Macular Degeneration: Kaiser PK

Kaiser PK. · No affiliation provided · Br J Ophthalmol. · Pubmed #19174397 No free full text.

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Kaiser PK. · No affiliation provided · Am J Ophthalmol. · Pubmed #15953443 No free full text.

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Chappelow AV, Kaiser PK. · Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Drugs. · Pubmed #18484796 No free full text.

Abstract: Age-related macular degeneration (AMD) affects an estimated 14 million people worldwide, and is the leading cause of severe, irreversible vision loss in individuals over the age of 50 years in Western societies. Choroidal neovascularization (CNV), the hallmark of 'wet', 'exudative' or 'neovascular' AMD, is responsible for approximately 90% of cases of severe vision loss due to AMD. Vascular endothelial growth factor (VEGF) has been shown to play a key role in the regulation of CNV and vascular permeability. Ranibizumab, the current gold standard in the US for the treatment of neovascular AMD, exerts its effect through binding and inhibition of all isoforms of VEGF. Randomized controlled clinical trials have established ranibizumab as the first US FDA-approved therapy for neovascular AMD to result in improvement in visual acuity. Despite impressive outcomes, treatment with ranibizumab requires sustained treatment regimens and frequent intravitreal injections. In this review, we discuss promising emerging therapies for neovascular AMD that aim to improve outcomes, safety and treatment burden through novel mechanisms of action. Currently in phase III clinical trials, VEGF Trap is a receptor decoy that targets VEGF with higher affinity than ranibizumab and other currently available anti-VEGF agents. Another promising therapeutic strategy is the blockade of VEGF effects by inhibition of the tyrosine kinase cascade downstream from the VEGF receptor; such therapies currently in development include vatalanib, TG100801, pazopanib, AG013958 and AL39324. Small interfering RNA technology-based therapies have been designed to downregulate the production of VEGF (bevasiranib) or VEGF receptors (AGN211745) by degradation of specific messenger RNA. Other potential therapies include pigment epithelium-derived factor-based therapies, nicotinic acetylcholine receptor antagonists, integrin antagonists and sirolimus.

Singh RP, Kaiser PK. · Cole Eye Institute, Cleveland Clinic Foundation, USA. · Indian J Ophthalmol. · Pubmed #17951897 links to  free full text

Abstract: Age-related macular degeneration (AMD) is one of the most common causes of severe vision loss in the western world. Both animal and human studies have established that vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of this process. Ranibizumab (Lucentis(TM) Genentech, South San Francisco, CA) is a monoclonal antibody fragment (Fab) directed toward all isoforms of VEGF-A that was specifically designed to target wet AMD. The human antibody fragment is produced by an E. coli expression system and has a molecular weight of 48kD allowing for excellent retinal penetration. The most common ocular complaints of patients receiving ranibizumab injections in randomized clinical trials were transient conjunctival hemorrhage, vitreous floaters, intraocular inflammation, increased intraocular pressure and eye pain. The rates of serious adverse events such as retinal detachment, cataract and endophthalmitis were similar to those that have been reported with other intravitreal injections and patients should always be treated under strict aseptic conditions to reduce this risk. There were no significant non-ocular events found during any study so far and the risk of thromboembolic events was less than 4% and not different than sham. The MARINA, ANCHOR and PIER studies validated the safety and efficacy of ranibizumab amongst a large population with different choroidal neovascular membrane lesion types against sham or standard of care treatment. These studies recommended monthly intravitreal ranibizumab for patients. However, the PIER study reported that an alternative dosing of every three months is acceptable but less effective than monthly injections.

de Mello PC, Brasil OF, Maia HS, Kaiser PK, Pereira MB, de Moraes HV. · No affiliation provided · Eye. · Pubmed #17618238 No free full text.

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Kaiser PK. · Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Curr Med Res Opin. · Pubmed #17355729 No free full text.

Abstract: OBJECTIVE: To discuss the rationale for combining anti-angiogenic treatment with verteporfin (Visudyne) photodynamic therapy in the management of choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) and evaluate available evidence for the therapeutic benefits of such approaches. SCOPE: The Medline and EMBASE databases were searched in October 2006 to retrieve relevant articles. Additional articles were obtained from the reference lists of retrieved articles, as well as from recent scientific meetings and company websites. FINDINGS: Treatments for CNV due to AMD can be directed at either the vascular component of CNV (the new vessels that proliferate and leak blood and fluid) or the angiogenic component that leads to the development of the condition. Verteporfin targets the vascular component, whereas anti-angiogenic agents (such as pegaptanib and ranibizumab) target key mediators of the angiogenic cascade. The different mechanisms of action of these approaches offer the potential for additive or synergistic effects with combination therapy. In addition, anti-angiogenic agents might counteract upregulation of angiogenic factors (including VEGF) that occur after verteporfin photodynamic therapy. Results from preclinical and clinical studies of the combination of ranibizumab or pegaptanib with verteporfin warrant continued investigation. CONCLUSIONS: The use of anti-angiogenic agents in combination with verteporfin may have the potential to improve visual outcomes and reduce the number of treatments in eyes with CNV due to AMD, and requires further evaluation in randomized, controlled clinical trials.

Kaiser PK, Do DV. · Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. · Int J Clin Pract. · Pubmed #17313620 No free full text.

Abstract: Age-related macular degeneration (AMD) is the leading cause of adult blindness among individuals aged 50 and older in the Western world, with the neovascular form of AMD responsible for the most severe and rapid visual loss. Although monotherapy with currently available treatments can slow the rate of loss of vision in eyes with neovascular AMD, they do not significantly improve vision. Vascular endothelial growth factor-A (VEGF-A) plays a critical role in the pathogenesis of neovascular AMD, and ranibizumab is a promising new treatment that targets all VEGF-A isoforms and their biologically active degradation products. Clinical trials have reported that ranibizumab treatment resulted in greater proportions of patients achieving a < 15 letter loss of visual acuity and improved vision at 12 and 24 months than control groups. The incidence of serious ocular and systemic adverse events was low in all ranibizumab trials to date. Currently, ranibizumab is the only treatment for neovascular AMD to demonstrate significant improvement in vision for many patients and represents a major advance in treating neovascular AMD.

Kaiser PK, Goldberg MF, Davis AA, Anonymous00002. · Cleveland Clinic Foundation, Cole Eye Institute, Cleveland, Ohio 44195, USA. · Surv Ophthalmol. · Pubmed #17240258 No free full text.

Abstract: OBJECTIVE: To develop a safe and effective transcleral delivery of anecortave acetate, a novel angiostatic cortisene, in therapeutic concentrations to the choroid and retina in the region of the macula in patients with age related macular degeneration. METHODS: In pre-clinical studies with rabbits and monkeys, several routes of delivery were studied including oral and other systemic routes as well as topical, subconjunctival, intravitreal injections and posterior juxtascleral administration. In addition, posterior juxtascleral depot administration using a specially designed blunt cannula was evaluated in humans. RESULTS: Oral and other systemic routes were not acceptable due to rapid systemic metabolism. Topical and subconjunctival administrations resulted in subtherapeutic concentrations in the macular region (<0.1 microm). Intravitreal injections resulted in adequate drug levels, but the visual axis was obscured due to the opaque nature of the drug, and this method carries risks of endophthalmitis and retinal detachment. Posterior juxtascleral depot administration in rabbits and monkeys resulted in adequate retinal and choroidal drug levels (>or=0.1 microm) up to 6 months after administration. In clinical studies, this administration technique was found to be safe. CONCLUSIONS: Posterior juxtascleral depot administration of anecortave acetate onto the scleral surface near the macula is a safe and effective method for delivering therapeutic concentrations of drug to the macular region of the choroid and retina for up to 6 months.

Singh R, Kaiser PK. · Cole Eye Institute - Retina Service, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Int Ophthalmol Clin. · Pubmed #17237674 No free full text.

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Bakri SJ, Kaiser PK. · Cole Eye Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk i3, Cleveland, OH 44195, USA. · Expert Opin Investig Drugs. · Pubmed #16433595 No free full text.

Abstract: This manuscript reviews the pharmacotherapeutics of the novel, angiostatic cortisene, anecortave acetate suspension, for the treatment of age-related macular degeneration. The chemistry, pharmacokinetics and pharmacodynamics of anecortave acetate are discussed, and the results of the multi-centre, randomised, controlled clinical trials for the treatment of subfoveal choroidal neovascularisation in age-related macular degeneration summarised. It also discusses ongoing clinical trials involving anecortave acetate for dry and wet age-related macular degeneration.

Kaiser PK. · Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · Curr Med Res Opin. · Pubmed #15969870 No free full text.

Abstract: Evidence from randomized, placebo-controlled, double-masked studies has demonstrated that verteporfin (Visudyne) therapy is effective in reducing the risk of visual acuity loss in selected groups of patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). Pilot studies of intravitreal triamcinolone acetonide monotherapy revealed promising results in patients with CNV due to AMD, but the visual acuity outcomes in a randomized, controlled study were lower than anticipated. Recently, however, there has been growing interest in the adjunctive use of triamcinolone to improve visual acuity and reduce regrowth of CNV in patients receiving verteporfin therapy. This review article surveys the currently available evidence, based on a Medline search covering the years 1980-2005 and abstracts from recent scientific meetings. A number of small-scale, uncontrolled pilot studies have indicated that the combination of triamcinolone acetonide with verteporfin therapy may be beneficial. Evidence is now needed from randomized, controlled studies to determine whether the potential benefits of combination therapy outweigh the possible risks of increased intraocular pressure, endophthalmitis, and progression of cataract that have been observed in trials of triamcinolone monotherapy.

Moshfeghi DM, Kim BY, Kaiser PK, Sears JE, Smith SD. · Stanford University Department of Ophthalmology, Stanford, California, USA. · Am J Ophthalmol. · Pubmed #15629286 No free full text.

Abstract: PURPOSE: To identify the risk factors, prognostic factors, and clinical outcomes of patients with perioperative appositional suprachoroidal hemorrhage (ASCH). DESIGN: Case-control study. SETTING: Tertiary referral center. METHODS: Subjects included all patients with perioperative ASCH documented by B-scan ultrasound between May 1990 and March 2001. Two or three control patients were selected for each case, matched by surgeon, procedure, and date of surgery within 1 month. Surgery was performed as necessary. main outcome measures. The odds of ASCH associated with clinical risk factors. secondary outcome measure: visual acuity. RESULTS: Thirty-seven cases with ASCH were identified. Ninety-two procedure- and surgeon-matched control subjects (2.48:1) were selected. Twenty-six cases (71%) of ASCH were related to a glaucoma operation. Risk factors for the development of ASCH included previous vitrectomy (P = .003, odds ratio of 12) and older age (P = .007, odds ratio 1.57/decade of increasing age). Hypertension was found to be protective (P = .02, odds ratio of 0.33). Factors associated with a poor visual outcome in patients with ASCH included apposition >30 days (P = .01), history of uveitis (P = .04), history of dry age-related macular degeneration (P = .05), and history of extracapsular cataract extraction (P = .05). Median pre-ASCH visual acuity was 20/100, and final median visual acuity was 20/1600. CONCLUSIONS: Risk factors for the development of ASCH include previous vitrectomy and older age. Patients with these risk factors should be informed of their greater chance of poor visual acuity and anatomic outcomes secondary to the development of ASCH.

Bakri SJ, Kaiser PK. · Cole Eye Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Expert Opin Pharmacother. · Pubmed #14680447 No free full text.

Abstract: This article reviews the pharmacotherapeutics of verteporfin (Visudyne), Novartis Pharma AG) used in ocular photodynamic therapy. The chemistry, pharmacokinetics and pharmacodynamics of the drug are reviewed. The article highlights and summarises the results of the multi-centre, randomised, controlled clinical trials with verteporfin to treat subfoveal choroidal neovascularisation in age-related macular degeneration, ocular histoplasmosis syndrome and pathologic myopia. In addition, the safety profile and side effects of verteporfin are discussed.

Sayanagi K, Sharma S, Kaiser PK. · Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · Br J Ophthalmol. · Pubmed #19208677 No free full text.

Abstract: AIMS: To evaluate the photoreceptor layer status after antivascular endothelial growth factor (VEGF) therapy in choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT). DESIGN: Prospective, consecutive case series. METHODS: Twenty-three eyes of 22 patients with CNV secondary to AMD with foveal thickness less than 250 microm after treatment with anti-VEGF therapy and no obvious leakage on time domain OCT, and eight healthy subjects as controls, were imaged with at least one of four different SD-OCT devices. The inner and outer segment (IS/OS) photoreceptor layers were graded, and correlated with various characteristics including visual acuity. RESULTS: The IS/OS layer was detected in eight eyes (35%) of patients with AMD and all eyes (100%) of the healthy control subjects (p = 0.002). Eyes in patients with AMD with preserved IS/OS had a significantly better BCVA and mean change in BCVA, and were more likely not to have had previous laser treatment compared with eyes with absent IS/OS. CONCLUSIONS: SD-OCT is a useful tool to visualise IS/OS status. IS/OS is often absent in patients who have received treatment with anti-VEGF therapy for CNV due to AMD. The IS/OS status after anti-VEFG therapy correlates with BCVA and mean change in vision.

Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, Anonymous00115. · Vitreoretinal Consultants, Methodist Hospital, Houston, Texas 77030, USA. · Ophthalmology. · Pubmed #19118696 No free full text.

Abstract: OBJECTIVE: The 2-year, phase III trial designated Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR) compared ranibizumab with verteporfin photodynamic therapy (PDT) in treating predominantly classic CNV. DESIGN: Multicenter, international, randomized, double-masked, active-treatment-controlled clinical trial. PARTICIPANTS: Patients with predominantly classic, subfoveal CNV not previously treated with PDT or antiangiogenic drugs. INTERVENTION: Patients were randomized 1:1:1 to verteporfin PDT plus monthly sham intraocular injection or to sham verteporfin PDT plus monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) injection. The need for PDT (active or sham) retreatment was evaluated every 3 months using fluorescein angiography (FA). MAIN OUTCOME MEASURES: The primary, intent-to-treat efficacy analysis was at 12 months, with continued measurements to month 24. Key measures included the percentage losing <15 letters from baseline visual acuity (VA) score (month 12 primary efficacy outcome measure), percentage gaining >or=15 letters from baseline, and mean change over time in VA score and FA-assessed lesion characteristics. Adverse events were monitored. RESULTS: Of 423 patients (143 PDT, 140 each in the 2 ranibizumab groups), the majority (>or=77% in each group) completed the 2-year study. Consistent with results at month 12, at month 24 the VA benefit from ranibizumab was statistically significant (P<0.0001 vs. PDT) and clinically meaningful: 89.9% to 90.0% of ranibizumab-treated patients had lost <15 letters from baseline (vs. 65.7% of PDT patients); 34% to 41.0% had gained >or=15 letters (vs. 6.3% of PDT group); and, on average, VA was improved from baseline by 8.1 to 10.7 letters (vs. a mean decline of 9.8 letters in PDT group). Changes in lesion anatomic characteristics on FA also favored ranibizumab (all comparisons P<0.0001 vs. PDT). Overall, there was no imbalance among groups in rates of serious ocular and nonocular adverse events. In the pooled ranibizumab groups, 3 of 277 (1.1%) patients developed presumed endophthalmitis in the study eye (rate per injection = 3/5921 [0.05%]). CONCLUSIONS: In this 2-year study, ranibizumab provided greater clinical benefit than verteporfin PDT in patients with age-related macular degeneration with new-onset, predominantly classic CNV. Rates of serious adverse events were low. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Kaiser PK, Brown DM, Zhang K, Hudson HL, Holz FG, Shapiro H, Schneider S, Acharya NR. · Cole Eye Institute, Cleveland, OH 44195, USA. · Am J Ophthalmol. · Pubmed #17949673 No free full text.

Abstract: PURPOSE: Subgroup data from a pivotal phase 3 study comparing ranibizumab (LUCENTIS) with verteporfin (VISUDYNE) photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) were retrospectively analyzed to identify patient and disease characteristics that may predict visual acuity (VA) treatment outcomes. DESIGN: Retrospective subgroup analysis of 12-month data from the ANCHOR study. METHODS: Univariate analyses were performed to assess VA outcomes across subgroups based on patients' gender and baseline age, VA score, CNV lesion size, CNV lesion type, and duration of neovascular AMD, followed by multivariate analyses to identify predictors of the VA score change from baseline at 12 months. main outcome measures: Proportion of patients losing <15 letters and proportion gaining > or =15 letters from baseline VA; mean change from baseline VA. RESULTS: On average, all subgroups of ranibizumab-treated patients did better than PDT patients for all three VA outcome measures. In the multivariate analysis, lower baseline VA score, smaller baseline CNV lesion size, and younger baseline age were associated with greater gain of letters with ranibizumab treatment and less loss of letters with PDT. CONCLUSIONS: Subgroup analysis of 12-month data from the ANCHOR study showed ranibizumab to be superior to PDT in all subgroups evaluated, and was consistent with the subgroup analysis of 24-month data from the other pivotal phase 3 study of ranibizumab (MARINA) in showing that the most important predictors of VA outcomes were, in decreasing order of impact, the patient's baseline VA score, CNV lesion size, and age.

Kaiser PK, Blodi BA, Shapiro H, Acharya NR, Anonymous00408. · Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Ophthalmology. · Pubmed #17628683 No free full text.

Abstract: OBJECTIVE: To assess pharmacodynamic responses to ranibizumab, an inhibitor of vascular endothelial growth factor A (VEGF-A), in a study of the treatment of minimally classic or occult with no classic choroidal neovascularization secondary to age-related macular degeneration (AMD) (designated MARINA [Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD]) and to compare these responses with those in a sham-injection control group. DESIGN: Retrospective (prespecified and ad hoc) analyses of 24-month data. PARTICIPANTS: Seven hundred sixteen patients, randomized to 0.3-mg ranibizumab (n = 238), 0.5-mg ranibizumab (n = 240), or a sham injection (n = 238). METHODS: Stereoscopic fundus photography and fluorescein angiography (FA) were done at baseline and months 3, 6, 12, and 24. Optical coherence tomography (OCT) was performed at a subset of investigative sites (46 patients) at baseline, day 7, and months 1 and 12. MAIN OUTCOME MEASURES: Prespecified secondary end points were mean change from baseline in total area of choroidal neovascularization and total area of leakage from choroidal neovascularization at months 12 and 24. Prespecified exploratory FA end points included mean change from baseline in the areas of the choroidal neovascularization lesion and serous sensory retinal detachment (SSRD) at months 12 and 24. Post hoc exploratory FA outcome measures included the proportion of patients with no leakage from choroidal neovascularization and mean change from baseline over time in the area of subretinal fibrous tissue/disciform scar. The prespecified exploratory end point for OCT was mean change from baseline over time in center point thickness. RESULTS: At 12 and 24 months, statistically significant benefits of ranibizumab over sham treatment were observed for mean change from baseline in the areas of choroidal neovascularization lesion, total choroidal neovascularization, leakage from choroidal neovascularization, SSRD, and disciform scar/subretinal fibrosis. At 12 months (final OCT), the mean change in foveal center point thickness on OCT was a significant decrease in the ranibizumab group compared with the sham group. CONCLUSIONS: Patients with minimally classic or occult with no classic neovascular AMD treated with ranibizumab demonstrated improvement that was consistent for visual acuity, FA, and OCT outcomes and superior to that in sham-treated patients.

Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, Anonymous00301. · Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, FL 33136, USA. · N Engl J Med. · Pubmed #17021318 links to  free full text

Abstract: BACKGROUND: Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration. METHODS: In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. RESULTS: We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab. CONCLUSIONS: Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].).

Bressler NM, Bressler SB, Haynes LA, Hao Y, Kaiser PK, Miller JW, Naor J, Potter MJ, Pournaras CJ, Reaves A, Rosenfeld PJ, Schmidt-Erfurth U, Slakter JS, Strong A, Vannier S. · No affiliation provided · Arch Ophthalmol. · Pubmed #16157822 No free full text.

This publication has no abstract.

Kaiser PK. · Cleveland Clinic, Cole Eye Institute, Cleveland, Ohio 44195, USA. · Retina. · Pubmed #19553797 No free full text.

Abstract: Radiotherapy is a promising adjunctive tool to antiangiogenesis therapies for control of the choroidal neovascularization that characterizes exudative (wet) age-related macular degeneration. Historically, radiation monotherapy sufficient to effectively eradicate choroidal neovascularization has been associated with mixed results; however, newer techniques and delivery platforms have been developed to improve efficacy. The most significant improvements are technical advances that improve the precision of energy delivery, so that tissue destruction remains confined to the target. In addition, several combination therapies are showing promise for enhanced effect. Other strategies, such as pretreating neovascular tissue to increase its sensitivity to radiation, thereby reducing the energy dose, may also be viable. However, even though the modern delivery systems permit relatively low dosages, there are risks of radiotherapy to ocular tissue, and its role remains speculative, pending results of ongoing trials.

Kaiser PK. · Vitreoretinal Department, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44106, USA. · Retina. · Pubmed #19553789 No free full text.

Abstract: Clinical trials increasingly support the premise that inhibition of vascular endothelial growth factor is a viable but insufficient target for long-term control of age-related macular degeneration (AMD). Additional biologic therapies targeted at very specific steps in the proliferative signaling pathway are being actively sought as alternatives or adjunctive strategies for the treatment of AMD. This rapidly advancing area of drug development is particularly encouraging because of the growing appreciation for the redundancies and interrelationships between the molecular events. The complexity of this signaling pathway supports the development of combination treatments for optimal control of biologic functions.

Kaiser PK, Anonymous00074. · Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · Curr Med Res Opin. · Pubmed #19530976 No free full text.

Abstract: OBJECTIVE: To determine whether verteporfin photodynamic therapy (PDT) can safely reduce the risk of vision loss in patients with subfoveal occult with no classic choroidal neovascularization (CNV) due to age-related macular degeneration. RESEARCH DESIGN AND METHODS: Eligible patients were > or =50 years of age with lesion size < or =6 disc areas and best-corrected vision 20/40-20/200. A total of 364 patients with occult with no classic CNV were randomly assigned 2 : 1 to verteporfin PDT (n = 244) or placebo (n = 120). The primary outcome measures were loss of > or =15 and > or =30 letters of visual acuity (VA) from baseline at 12 and 24 months. CLINICAL TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov on 20 July 2005. ClinicalTrials.gov identifier: NCT00121407. RESULTS: A total of 37% and 47% of verteporfin-treated patients versus 45% and 53% of placebo recipients lost > or =15 letters of VA at month 12 and month 24, respectively; 16% and 23% of verteporfin-treated patients versus 17% and 25% of placebo recipients lost > or =30 letters at month 12 and month 24, respectively. These differences were not statistically significant. Four (1.6%) verteporfin-treated patients and one placebo patient (who received verteporfin in error) experienced an acute severe VA decrease; all five patients recovered some degree of vision. No unexpected ocular or systemic adverse events were identified. CONCLUSIONS: Verteporfin PDT in the treatment of occult with no classic CNV was safe and well-tolerated. The differences between the two groups in the primary efficacy variables were not significant. Baseline characteristics and patient selection methods may have contributed to the small treatment effect.

Taban M, Sharma S, Williams DR, Waheed N, Kaiser PK. · Cole Eye Institute, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, USA. · Ophthalmology. · Pubmed #19410954 No free full text.

Abstract: PURPOSE: To compare automated retinal thickness values generated by the fast macular thickness maps (FMTM) and customized 6-radial line scans (RLS) versus manual retinal measurements on Stratus optical coherence tomography (OCT) (Carl Zeiss Meditec, Dublin, CA). DESIGN: Prospective, observational case series. PARTICIPANTS: Patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD), diabetic macular edema (DME), or branch/central retinal vein occlusion (RVO). METHODS: Patients were prospectively imaged using the FMTM and customized RLS patterns on Stratus OCT at the same sitting. Each scan was evaluated for errors in retinal segmentation (i.e., correct retinal boundaries [CRB]). Automated values were recorded while central retinal thickness measurements were determined manually for both patterns. The presence or absence of epiretinal phenomenon, cystoid spaces, pigment epithelial detachment, and subretinal fluid was also noted. MAIN OUTCOME MEASURES: Errors in retinal segmentation at and outside the fovea (i.e., CRB) and percentage of automated values within a clinically acceptable margin (+/-25 mum) of the manual central retinal thickness. RESULTS: A total of 147 eyes of 147 patients (95 eyes with exudative AMD, 41 eyes with DME, and 11 eyes with macular edema caused by RVO) were included. For wet AMD, the total number of CRB at the fovea and outside the fovea was 363 (63.7%) and 360 (63.2%), respectively, in FMTM and 428 (75.1%) and 426 (74.7%), respectively, in RLS (P<0.0001 for both). For DME and RVO, the total number of CRB at the fovea and outside the fovea was 274 (87.8%) and 256 (82.1%), respectively, in FMTM and 287 (92.0%) and 270 (86.5%), respectively, in RLS (P = 0.11, P = 0.15, respectively). Some 40% and 56% of automated foveal center point thicknesses on FMTM and RLS, respectively, were within +/-25 mum of the manual central retinal thickness for AMD (P = 0.042), versus 94% and 81% for DME and RVO, respectively (P = 0.07). CONCLUSIONS: For exudative AMD, the RLS protocol provides fewer segmentation errors than the FMTM protocol, and its automated retinal thickness values (e.g., foveal center point, central subfield) correlate better with manual retinal thickness measurement than FMTM. In DME and RVO, however, both protocols provide similar and low segmentation errors, and their automated results are close to manual measurements. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Barakat MR, Kaiser PK. · Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. · Expert Opin Investig Drugs. · Pubmed #19388880 No free full text.

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world for those patients aged 50 years or older. Neovascular AMD, a subtype characterized by the growth of new, pathologic blood vessels, results in most of the cases of severe and rapid vision loss associated with AMD. A critical activator of angiogenesis in neovascular AMD is VEGF. Several therapies have been and are now being developed for neovascular AMD, with the goal of inhibiting VEGF. These VEGF inhibitors include the RNA aptamer pegaptanib, partial and full-length antibodies ranibizumab and bevacizumab, VEGF receptor decoy VEGF Trap, small interfering RNA-based therapies bevasiranib and AGN211745, sirolimus, and tyrosine kinase inhibitors including vatalanib, pazopanib, TG100801, TG101095, AG013958 and AL39324. At present, established therapies have met with great success in reducing the vision loss associated with neovascular AMD, whereas those still investigational in nature offer the potential for further advances.

Kaiser PK, Anonymous00056, Boyer DS, Garcia R, Hao Y, Hughes MS, Jabbour NM, Kaiser PK, Mieler W, Slakter JS, Samuel M, Tolentino MJ, Roth D, Sheidow T, Strong HA. · Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · Ophthalmology. · Pubmed #19243834 No free full text.

Abstract: PURPOSE: To assess outcomes for patients with choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) treated with verteporfin photodynamic therapy (PDT) and bevacizumab. DESIGN: Retrospective, case series database study (registry). PARTICIPANTS: We included 1196 patients with CNV due to AMD who received > or =1 combination treatment of 1.25 mg intravitreal bevacizumab within 14 days of verteporfin PDT. METHODS: Retrospective analysis of baseline data with ongoing follow-up. Physicians from 45 clinical centers entered patient data at baseline and follow-up examinations, including subsequent treatments, into a secure, Web-accessed database. Snellen visual acuity (VA) was converted to logarithm of the minimum angle of resolution (logMAR) for statistical analyses. MAIN OUTCOME MEASURES: Change from baseline in VA and retreatment rates of any therapy after the initial combination treatment. RESULTS: Of 1196 patients, 1073 patients had > or =6 months of follow-up. For these 1073 patients, mean baseline VA was 0.967 logMAR (approximate Snellen 20/185) and 56.3% of patients (604/1073) were treatment naïve. After their baseline combination treatment, patients received a mean of 0.6 additional verteporfin PDT retreatments and 2.0 bevacizumab retreatments over a mean follow-up period of 15.0 months. By 12 months, 82% of patients (578/701) had stable or improved vision (loss of <3 lines or a gain in VA), 36% (255/701) improved by > or =3 lines, and 17% (121/701) improved by > or =6 lines. By 12 months, patients gained approximately 1.2 lines (6 letters) of VA from baseline. Patients who were treatment naïve gained significantly more VA by month 12 (+8.4 letters) compared with those who had been previously treated (+2.4 letters; P<0.01). Most serious adverse events (26/30) were judged by investigators as not related to any study treatment, although 3 ocular events were judged related to bevacizumab alone, and 1 ocular event was judged related to both bevacizumab and PDT. CONCLUSIONS: Combination therapy with PDT and bevacizumab led to vision benefit for most patients, particularly those who were treatment naïve at baseline. The number of retreatments was lower than published reports with either treatment delivered as monotherapy. Randomized clinical trials are underway to confirm these findings.