SUMMARY. Heather Casparis, MD,* and Neil M. Bressler, MD MARINA AND ANCHOR

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1 The following are summaries of selected presentations and posters from the American Society of Retina Specialists and European VitreoRetinal Society Annual Meeting held September 9 13, 2006, in Cannes, France Heather Casparis, MD,* and Neil M. Bressler, MD MARINA AND ANCHOR Based on paper presentations by Schmidt-Erfurth 1 ; Loewenstein 2 ; and Lanzetta. 3 Ranibizumab is a humanized antibody fragment that binds to and inactivates all active forms of vascular endothelial growth factor-a (VEGF-A). This antiangiogenic molecule was recently approved by the US Food and Drug Administration for the treatment of choroidal neovascularization (CNV) due to agerelated macular degeneration (AMD) based on the favorable results of randomized multicenter clinical trials. Both the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) trials are multicenter phase III trials that evaluated the efficacy and safety of 24 monthly ranibizumab injections in patients with subfoveal CNV. Several presentations reported on the safety and efficacy of monthly ranibizumab at the September 2006 Cannes American Society of Retina Specialists and European VitreoRetinal Society (ASRS/EVRS) annual meeting. Dr Schmidt-Erfurth reported the 2-year safety and efficacy results for MARINA, Dr Loewenstein presented a side-by-side presentation *Advanced Speciality Training Physician, Wilmer Eye Institute, The Johns Hopkins Hospital, Baltimore, Maryland. James P. Gills Professor of Ophthalmology, Chief, Retina Division, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to: Heather Casparis, MD, Advanced Speciality Training Physician, Wilmer Eye Institute, The Johns Hopkins Hospital, Maumenee 205, 600 North Wolfe Street, Baltimore, MD hbartle1@jhmi.edu. of the MARINA and ANCHOR outcomes, and Dr Lanzetta discussed the side-by-side presentation of the safety results of these trials. MARINA DESIGN MARINA is a randomized, double-masked, sham-injection controlled study of the efficacy and safety of monthly intravitreal injections of ranibizumab in patients with minimally classic or occult CNV due to AMD and presumed recent disease progression. A total of 716 patients were randomized in a 1:1:1 ratio to a sham injection, 0.3 mg of intravitreal ranibizumab, or 0.5 mg of ranibizumab. Eligibility criteria included age of at least 50 years, visual acuity (Snellen equivalent) of 20/40 to 20/320, and no prior treatment with photodynamic therapy (PDT). Injections were performed on a monthly basis for the 2-year study duration and additional treatment with PDT was allowed at the discretion of the investigator if a predominantly classic lesion developed, or when lesions developed that were approved for coverage by the Centers for Medicare and Medicaid Services in selected cases of occult with no classic lesions or minimally classic lesions. The primary efficacy endpoint was the proportion of study subjects losing less than 15 letters of best-corrected visual acuity at 1 year, and secondary endpoints included the mean change in visual acuity from baseline, the proportion of subjects with a 15-letter or greater gain, the proportion of subjects with visual acuity of 20/200 or worse, changes in fluorescein angiographic leakage, and vision-related quality-of-life measurements. All sham patients were offered treatment with ranibizumab in October of 2005, and 12 subjects received such treatment before the month 24 visit. 8 Vol. 4, No. 1 February 2007

2 MARINA RESULTS Dr Schmidt-Erfurth presented the 2-year efficacy and safety results of MARINA at ASRS/EVRS. 1 The primary efficacy endpoint of approximately 95% of treated patients avoiding 15-letter or more loss at 12 months was maintained for ranibizumab at 24 months in MARINA, with 53% of the sham, 92% of the 0.3- mg, and 90% of the 0.5-mg subjects losing less than 3 lines of best-corrected vision (P <.0001). In addition, all secondary outcomes that favored ranibizumab at 12 months maintained these favorable outcomes at 24 months. Ranibizumab-treated patients showed a mean improvement of 5.4 letters (0.3 mg) or 6.6 letters (0.5 mg) over baseline, whereas sham patients lost an average of 14.9 letters. The proportion of individuals gaining 15 letters or more at 12 months was similar at 24 months with approximately 4% of sham, 26% of 0.3-mg, and 33% of 0.5-mg subjects gaining 3 or more lines. A 6- line or greater gain was seen in less than 1% of sham and in approximately 5% of the ranibizumab subjects. A visual loss of 30 or more letters (approximately 6 lines or more) was seen in 23% of the sham and 3% of the ranibizumab group. Vision of 20/200 or worse was seen in approximately 14% of all subjects at baseline and increased to 48% in the sham group and 15% of patients receiving ranibizumab at 24 months. The 2-year safety results were similar to what already had been reported at 12 months. Serious ocular adverse events (AEs) included endophthalmitis, uveitis, retinal tear or detachment, vitreous hemorrhage, and lens damage. The overall incidence of serious ocular AEs was similar between groups, with 7.2% of sham, 8.4% of 0.3-mg ranibizumab, and 8.8% of 0.5-mg ranibizumab subjects experiencing such an event. Endophthalmitis was seen in approximately 1% of ranibizumab subjects, as was uveitis. Serious systemic AEs were uncommon. Death occurred in 2.5% of the sham and 2.1% and 2.5% of the 0.3-mg and 0.5-mg ranibizumab-treated subjects during the course of the study. ANCHOR DESIGN ANCHOR is a randomized, double-masked study comparing the efficacy and safety of monthly intravitreal ranibizumab to verteporfin PDT in patients with predominantly classic subfoveal CNV due to AMD. A total of 423 subjects with lesions no greater than 5400 microns in greatest linear dimension were randomized in a 1:1:1 manner to PDT with sham intravitreal injection (n = 143), sham PDT with 0.3 mg ranibizumab (n = 140), and sham PDT with 0.5 mg ranibizumab (n = 140). Each patient received PDT or sham PDT at baseline, and the treatment was repeated as often as every 3 months if there was fluorescein leakage from CNV. All patients also received ranibizumab or sham injection at baseline and repeat treatment every month for the study duration. The primary efficacy endpoint of ANCHOR, similar to MARINA, was the proportion of subjects losing less than 15 letters of best-corrected visual acuity. Secondary endpoints at 1 year included the proportion gaining 15 letters or more, the proportion with 20/200 or worse vision, and the mean change in baseline acuity. COMBINED MARINA AND ANCHOR RESULTS Dr Loewenstein presented the efficacy results of MARINA and ANCHOR in a side-by-side presentation at ASRS/EVRS. 2 Regardless of baseline lesion composition, lesion size, or visual acuity, the efficacy of monthly injections of ranibizumab in patients with AMD with subfoveal CNV was similar to what was reported for the entire cohort in both MARINA and ANCHOR. Dr Lanzetta presented the safety results of ranibizumab-treated MARINA and ANCHOR subjects in a side-by-side presentation. 3 More than 9000 injections were performed in the 754 treated patients. There was a less than 1% rate of each serious ocular AE. ANCHOR had one culture-positive endophthalmitis case and 4 additional culture-negative cases. At 12 months, none of the 5 patients had lost more than 15 letters of best-corrected visual acuity. The per-injection rate of serious ocular AEs was 0.12% or lower for each dose group. There was no statistically significant imbalance in the incidence of systemic serious AEs between ranibizumab-treated and control groups in either study. Although the frequency of systemic serious AEs was so low in both ranibizumab-treated groups and the control group, even a modest increase of such events cannot be ruled out by the existing data. No death in either study was attributed to ranibizumab. REFERENCES 1. Schmidt-Erfurth U. Two-year efficacy and safety results from the MARINA study. Paper presented at: 24th Annual American Society of Retina Specialists and 6th Annual European VitreoRetinal Society Meeting; September 9-13, 2006; Cannes, France. 2. Loewenstein A. Combined efficacy of intravitreal ranibizumab in two phase III studies of choroidal neovascularization secondary to age-related macular degeneration. Paper pre- Johns Hopkins Advanced Studies in Ophthalmology 9

3 sented at: 24th Annual American Society of Retina Meeting; September 3. Lanzetta P. Combined safety of intravitreal ranibizumab in two phase III studies of choroidal neovascularization secondary to age-related macular degeneration. Paper presented at: 24th Annual American Society of Retina Specialists and 6th Annual European VitreoRetinal Society Meeting; September TRIALS USING LESS FREQUENT RANIBIZUMAB DOSING Based on paper presentations by Abraham 1 ; Mieler 2 ; and Rosenfeld. 3 PIER DESIGN PIER (Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to Age-Related Macular Degeneration) is a 2-year study of the efficacy and safety of intravitreal ranibizumab on subfoveal choroidal neovascularization (CNV; either with no prior laser photocoagulation or recurrent CNV after photocoagulation that did not involve the center of the macula) due to agerelated macular degeneration (AMD) compared to a sham injection. This multicenter, double-masked, controlled phase IIIb trial randomized patients in a 1:1:1 manner to sham injection, 0.3 mg ranibizumab, or 0.5 mg ranibizumab. Patients of at least 50 years of age with Snellen equivalent best-corrected visual acuity of 20/40 to 20/320 were eligible. Minimally classic and occult with no classic lesions were included only in the presence of recent disease progression; predominantly classic lesions did not have this requirement. Subjects were treated with monthly injections for 3 doses and then retreated every 3 months. Photodynamic therapy (PDT) with verteporfin was offered at investigator discretion if the lesion composition became predominantly classic, or if the lesion composition was minimally classic or occult with no classic with presumed recent disease progression and there was a best-corrected visual acuity loss of 20 letters or more on 2 consecutive study visits. A total of 10 injections were given to each subject over the 2-year course of the PIER study, which was in contrast to the MARINA (Minimally Classic/Occult Trial of the Anti- VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) studies in which patients received 24 monthly injections for 2 years. The primary 1-year efficacy endpoint was the mean change from baseline best-corrected visual acuity. Some clinically relevant secondary outcomes included the proportion of subjects with at least a 3-line increase in vision, at least a 3-line decrease in vision, 20/200 or worse vision, 20/40 or better vision, in addition to a centralized reading center assessment of the change in lesion morphology by fluorescein angiography (FA). Optical coherence tomography (OCT) images also were collected. Ocular and nonocular adverse events were also monitored. SAFETY AND EFFICACY RESULTS Dr Abraham presented the 1-year results of PIER at the American Society of Retina Specialists and European VitreoRetinal Society (ASRS/EVRS) annual meeting. 1 A total of 184 patients were enrolled and randomized and the groups were well balanced in demographics and visual acuity. Follow-up was excellent with 86% to 98% retention at 1 year. Twenty-seven sham patients got PDT versus 2% of each ranibizumab group. The primary outcome of mean change in visual acuity showed sham subjects losing 16.3 letters as compared to 1.6- and 0.2-letter losses for the 0.3-mg and 0.5-mg ranibizumab groups. In addition, 49% of sham subjects lost less than 15 letters compared to 83% for 0.3 mg of ranibizumab and 90% for 0.5 mg of ranibizumab. Visual acuity of 20/200 or worse was seen in 52% of sham subjects versus 23% of each ranibizumab group, and visual acuity of 20/40 or better was seen in 11% of sham versus 28% to 30% of ranibizumab subjects. There was little difference among the groups for a 3-line or more increase at 1 year, with this outcome occurring in 10% of sham subjects, 12% of 0.3-mg subjects, and 13% of 0.5-mg subjects. No serious ocular adverse event was seen at 1 year in PIER. Most subjects had no or trace intraocular inflammation, and the few that had 2+ or less cell or flare were asymptomatic. No arteriothrombotic event or death was registered, and there was no imbalance in any of the key systemic events monitored. One patient was found to have systemic immunoreactivity to ranibizumab at baseline and 2 were antibody-positive at 1 year. PIER FLUORESCEIN ANGIOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY RESULTS Dr Mieler presented the 1-year FA and OCT results from PIER. 2 FA was obtained at screening and 10 Vol. 4, No. 1 February 2007

4 repeated at months 3, 5, 8, and 12. OCT was performed at baseline and months 1, 2, 3, 5, 8, and 12. The change in leakage area and lesion size by FA was measured in addition to retinal thickness and retinal volume by OCT. At 1 year, there was a 2-disc area (DA) difference in FA leakage area between the sham and ranibizumab-treated subjects, with a 1 DA increase in leakage being seen in sham subjects and a 1 DA decrease being seen with ranibizumab. The average change from baseline to 1 year in foveal thickness as measured by OCT was a decrease of 30 microns in the sham group as compared to 120 microns in the treatment group. Decreases in OCT thickening were seen as early as 1 month. The 1-year results of PIER suggest that an initial induction with 3 monthly ranibizumab treatments followed by quarterly injections may confer visual acuity, FA, and OCT benefits compared to sham. Although such a regimen decreases the inconvenience and risk of more frequent injections, it is unknown if this regimen is almost as good, better, or worse with respect to safety and efficacy compared to the monthly treatments used in the completed MARINA and ANCHOR trials. PRONTO DESIGN Dr Rosenfeld reported the most recent results of his PrONTO (Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intra-Ocular Ranibizumab) study at ASRS/EVRS. 3 This ongoing investigator-initiated phase I/II trial from the Bascom Palmer Eye Institute was designed to assess the effectiveness of a less-frequent dosing regimen than MARINA or ANCHOR with some retreatments given if patients met certain criteria of subfoveal CNV due to AMD. Patients with subfoveal CNV, OCT central subfield retinal thickness of at least 300 microns, and Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity of 20/40 to 20/400 were eligible for the PrONTO study. All lesion types were included and prior treatment with verteporfin, pegaptanib, or triamcinolone acetonide was allowed. Each enrolled patient received 3 consecutive monthly injections of 0.5 mg of ranibizumab in the study eye. Patients were assessed with OCT, visual acuity, and FA. OCT measurements were obtained at baseline and on postinjection days 1, 2, 4, 7, 14, and 30 and monthly thereafter. Visual acuity on an ETDRS chart was measured at baseline and on postinjection days 14, 30, 45, 60, and then on a monthly basis. Fluorescein angiography was performed at baseline and then every 3 months. After the initial 3 PrONTO injections, retreatment with ranibizumab was performed only for increase in OCT thickness of 100 or more microns, residual fluid seen on OCT (intraretinal or subretinal fluid), visual loss of 5 letters with recurrent fluid on OCT, new classic CNV, or new macular hemorrhage. PRONTO RESULTS Forty patients were enrolled between August 2004 and April The mean age was in the mid 80s, 66% were women, and all were Caucasian. The mean baseline visual acuity was 20/80 and the mean OCT central retinal thickness was almost 400 microns. Lesions were classified as minimally classic in 57.5% of patients, occult with no classic in 25%, and predominantly classic in 17.5%. An anastomosis of a retinal vessel to the neovascular lesion (also called retinal angiomatous proliferation) was seen in 25%. All subjects were present for 12 months of follow-up. A median of 5 injections was performed per subject per year. Three to 5 injections were performed in the majority of subjects, and 12 or 13 injections were rarely required. The mean and median times to reinjection were 4.5 and 3 months, respectively. In addition, 7 of 40 enrolled subjects received only the 3 initial injections. A decrease in cystoid abnormalities was the earliest OCT abnormality seen. Resolution of cystoid abnormalities was seen at 1 week, whereas subretinal fluid tended to resolve more slowly. Pigment epithelial detachment resolution occurred even more slowly and did not occur in all subjects. A mean OCT decrease of approximately 180 microns was seen at 12 months. Thirty-two patients achieved a fluid-free macula. There was a mean increase of 9.3 letters from baseline at 12 months. The vast majority (95%) of subjects avoided a 15-letter or greater loss of vision, and 35% gained 15 or more letters. No serious adverse ocular or systemic event was observed. Dr Rosenfeld emphasized that a decrease in OCT thickness was seen by postinjection day 1, and additional decreased central retinal thickness was maintained at 12 months. Improvement in visual acuity was observed at the first postinjection measurement on day 14, and further increased acuity was maintained at 1 year. The 1-year results of this study suggest that, in some patients, improvement in visual activity with ranibizumab therapy may be maintained with an initial series of monthly injections followed by a reinjec- Johns Hopkins Advanced Studies in Ophthalmology 11

5 tion strategy tailored to OCT, visual acuity, and clinical findings, although it is unknown if this regimen is almost as good, better, or worse with respect to efficacy and safety compared to monthly injections performed in MARINA and ANCHOR or less frequent fixed injections in PIER. The PrONTO study followup is planned through 24 months. REFERENCES 1. Abraham P. PIER: Year 1 results of a phase IIIb study of ranibizumab efficacy and safety in choroidal neovascularization due to age-related macular degeneration. Paper presented at: 24th Annual American Society of Retina Meeting; September 2. Mieler W. PIER: Year 1 FA/OCT results in a study of ranibizumab (Lucentis) for choroidal neovascularization (CNV) due to age-related macular degeneration. Paper presented at: 24th Annual American Society of Retina Meeting; September 3. Rosenfeld P. An OCT-guided variable-dosing regimen with Lucentis (ranibizumab) in neovascular AMD: one-year results from the PrONTO study. Paper presented at: 24th Annual American Society of Retina Specialists and 6th Annual European VitreoRetinal Society Meeting; September 9-13, 2006; Cannes, France. RANIBIZUMAB AND QUALITY OF LIFE Based on paper presentations by Chang 1 and Bressler. 2 The central visual loss seen in neovascular agerelated macular degeneration (AMD) has a profound and often devastating effect on an individual s ability to perform basic activities of daily living and to maintain an independent lifestyle. The National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) was developed as an attempt to measure a patient s subjective assessment of vision-related functioning and quality of life (QOL). The MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) trials were the first AMD trials to collect this type of information. The NEI- VFQ 25 was administered to MARINA and ANCHOR subjects by a trained interviewer at baseline and at months 1, 2, 3, 6, 9, 12, 18, and 24. The NEI- VFQ 25 subscales were scored from 0 to 100, and a positive difference represents improved functioning or reduced dependency. Of 11 subscales, 3 were prespecified as important secondary outcomes: near activities (eg, reading a newspaper), distance activities (eg, going down stairs in dim light), and vision-related dependency (eg, being dependent on others to pay household bills). Vision-specific QOL was assessed by calculating the change from baseline in the mean score for each of the questionnaire s subscales using the last observation carried over for missing values. A meaningful change in an individual was defined as a 10-point change in the questionnaire composite or subscale scores. MARINA QUALITY-OF-LIFE RESULTS Dr Chang reported the 24-month vision-specific QOL results of MARINA at the American Society of Retina Specialists and European VitreoRetinal Society annual meeting. 1 Ranibizumab-treated patients in MARINA had higher mean NEI-VFQ 25 scores than controls at 24 months. Of the 716 subjects, 663 had mean overall score changes measured at 12 months with a 2.8-point drop in sham patients as compared to a 5.2- to 5.6-point increase in the 0.3-mg and 0.5-mg ranibizumab groups (P <.001). Differences in mean scores were seen as early as 2 months with a peak at 3 months. There was an approximately 11-point difference in the mean change in score from baseline between sham and ranibizumab-treated subjects at 24 months. The proportion of ranibizumab-treated patients with a 10- point increase (judged clinically relevant in composite and subscale scores) was 3 times higher than that seen in sham subjects. There was also a 3-fold reduction in a 10- point decrease with treatment. More than 40% of ranibizumab-treated subjects had a 10-point or greater increase in near and distance QOL measures and 35% had a 10-point improvement in dependency measures. Dr Chang emphasized that the QOL outcomes seen at 12 months were maintained at 24 months in MARINA. Less than 50% of subjects were being treated in their better seeing eye, so that these outcomes are relevant even when the worst seeing eye is being treated (eg, when the eye initiating ranibizumab is 20/100 and the fellow eye is 20/20). As seen at 12 months, ranibizumab-treated patients were more likely to have a 10-point improvement in NEI-VFQ 25 scores at 2 years. Higher scores on the prespecified near activities, 12 Vol. 4, No. 1 February 2007

6 distance activities, and vision-related dependency subscales were also seen in ranibizumab-treated patients. These results are consistent with the favorable visual acuity outcomes reported at 24 months. ANCHOR QUALITY-OF-LIFE RESULTS Dr Bressler reported the 1-year QOL results for ANCHOR. 2 As in MARINA, less than 50% of subjects were being treated in their better-seeing eye; however, in this study, all arms received an active treatment. At baseline, 418 subjects completed the NEI-VFQ 25 and 379 subjects completed the questionnaire at month 12. Mean changes in the overall score from baseline were +2.2 for verteporfin photodynamic therapy (PDT), +5.9 for 0.3-mg ranibizumab (P =.0025 vs PDT), and +8.1 for the 0.5-mg group (P <.0001 vs PDT). A clinically relevant 10-point gain was more likely in ranibizumabtreated subjects. Although all arms had subjects who gained, 20% of PDT subjects had a 10-point increase as compared to 33% to 34% of the ranibizumab groups. Ranibizumab-treated patients were less likely to have a clinically relevant decrease in QOL as measured in ANCHOR. The beneficial QOL effect was also present for the prespecified near, distance, and vision-related dependency NEI-VFQ 25 subscales. Mean changes in near activities were +3.7 for PDT, +6.6 for 0.3-mg ranibizumab (P =.0932 vs PDT), and +9.1 for 0.5-mg ranibizumab (P <.0093 vs PDT). Distance activity scores were +1.7 for PDT, +6.4 for 0.3-mg ranibizumab (P =.0071 vs PDT), and +9.3 for the 0.5-mg group (P <.0001). Mean changes in baseline in the vision-related dependency subscale were -1.4 for PDT, +7.6 for 0.3-mg ranibizumab, and +8.9 for the 0.5-mg dose (P <.0001 for each group vs PDT). As with MARINA, the QOL results seen in ANCHOR are consistent with favorable visual acuity in ranibizumab-treated subjects. REFERENCES 1. Chang T. Ranibizumab (Lucentis) vision-specific quality of life through 24 months in neovascular AMD subjects in MARINA: a phase III clinical trial. Paper presented at: 24th Annual American Society of Retina Specialists and 6th 2. Bressler NB. Vision-specific quality of life at 12 months in predominantly classic neovascular AMD in ANCHOR: a phase III trial of ranibizumab and verteporfin PDT. Paper presented at: 24th Annual American Society of Retina Meeting; September ADDITIONAL ANTI-VEGF PRESENTATIONS Based on paper presentations by Korobelnik 1 ; Antoszyk 2 ; Wolf 3 ; Brown 4 ; Tezel 5 ; Khan. 6 CONTRAST SENSITIVITY IN MARINA AND ANCHOR Dr Korobelnik reported the contrast sensitivity results of the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD), ANCHOR (Anti- VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD), and PIER (Phase IIIb, Multicenter, Randomized, Double- Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to Age-Related Macular Degeneration) trials at the American Society of Retina Specialists and European VitreoRetinal Society (ASRS/EVRS) annual meeting. 1 These results were at 24 months for MARINA, 12 months for ANCHOR, and 3 months for PIER. The Pelli-Robson chart was used to measure contrast sensitivity at each visit in these studies. This chart is read at a standard distance (often 1 meter) under standard illumination and consists of letters that are all the same size (a Snellen equivalent of approximately 20/750) but differ in contrast sensitivity as measured in 0.15 log unit increments. In MARINA, sham subjects had a 4.8-letter score decrease in contrast sensitivity scores, whereas ranibizumab subjects had a 1.7- to 1.8-letter score increase. Ranibizumab-treated ANCHOR subjects had favorable contrast sensitivity scores at 12 months, with a mean 3.1 decrease of Pelli-Robson numbers being seen in patients receiving photodynamic therapy (PDT) as compared to a 3- to 4-point increase in the ranibizumab groups. PIER control subjects had a 3.8- point decrease in score compared to a 1.4- and 0.8-letter score increase in the 0.3-mg and 0.5-mg ranibizumab groups, respectively. These contrast sensitivity results are consistent with the favorable effect on visual acuity seen with ranibizumab treatment in MARINA, ANCHOR, and PIER. FOCUS Dr Antoszyk presented the 2-year results of FOCUS (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) at ASRS/EVRS. 2 This phase I/II randomized, multicen- Johns Hopkins Advanced Studies in Ophthalmology 13

7 ter, single-masked study was designed to evaluate the safety, tolerability, and efficacy of combination therapy with PDT and ranibizumab in patients with predominantly classic subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). In FOCUS, subjects were randomized in a 2:1 manner to verteporfin PDT followed by either 0.5-mg injections of lyophilized ranibizumab (n = 105) or sham injections (n = 56) for 23 months. Patients older than 50 years with visual acuity of 20/40 to 20/320 and no fibrosis were enrolled. A history of prior PDT was acceptable. Early in the study, PDT was performed 7 days before the initial ranibizumab or sham injection and then every 3 months as clinically indicated. However, because of a higher than expected incidence of uveitis when lyophilized ranibizumab (not the formulation currently approved for use by the US Food and Drug Administration [FDA]) was administered 7 days after PDT, the verteporfin-injection interval was lengthened to 28 days. The primary efficacy endpoint was the proportion of subjects who lost less than 15 letters of best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity at 12 months. Secondary endpoints included mean change in visual acuity from baseline, the proportion of subjects with a 15-letter or greater increase in vision, the proportion with a 30-letter or greater increase in vision, and the proportion of patients with 20/200 or worse vision. Fundus photography and fluorescein angiography were used to assess morphologic changes in the CNV, and ocular and nonocular events were monitored for safety purposes. A total of 162 patients were enrolled in FOCUS and the groups were well balanced in baseline characteristics. The 1-year primary outcome result of ranibizumab with PDT was maintained, with 75% of PDT alone and 87.5% of PDT plus ranibizumab subjects losing less than 15 letters at 2 years. The mean change in visual acuity was a 7.8-letter loss for PDT alone versus a 4.6-letter gain for combination patients at 2 years. A 15-letter or greater gain was seen in 7.1% of patients receiving PDT as compared to 24.5% of combination patients, and a 30-letter or greater gain was also more common with PDT plus ranibizumab. Fifty percent of PDT alone subjects had 20/200 or worse vision at 2 years as compared to 30.5% of combination subjects. Subgroup analysis was performed and suggested that patients with prior PDT were possibly more likely to lose vision in this trial. Subjects in the ranibizumab group needed fewer PDT sessions with an average of 4 treatments per year being performed in the PDT alone group as compared to 1.4 treatments per year in the combination group. The lyophilized ranibizumab used at the onset of FOCUS differs from the liquid formulation used in other ranibizumab studies and may have led to the intraocular inflammation initially seen with the combination group. Uveitis events were clustered around the time of PDT and decreased with the earlier-mentioned change in protocol. There was a 5.7% rate of presumed endophthalmitis (endophthalmitis cases plus uveitis) over the 2-year study duration, although only 1 of the 5 reported cases was culture-positive. Arteriothrombolic events were not increased in a statistically significant manner. There was 1 case of hypertension. Systemic immunoreactivity to ranibizumab was higher in treated subjects. The results of combination therapy with PDT and ranibizumab at 1 year were maintained at 2 years in the FOCUS trial. An initial protocol amendment increased the PDT-ranibizumab interval from 7 to 28 days and was associated with a decrease in the rate of intraocular inflammation. PDT plus ranibizumab subjects avoided a 15-letter loss of vision 87.5% of the time over the course of FOCUS as compared to 75% of the PDT alone group. Secondary outcomes were also favorable for combination therapy, with PDT plus ranibizumab subjects being more likely to gain vision as compared to baseline and less likely to have 20/200 or worse vision. It is unknown if the outcomes were due to the addition of ranibizumab to PDT, or due to the ranibizumab alone. PROTECT Dr Wolf presented the 4-month results of the PROTECT study at ASRS/EVRS. 3 PROTECT is an open-label, multicenter, phase II study designed to assess the safety and efficacy of same-day verteporfin PDT and ranibizumab formulation as is currently approved by the US FDA, not the lyophilized formulation used in FOCUS described earlier in this article when some instances of inflammation were noted. Patients with PDT-eligible predominantly classic or occult with no classic subfoveal CNV secondary to AMD were given an initial combination treatment of PDT and a same-day intravitreal injection of 0.5-mg ranibizumab. Subjects then received 3 additional injections in addition to PDT as indicated by clinical 14 Vol. 4, No. 1 February 2007

8 findings. The primary outcome of PROTECT was the proportion of patients with a 30-letter or greater visual activity loss that persisted past 14 days. Secondary outcomes included additional visual acuity measurements and fluorescein angiographic findings. A total of 32 patients were enrolled. Twenty-two subjects were women and the mean age was 76 years. Predominantly classic CNV was present in 13 subjects and occult CNV with recent disease progression was present in the remaining 19 subjects. The baseline visual acuity letter score was 50. No patient in PRO- TECT met the primary endpoint of a 30-letter or greater loss of vision that persisted past 14 days. One patient had a loss of 3 or more lines. Treated patients gained a mean of 6.9 letters at 4 months. A reduction of mean foveal thickness from 400 microns to 200 microns was seen at 1 month and persisted at 4 months. The mean fluorescein angiographic leakage area decreased with treatment. Three ocular SE were reported. One patient had a rip of the retinal pigment epithelium. No death was registered. VALUE-BASED MEDICINE ANALYSIS Dr Brown presented an analysis of the value and cost effectiveness of interventions for subfoveal CNV due to AMD at ASRS/EVRS. 4 Such measurements rely on the integration of evidence-based data from clinical trials with value-based medicine utility data and cost-effectiveness principles. The variation in study designs and outcomes can make it difficult to objectively compare treatment benefits for a given condition, and the type of analysis discussed by Dr Brown aims to objectively evaluate and compare clinical trials so that rational treatment recommendations may be made. In this value-based medicine analysis, visual acuity data from clinical trials are converted to value-based form using patient utility analysis values. Value is assessed by measuring the improvement of an intervention on quality and/or quantity of life. Benefits and adverse effects of treatments are incorporated and outcomes are measured in the percent improvement in value conferred by the intervention and the number of quality-adjusted life-years gained. This most often means the measurement of quality of life years (QOLY) in ophthalmology. The best evidence-based data allow calculation of a value form that allows comparison of costs and values. Dr Brown presented several examples of the use of value-based medicine in the AMD setting. Using the data available from clinical studies she found a 17.2% gain in QOLY for ranibizumab therapy for predominantly classic CNV. Calculated values for lesions that were occult with no classic CNV were 5.9% for pegaptanib, 6.3% for PDT (if GLD 4 disc areas or less), and 16.2% for ranibizumab (if GLD less than 9 disc areas). Not only is ranibizumab superior when judged by efficacy outcomes compared with PDT in the ANCHOR trial, ranibizumab was seen as a clear leader by this values-based medicine assessment with QOLY values similar to those seen with statin therapy. EFFECT OF INTRAVITREAL INJECTIONS IN ONE EYE ON PATHOLOGY IN THE FELLOW EYE Dr Tezel presented the results of a prospective masked case series designed to determine whether intravitreally administered antivascular endothelial growth factor (VEGF) drugs exert any biological effect in the contralateral eye. 5 This series included patients receiving intravitreal bevacizumab, pegaptanib, or bevacizumab with triamcinolone. Bilateral optical coherence tomography (OCT) measurements were made pre- and postinjection, and a standardized volumetric change index was calculated from the thickness change in 9 OCT zones. A 2 standard deviation change was deemed statistically significant. This series enrolled 65 patients who underwent a total of 80 injections. Bevacizumab therapy appeared to have a biphasic effect on the fellow eye with a peak at 26 days. Pegaptanib also had a biphasic response, but the peak was seen at 15 days. Twenty-four percent more response was seen in the fellow eye (compared to the treated eye) of patients receiving pegaptanib. Triamcinolone had a 20% response on the fellow eye. This study suggests that intravitreal injection of anti-vegf drugs may exert an effect on the macular thickness of the other eye, either through systemic absorption or some other pathway. Further studies are necessary to validate these observations and to better assess their clinical significance. BEVACIZUMAB FOR CNV IN AMD Dr Khan presented the results of a retrospective chart review of patients undergoing intravitreal bevacizumab therapy for neovascular AMD. 6 Fifty-two patients were enrolled. OCT and visual acuity measurements at 1, 3, and 6 months were analyzed. The mean OCT central subfield retinal thickness decreased from 325 microns at baseline to 240 microns at 1 Johns Hopkins Advanced Studies in Ophthalmology 15

9 month, 247 microns at 3 months, and 257 microns at 6 months. Visual acuity improved from 20/200 at baseline to 20/135 at 1 month, 20/157 at 3 months, and 20/155 at 6 months. Three of the 52 patients had a complication of therapy with 1 case of rhegmatogenous retinal detachment, 1 endophthalmitis, and 1 uveitis being recorded. This small, uncontrolled retrospective chart review suggests that bevacizumab has OCT and visual acuity benefits in the setting of neovascular AMD. REFERENCES 1. Korobelnik JF. Consistency of effect of ranibizumab at 2 doses on contrast sensitivity in 3 phase III and IIIb studies of patients with CNV secondary to AMD. Paper presented at: 24th Annual American Society of Retina Specialists and 6th 2. Antoszyk AN. Intravitreal ranibizumab (Lucentis) plus verteporfin photodynamic therapy for neovascular age-related macular degeneration: FOCUS 2-year results. Paper presented at: 24th Annual American Society of Retina Meeting; September 3. Wolf S. Open-label, multicenter, phase II study assessing the safety and efficacy of same-day verteporfin and liquid ranibizumab 0.5 mg (PROTECT Study). Paper presented at: 24th Annual American Society of Retina Specialists and 6th 4. Brown MM. The value and cost effectiveness of interventions for subfoveal, neovascular, age-related macular degeneration (ARMD). Paper presented at: 24th Annual American Society of Retina Specialists and 6th Annual European VitreoRetinal Society Meeting; September 9-13, 2006; Cannes, France. 5. Tezel TH. Intravitreally injected anti-vegf drugs exert a biological effect in the fellow eye. Paper presented at: 24th Annual American Society of Retina Specialists and 6th 6. Khan S. Six-month follow-up on 50 consecutive patients with intravitreal bevacizumab injections for neovascular age-related macular degeneration. Paper presented at: 24th Annual American Society of Retina Specialists and 6th 16 Vol. 4, No. 1 February 2007