Highlights of the 26th Annual Meeting of the ASRS
Highlights of the 26th Annual Meeting of the ASRS
With the efficacy of vascular endothelial growth factor (VEGF) inhibition established for the treatment of age-related macular degeneration (AMD), new research has focused increasingly on ways to improve and enhance therapy. The 2008 Annual Meeting of the American Society of Retina Specialists (ASRS) reflected this trend, as results of both novel and combination therapies for AMD were presented.
New Treatments for AMD
Jason Slakter presented 1-year optical coherence tomographic (OCT) and fluorescein angiographic results from the CLEAR-IT 2 trial -- a double-masked, multicenter, phase 2 trial that is examining the use of intravitreal VEGF Trap for neovascular AMD. A total of 157 patients received either VEGF Trap 0.5 mg or 2 mg monthly, or 0.5 mg, 2 mg, or 4 mg quarterly for 12 weeks followed by as-needed use thereafter. As-needed usage of VEGF Trap was determined by an investigator and followed PrONTO (Prospective OCT Study With Lucentis for Neovascular AMD) retreatment criteria during the following 40 weeks; the dosage was the same as what was given initially.
On average, patients gained 9 letters of ETDRS (Early Treatment Diabetic Retinopathy Study) visual acuity by the end of the trial. There was a statistical difference between those who received every 4-week injections during the induction period vs those who received every 12-week injections. The every 4-week population had better vision and OCT outcomes at the end of the 1-year trial. The mean number of treatments in the as-needed portion of the trial was 2.01 and the mean time to first retreatment was 3 months. Dr. Slakter noted that one third of patients received either no retreatment or 1 retreatment during the as-needed period -- indicating a durability of VEGF Trap. There were a few nonsignificant adverse events reported, including 1 case of culture-negative endophthalmitis. In the wake of these positive findings, further study of VEGF Trap is also ongoing. The upcoming VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet age related macular degeneration) trial will randomize 1200 patients to 0.5 mg of VEGF Trap every 4 weeks, 0.5 mg of VEGF Trap every 8 weeks, and 2 mg of VEGF Trap every 8 weeks. The study is set to begin enrollment in May 2009.
Richard Kaiser presented results from a phase 1 trial that used antagonists for platelet-derived growth factor (PDGF)-BB. Pericytes are an important component to the choroidal neovascular complex, providing stabilization of vessels; it is also thought that they may limit the penetration of anti-VEGF agents. PDGF-BB is the key regulator of the pericyte endothelial bond. Preclinical models have shown that the combination of VEGF and PDGF treatments appears to have a significant ability to suppress angiogenesis. Dr. Kaiser's phase 1 study examined the use of E10030 (an anti-PDGF pegylated aptamer) in combination with the anti-VEGF agent ranibizumab. Patients received E10030 at the time of the initial visit, followed by ranibizumab at weeks 2, 6, and 10. In the second arm of the study, simultaneous injections of E10030 with ranibizumab were given. Visual acuity improved by 21-27 letters from baseline at 8 weeks within the 2 arms tested. At 4 weeks, 43% of patients had gained 3 lines; 54% had gained 3 lines of vision at 8 weeks; and 62.5% had gained 3 lines by 12 weeks. Although these results are very preliminary, the findings are promising for the targeting of PDGF-BB in neovascular AMD. Further trials are currently being developed.
Jeffrey Heier presented results from an open-label study of intravitreal integrin-antagonist JSM6427. This molecule antagonizes the a5b1 integrins, which are known to play significant roles in the neovascular AMD complex. The phase 1, open-label, first-in-human, dose-escalation trial evaluated the safety, tolerability, and pharmacokinetics of multiple injections of JSM6427. At the end of the trial, there were no adverse events attributed to the drug and no signs of toxicity to date. The efficacy outcome showed stability of both best-corrected visual acuity and OCT readings at the end of the 6 weeks of treatment. Dr. Heier suggested that the stability may be due to the short vitreous half-life of the formulation (less than 17 hours). Studies are now being planned to use an anti-VEGF agent in combination with this integrin antagonist agent to simultaneously inhibit multiple pathways involved in the pathophysiology of neovascular AMD.
Updates on Existing Anti-VEGF Agents for AMD
Dr. Carl Awh presented the Horizon Extension Trial of Ranibizumab for Neovascular AMD, a multicentered, randomized clinical trial that examined the long-term safety and efficacy of intravitreal ranibizumab for patients with subfoveal neovascular AMD. Patients in the Horizon trial had completed one of the 3 formative anti-VEGF trials (MARINA, ANCHOR, or FOCUS). They were then allowed to receive as-needed treatment for the following year. The treatments were given at the discretion of the treating physician, and quarterly measurements were performed prior to the start of the as-needed treatment year. Patients on average had a 9.4-letter gain of visual acuity over baseline before enrollment into Horizon. At the end of year 1 on Horizon, there was a decline in vision to +4.1 letters over baseline -- demonstrating almost a single-line loss of vision from the conversion of monthly therapy to as-needed therapy. There were no significant adverse events reported, and the adverse event rate appeared to be lower than it was in age-matched controls. On average, patients received between 3 and 4 injections over the entire year. These results indicate that monthly dosing is still the gold standard for achieving optimal outcomes.
Tom Chang presented a study comparing remission intervals between ranibizumab and bevacizumab in patients with neovascular AMD. In this retrospective analysis, patients were given 3 consecutive injections of either ranibizumab or bevacizumab (physician preference), followed by monthly monitoring with OCT, clinical evaluation, and determination of best-corrected visual acuity. Remission was defined as a time period between the end of the induction and the start of the reinduction; the time of reinjection was determined on the basis of clinical exam, OCT, or best-corrected acuity. The mean interval of remission for bevacizumab was 6.6 months vs 3.85 months for ranibizumab. Stated differently, 1 of 5 patients with AMD treated with bevacizumab did not require retreatment after the initial induction therapy during the entire year. In comparison, only 2% of patients receiving ranibizumab did not need treatment after the induction period for the entire year. These results suggest that bevacizumab has improved durability over ranibizumab -- findings that could have implications when examining the efficacy of combination treatment trials.
Dr. David Williams presented an update on behalf of Dr. Daniel Martin for CATT (Comparisons of Age-Related Macular Degeneration Treatments Trials). This study is set to examine the use of ranibizumab vs bevacizumab in 1209 patients with neovascular AMD (best-corrected visual acuity between 20/25 and 20/320) in both a fixed and variable treatment paradigm. Currently, 42 sites have been certified and 350 patients enrolled. Patients are being randomized to ranibizumab or bevacizumab on either a monthly basis or a variable basis after a single intravitreal injection. Enrollment is expected to be completed by fall 2009, and results should be appearing by late 2010.
Combination Therapy for AMD
Dr. David Brown presented data from a phase 2 study that combined the use of epiretinal (strontium-90) brachytherapy with bevacizumab for the treatment of neovascular AMD. The 1-year study enrolled 34 patients. Significant reductions in retinal thickness on OCT and significant improvements of visual acuity were obtained at the end of 12 months. No patients were retreated during that 12-month interval.
Dr. Brown's review of the OCT scans showed that there was a significant percentage of undertreatment on the basis of criteria suggesting leakage. However, reexamination of many of these patients found that there was also spontaneous resolution over that period of time. Dr. Brown concluded that although the combination treatment of strontium-90 plus bevacizumab appeared to have significant efficacy outcomes, retreatment rates might be expected to be higher if applied in general clinical practice. Efficacy outcomes might then improve as a result of the continued retreatment during the postradiation period.
Treatment for Diabetic Retinopathy and Diabetic Macular Edema
J. Fernando Arevalo presented on en bloc perfluorodissection for tractional retinal detachment and proliferative retinopathy. His surgical technique involves incising the peripheral posterior hyaloid in cases of tractional retinal detachment and infusing perfluorocarbon liquid below the area of the hyaloid to further separate the retinal planes from the posterior hyaloidal planes. During surgery, a hole is initially created in the midperipheral posterior hyaloid, and the perfluorocarbon liquid is injected mechanically to separate the posterior hyaloid from the retina. Once all the epiretinal tissues have been lysed after slow infusion of perfluorocarbon liquid underneath the hyaloidal surface, the vitrectomy is then completed and laser applied under the perfluorocarbon liquid. This results in an air-fluid exchange, in which air is exchanged for gas.
In the prospective, interventional, nonrandomized case series, Dr. Arevalo performed 57 surgeries with this technique for the indication of tractional retinal detachment and peripheral diabetic retinopathy. None of the patients developed ocular hypertension or inflammation during the postoperative period, an anatomic success rate of 100%. Best-corrected visual acuity remained stable in approximately one quarter (24.5%) of eyes. Complications of the procedure included phthisis bulbi in one eye (1.7%), iatrogenic retinal breaks in 7% of eyes, vitreous hemorrhage requiring another procedure in 7% of eyes, and cataract in 26.3% of eyes. Dr. Arevalo argued that this technique had significant advantages over traditional surgery, including increased retinal stability at the time of vitreous removal, better visualization of the vitreous and intraocular structures, rapid retinal reattachment, less blood in the vitreous cavity, subretinal fluid resolution, blood confinement, and easier dissection of the epiretinal membranes with perfluorocarbon liquid.
Pravin Dugel presented safety and tolerability results for the use of sirolimus (rapamycin) in diabetic macular edema (DME) and exudative AMD. Sirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR), which has antiangiogenic, antifibrotic, antiproliferative, and anti-inflammatory effects. The drug is given either intravitreally or subconjunctivally and was evaluated in 2 separate multirandomized, open-label, dose-escalation trials.
A total of 50 patients were enrolled in the DME trial and 30 patients in the AMD trial. The injections were given at day 0, and patients were followed for a period of 90 days. In the AMD population, best-corrected visual acuity improved by 4.5 letters by day 7 and declined back to baseline by day 90. In the DME population, best-corrected visual acuity improved by day 14 and remained stable during the entire course of the 90-day period, for a mean gain of 4 letters of ETDRS visual acuity. Both the subconjunctival and intravitreal administration showed significant efficacy in improving visual acuity and reducing retinal thickness in the 90-day follow-up period. In a subgroup analysis of the DME patients who received subconjunctival injections of sirolimus, best-corrected visual acuity peaked at 9.0 letters and retinal thickness dropped by 48.8 microns. In the patients with AMD, best-corrected visual acuity peaked at 6.5 letters and retinal thickness dropped by 60 microns in those who received sirolimus subconjunctivally. Significant pharmacologic effects were seen in patients with both DME and AMD, and phase 2 studies are pending.
With the efficacy of vascular endothelial growth factor (VEGF) inhibition established for the treatment of age-related macular degeneration (AMD), new research has focused increasingly on ways to improve and enhance therapy. The 2008 Annual Meeting of the American Society of Retina Specialists (ASRS) reflected this trend, as results of both novel and combination therapies for AMD were presented.
New Treatments for AMD
Jason Slakter presented 1-year optical coherence tomographic (OCT) and fluorescein angiographic results from the CLEAR-IT 2 trial -- a double-masked, multicenter, phase 2 trial that is examining the use of intravitreal VEGF Trap for neovascular AMD. A total of 157 patients received either VEGF Trap 0.5 mg or 2 mg monthly, or 0.5 mg, 2 mg, or 4 mg quarterly for 12 weeks followed by as-needed use thereafter. As-needed usage of VEGF Trap was determined by an investigator and followed PrONTO (Prospective OCT Study With Lucentis for Neovascular AMD) retreatment criteria during the following 40 weeks; the dosage was the same as what was given initially.
On average, patients gained 9 letters of ETDRS (Early Treatment Diabetic Retinopathy Study) visual acuity by the end of the trial. There was a statistical difference between those who received every 4-week injections during the induction period vs those who received every 12-week injections. The every 4-week population had better vision and OCT outcomes at the end of the 1-year trial. The mean number of treatments in the as-needed portion of the trial was 2.01 and the mean time to first retreatment was 3 months. Dr. Slakter noted that one third of patients received either no retreatment or 1 retreatment during the as-needed period -- indicating a durability of VEGF Trap. There were a few nonsignificant adverse events reported, including 1 case of culture-negative endophthalmitis. In the wake of these positive findings, further study of VEGF Trap is also ongoing. The upcoming VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet age related macular degeneration) trial will randomize 1200 patients to 0.5 mg of VEGF Trap every 4 weeks, 0.5 mg of VEGF Trap every 8 weeks, and 2 mg of VEGF Trap every 8 weeks. The study is set to begin enrollment in May 2009.
Richard Kaiser presented results from a phase 1 trial that used antagonists for platelet-derived growth factor (PDGF)-BB. Pericytes are an important component to the choroidal neovascular complex, providing stabilization of vessels; it is also thought that they may limit the penetration of anti-VEGF agents. PDGF-BB is the key regulator of the pericyte endothelial bond. Preclinical models have shown that the combination of VEGF and PDGF treatments appears to have a significant ability to suppress angiogenesis. Dr. Kaiser's phase 1 study examined the use of E10030 (an anti-PDGF pegylated aptamer) in combination with the anti-VEGF agent ranibizumab. Patients received E10030 at the time of the initial visit, followed by ranibizumab at weeks 2, 6, and 10. In the second arm of the study, simultaneous injections of E10030 with ranibizumab were given. Visual acuity improved by 21-27 letters from baseline at 8 weeks within the 2 arms tested. At 4 weeks, 43% of patients had gained 3 lines; 54% had gained 3 lines of vision at 8 weeks; and 62.5% had gained 3 lines by 12 weeks. Although these results are very preliminary, the findings are promising for the targeting of PDGF-BB in neovascular AMD. Further trials are currently being developed.
Jeffrey Heier presented results from an open-label study of intravitreal integrin-antagonist JSM6427. This molecule antagonizes the a5b1 integrins, which are known to play significant roles in the neovascular AMD complex. The phase 1, open-label, first-in-human, dose-escalation trial evaluated the safety, tolerability, and pharmacokinetics of multiple injections of JSM6427. At the end of the trial, there were no adverse events attributed to the drug and no signs of toxicity to date. The efficacy outcome showed stability of both best-corrected visual acuity and OCT readings at the end of the 6 weeks of treatment. Dr. Heier suggested that the stability may be due to the short vitreous half-life of the formulation (less than 17 hours). Studies are now being planned to use an anti-VEGF agent in combination with this integrin antagonist agent to simultaneously inhibit multiple pathways involved in the pathophysiology of neovascular AMD.
Updates on Existing Anti-VEGF Agents for AMD
Dr. Carl Awh presented the Horizon Extension Trial of Ranibizumab for Neovascular AMD, a multicentered, randomized clinical trial that examined the long-term safety and efficacy of intravitreal ranibizumab for patients with subfoveal neovascular AMD. Patients in the Horizon trial had completed one of the 3 formative anti-VEGF trials (MARINA, ANCHOR, or FOCUS). They were then allowed to receive as-needed treatment for the following year. The treatments were given at the discretion of the treating physician, and quarterly measurements were performed prior to the start of the as-needed treatment year. Patients on average had a 9.4-letter gain of visual acuity over baseline before enrollment into Horizon. At the end of year 1 on Horizon, there was a decline in vision to +4.1 letters over baseline -- demonstrating almost a single-line loss of vision from the conversion of monthly therapy to as-needed therapy. There were no significant adverse events reported, and the adverse event rate appeared to be lower than it was in age-matched controls. On average, patients received between 3 and 4 injections over the entire year. These results indicate that monthly dosing is still the gold standard for achieving optimal outcomes.
Tom Chang presented a study comparing remission intervals between ranibizumab and bevacizumab in patients with neovascular AMD. In this retrospective analysis, patients were given 3 consecutive injections of either ranibizumab or bevacizumab (physician preference), followed by monthly monitoring with OCT, clinical evaluation, and determination of best-corrected visual acuity. Remission was defined as a time period between the end of the induction and the start of the reinduction; the time of reinjection was determined on the basis of clinical exam, OCT, or best-corrected acuity. The mean interval of remission for bevacizumab was 6.6 months vs 3.85 months for ranibizumab. Stated differently, 1 of 5 patients with AMD treated with bevacizumab did not require retreatment after the initial induction therapy during the entire year. In comparison, only 2% of patients receiving ranibizumab did not need treatment after the induction period for the entire year. These results suggest that bevacizumab has improved durability over ranibizumab -- findings that could have implications when examining the efficacy of combination treatment trials.
Dr. David Williams presented an update on behalf of Dr. Daniel Martin for CATT (Comparisons of Age-Related Macular Degeneration Treatments Trials). This study is set to examine the use of ranibizumab vs bevacizumab in 1209 patients with neovascular AMD (best-corrected visual acuity between 20/25 and 20/320) in both a fixed and variable treatment paradigm. Currently, 42 sites have been certified and 350 patients enrolled. Patients are being randomized to ranibizumab or bevacizumab on either a monthly basis or a variable basis after a single intravitreal injection. Enrollment is expected to be completed by fall 2009, and results should be appearing by late 2010.
Combination Therapy for AMD
Dr. David Brown presented data from a phase 2 study that combined the use of epiretinal (strontium-90) brachytherapy with bevacizumab for the treatment of neovascular AMD. The 1-year study enrolled 34 patients. Significant reductions in retinal thickness on OCT and significant improvements of visual acuity were obtained at the end of 12 months. No patients were retreated during that 12-month interval.
Dr. Brown's review of the OCT scans showed that there was a significant percentage of undertreatment on the basis of criteria suggesting leakage. However, reexamination of many of these patients found that there was also spontaneous resolution over that period of time. Dr. Brown concluded that although the combination treatment of strontium-90 plus bevacizumab appeared to have significant efficacy outcomes, retreatment rates might be expected to be higher if applied in general clinical practice. Efficacy outcomes might then improve as a result of the continued retreatment during the postradiation period.
Treatment for Diabetic Retinopathy and Diabetic Macular Edema
J. Fernando Arevalo presented on en bloc perfluorodissection for tractional retinal detachment and proliferative retinopathy. His surgical technique involves incising the peripheral posterior hyaloid in cases of tractional retinal detachment and infusing perfluorocarbon liquid below the area of the hyaloid to further separate the retinal planes from the posterior hyaloidal planes. During surgery, a hole is initially created in the midperipheral posterior hyaloid, and the perfluorocarbon liquid is injected mechanically to separate the posterior hyaloid from the retina. Once all the epiretinal tissues have been lysed after slow infusion of perfluorocarbon liquid underneath the hyaloidal surface, the vitrectomy is then completed and laser applied under the perfluorocarbon liquid. This results in an air-fluid exchange, in which air is exchanged for gas.
In the prospective, interventional, nonrandomized case series, Dr. Arevalo performed 57 surgeries with this technique for the indication of tractional retinal detachment and peripheral diabetic retinopathy. None of the patients developed ocular hypertension or inflammation during the postoperative period, an anatomic success rate of 100%. Best-corrected visual acuity remained stable in approximately one quarter (24.5%) of eyes. Complications of the procedure included phthisis bulbi in one eye (1.7%), iatrogenic retinal breaks in 7% of eyes, vitreous hemorrhage requiring another procedure in 7% of eyes, and cataract in 26.3% of eyes. Dr. Arevalo argued that this technique had significant advantages over traditional surgery, including increased retinal stability at the time of vitreous removal, better visualization of the vitreous and intraocular structures, rapid retinal reattachment, less blood in the vitreous cavity, subretinal fluid resolution, blood confinement, and easier dissection of the epiretinal membranes with perfluorocarbon liquid.
Pravin Dugel presented safety and tolerability results for the use of sirolimus (rapamycin) in diabetic macular edema (DME) and exudative AMD. Sirolimus is a specific inhibitor of the mammalian target of rapamycin (mTOR), which has antiangiogenic, antifibrotic, antiproliferative, and anti-inflammatory effects. The drug is given either intravitreally or subconjunctivally and was evaluated in 2 separate multirandomized, open-label, dose-escalation trials.
A total of 50 patients were enrolled in the DME trial and 30 patients in the AMD trial. The injections were given at day 0, and patients were followed for a period of 90 days. In the AMD population, best-corrected visual acuity improved by 4.5 letters by day 7 and declined back to baseline by day 90. In the DME population, best-corrected visual acuity improved by day 14 and remained stable during the entire course of the 90-day period, for a mean gain of 4 letters of ETDRS visual acuity. Both the subconjunctival and intravitreal administration showed significant efficacy in improving visual acuity and reducing retinal thickness in the 90-day follow-up period. In a subgroup analysis of the DME patients who received subconjunctival injections of sirolimus, best-corrected visual acuity peaked at 9.0 letters and retinal thickness dropped by 48.8 microns. In the patients with AMD, best-corrected visual acuity peaked at 6.5 letters and retinal thickness dropped by 60 microns in those who received sirolimus subconjunctivally. Significant pharmacologic effects were seen in patients with both DME and AMD, and phase 2 studies are pending.
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