off label in the treatment of AMD refractory to other treatments. While the drug does cause blood clotting problems given IV, they have never been seen with the intravitreal dose of Avastin or Lucentis. Genentech is asking the FDA for fast track approval of Lucentis, which if approved would not occur until mid As of this printing, they have not agreed to fast track this drug, therefore it will not be available for use for at least 1 year. ANECORTATE ACETATE (RETAANE, ALCON LABS) (FIGURE 18, 19) Retaane (Anecortave acetate) is an analog of cortisol acetate; among the modifications to the steroid are the removal of the 11ß hydroxyl OH group and an addition of a 21-acetate group. As a result of these modifications, anecortave acetate lacks the typical antiinflammatory and immunosuppressive properties of glucocorticoids. Anecortave acetate functions as an antiangiogenic agent, inhibiting blood vessel growth by decreasing extracellular protease expression and inhibiting endothelial cell migration. Retaane blocks signals from multiple growth factors because it acts downstream and independent of the initiating angiogenic stimuli and inhibits angiogenesis subsequent to the angiogenic stimulation. Alcon Inc. is developing and marketing Retaane. In its May 24, 2005, press release, Alcon reported that it has received conditional approval from the Food and Drug Administration for Retaane to treat wet AMD. NERA participated in the Retaane clinical trials. Visual outcomes following Retaane injection were compared with that of Visudyne PDT treatment. In the study, the percentage of patients who maintained vision (defined as less than a three line loss in logmar visual acuity) 1 year after Retaane treatment was 45 percent, compared to 49 percent after PDT treatment. Although Retaane did not meet the primary non-inferiority endpoint of the clinical study, these overall results indicate that the two therapies are not statistically different from each other. The first clinical study demonstrated that after one year 79 percent of patients treated with Retaane maintained their vision, compared to 53 percent of those who received a sham application. The second clinical study demonstrated that after one year the visual outcomes in patients who received Retaane suspension were not statistically different from those of patients who received photodynamic therapy with Visudyne. The FDA believes reflux of the drug needs to be better controlled. Alcon has initiated changes in the procedure, expanded training measures and developed a simple counter pressure device (CPD) which has been deemed effective. Expect to see Retaane used in combination and prophylactic treatment of CNV-AMD by years end. Cost of the drug is not yet known, but predictions are that it will be $600 per treatment. It is not yet clear that any of these drugs is better than IVTA. No clinical trials have yet compared the above drugs side by side. TRANSPUPILLARY THERMOTHERAPY (TTT). TTT is performed using infrared diode laser from Iridex. It works by raising the retinal tissue temperature to and inducing occlusion of choroidal neovascularization. Hyperthermia during TTT leads to vascular endothelial damage with subsequent intravascular thrombosis, platelet aggregation and leucocyte adhesion. The formation of new vessels promoted by angiogenic inducers appears to be impaired after heat treatment. These effects cannot be explained by direct cytotoxicity, but are dependent on modulation of angiogenesis-involved genes. TTT alone in clinical trials showed a statistically significant reduction in vision loss and vision stabilization in eyes with 20/100 vision or worse vision according to the multi-center clinical trial TTT4CNV. INDOCYANINE GREEN BASED PHOTODYNAMIC THERAPY (IPDT) + IVTA. At NERA, we have developed a novel technique of using ICG as a chromophore. ICG is an anionic tricarbocyanine dye that has been used for imaging the retina and choroid for 30 years. ICG is given intravenously and works by the same mechanism that verteporfrin does. In our original study, we have shown that 73% of patients with complex CNV from AMD have stable or improved vision following this treatment. Complex CNV is defined as ill defined combination (mixed type occult/classic) with the presence of subretinal blood covering more than that of the lesion with the presence of pigment epithelial detachment. These cases are not candidates for conventional laser photocoagulation or verteporfrin-based PDT. The cost of the drugs in this treatment total $240. This would be compared to Visudyne $ Macugen $1000 = $2300. We have submitted a research paper on this technique for publication. FIGURE 18 FIGURE 19

10 Liggett Newsletter FINAL 11/10/05 1:02 PM Page 10 angiogenesis could be an effective tool in view of future gene therapy applications in the treatment of retinal disease. We will enter our first clinical trial of a sirna this fall. PKC INHIBITORS RUBOXISTAURIN (LY379196) FOR DIABETIC MACULAR EDEMA Endothelial barrier dysfunction plays a pivotal role in the pathogenesis of diabetic vascular complications. Recent studies have established a link between protein kinase C (PKC) pathway and hyperglycemia-induced vascular permeability. VEGF (VEGFR2) activates Protein kinase D (PKD), a newly described serine/threonine protein kinase which has been implicated in many signal transduction pathways leading to increased vascular permeability and cell proliferation. Protein kinase inhibitors have been shown in experimental models to inhibit PKC which significantly reduced VEGF-induced PKD activation. Initial Results of the Protein Kinase C {beta} Inhibitor Diabetic Retinopathy Study (PKC- DRS) Multicenter Randomized Clinical Trial: The Effect of Ruboxistaurin on Visual Loss in Patients With Moderately Severe to Very Severe Nonproliferative Diabetic Retinopathy: 32 mg/day RBX significantly reduced the risk of MVL compared with New Trials FIGURE 20 placebo (hazard ratio 0.37 [95% CI ], P = 0.012). In this clinical trial, RBX was well tolerated and reduced the risk of visual loss but did not prevent VERTOPORFRIN-BASED PDT + IVTA + MACUGEN Understanding the best uses of such a combination of vertoporfrin-based PDT + IVTA is an imperative need. We will be entering into collaborative efforts in the fall to do a randomized multi-center, controlled clinical trial of combination therapies, including Visudyne, anti-vascular endothelial growth factor, and IVTA. SIRNA FOR SUBFOVEAL CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION (FIGURE 20) RNA interference (RNAi) is an evolutionarily conserved mechanism for silencing gene expression. In primitive organisms, RNAi protects the genome from viruses and other insertable genetic elements and regulates gene expression during development. RNA interference technology is emerging as a very potent tool to obtain a cellular knockdown of a desired gene. RNAi may provide an important new therapeutic modality for AMD and other retinal degenerations. Recent experiments have shown that transduction with a plasmid carrying a small interfering RNA targeting all isoforms of VEGF dramatically impairs the expression of this growth factor in cell culture. Vectorbased RNA interference approach to inhibit DR progression. MACUGEN FOR DIABETIC MACULAR EDEMA We will be investigating whether vascular endothelial growth factor (VEGF) or soluble intercellular adhesion molecule 1 (sicam-1) is related to diabetic macular edema (DME). In human studies, both VEGF and sicam-1 were elevated in the vitreous fluid of patients with hyperfluorescent DME. These results suggest that VEGF and ICAM-1 are related to the increase of vascular permeability in DME patients and may respond with intravitreal injection of Macugen. The Future In May, South Korean cloning pioneer Hwang Woo Suk announced that his team at Seoul National University had created human stem-cell lines that completely match the DNA of their patient donors. In February, 2004, he reported the first cloning of human embryos, from which his team harvested embryonic stem cells. His findings, published in the journal Science, marked a giant step toward growing tissues and cells to repair or replace damaged organs including photoreceptors and RPE cells damaged by AMD or diabetes. (FIGURE 21) FIGURE 21