I have received brief writeups from both Ophthalmology Times and Ocular Surgery News covering the first day of the Retina 2007 Subspecialty Day presentations. Here are some of the highlights, along with links to the various stories.
First, some updates of on-going studies:
PRONTO (OSN, OT)
The 2-year results of the PrONTO Study, an exploratory open-label trial, indicated that intravitreal injection of ranibizumab (Lucentis, Genentech) produces rapid improvements in visual acuity and findings on optical coherence tomography (OCT) in patients treated for neovascular age-related macular degeneration, said Philip Rosenfeld, MD, PhD professor of ophthalmology, Bascom Palmer Eye Institute, University of Miami.
Forty patients underwent three consecutive monthly injections with 0.5-mg intravitreal ranibizumab during the first year and three patients withdrew during year 2. From months 3 to 24, OCT images were obtained monthly and fluorescein angiography images every 3 months with the goal of determining if OCT-guided regimens could be used over 2 years to maintain visual acuity improvements and OCT outcomes achieved after the three consecutive monthly doses of the drug.
"By day 1 after treatment, we saw about a 50-μm decrease in the central retinal thickness, a 190-μm decrease by 3 months, a 178-μm decrease by 12 months, and a 215-μm decrease by 24 [months]," Dr. Rosenfeld reported.
Patients each received an average of 10 injections during the study period. There was an increase in visual acuity (6 letters) by 14 days after the first treatment that continued to 3 months (11 letters). At 24 months, the mean improvement in visual acuity from baseline was 10.7 letters.
"The PrONTO Study showed that visual acuity and OCT changes appeared to be rapid after intravitreal ranibizumab," he concluded. "The OCT changes always preceded the visual acuity changes, whether for better or worse. OCT-guided treatment appears to preserve the benefits seen after three monthly doses of ranibizumab. A larger prospective study is necessary."
ANCHOR (OSN, OT)
Visual acuity endpoints in the ANCHOR Study showed that ranibizumab (Lucentis, Genentech) surpassed photodynamic therapy (PDT) with verteporfin, (Visudyne, Novartis Ophthalmics/QLT) for treating predominantly classic choroidal neovascularization lesions in age-related macular degeneration, reported Jeffrey Heier, MD, assistant professor ophthalmology, Tufts University School of Medicine, and clinical instructor in ophthalmology, Harvard Medical School, Boston.
"Ranibizumab was found to be a remarkably consistent therapy," said Dr. Heier, Analysis of subgroups in the 2-year ANCHOR Study indicated that the treatment effects of ranibizumab were consistent with all of the primary findings of the drug. Regarding age, the visual acuity results were consistent across all age groups, with the patients treated with PDT more likely to lose three or more lines of visual acuity.
"A gain of about three lines or more of vision was very likely in most age groups treated with ranibizumab," he said. "This finding was slightly less robust in the oldest patients."
Regarding baseline vision, the patients with better vision who were treated with PDT were more likely to lose three lines of vision, according to Dr. Heier. Patients treated with ranibizumab had very consistent results; the only patients who did not gain three lines or more were those with the highest baseline vision, he said.
Compared to PDT, ranibizumab showed a better gain in vision and a threefold greater decline in leakage. The overall treatment benefits were seen across all age groups and lesion sizes, he said.
The ANCHOR study was a multicenter, double-masked, controlled phase 3 study that randomly assigned 423 patients to either verteporfin PDT plus monthly sham or sham verteporfin PDT plus monthly intravitreal ranibizumab, dosed at either 0.3 mg or 0.5 mg.
"Ranibizumab remains a consistent and highly effective treatment," Dr. Heier concluded.
AVASTIN vs. LUCENTIS
Cost disparity between anti-VEGF agents raises economic, moral issues
The substantial difference in cost between ranibizumab, which has U.S. regulatory approval, and off-label bevacizumab presents an economic and moral dilemma for ophthalmologists, according to George A. Williams, MD.
"The retina world changed for better and forever" when bevacizumab (Avastin, Genentech) was introduced as a treatment for AMD [age-related macular degeneration]. He described its impact as "the bevacizumab tsunami, which continues today."
To conduct his economic analysis of the two drugs, Dr. Williams started with the assumption that ranibizumab and bevacizumab are equally effective and are used at the same frequencies. On a microeconomic level, he looked at the cost of each medication both to the physician and to the patient. On a macroeconomic level, he evaluated the cost of each drug to Medicare.
For the physician, bevacizumab costs $45 and ranibizumab costs $2,030.92 per injection; for the patient, Medicare co-pays are $9 and $406, respectively. Referring to delayed reimbursements, Dr. Williams called this the "no pay co-pay."
Dr. Williams estimated that ranibizumab is 44 times more expensive than bevacizumab, on a macroeconomic scale. The disparity raises the question of efficacy vs. cost effectiveness. If put to "the mother test" — referring to which drug surgeons would choose to administer to their mothers — bevacizumab might fail, even though it is cheaper.
He said the upcoming CATT study, the much-anticipated head-to-head comparison of the two drugs funded by the U.S. National Institutes of Health and the National Eye Institute, will hopefully shed more light on the efficacy and safety of both drugs.
Bevacizumab's impact felt despite lack of clinical data
Citing the downturn in sales of verteporfin and pegaptanib, David F. Williams, MD explained how bevacizumab has greatly impacted age-related macular degeneration treatment, despite the fact that is has not gained U.S. approval for treating the disease and the lack of clinical trial data to support its use.
"In 2005 and early 2006, mostly anecdotal reports existed regarding the efficacy of intravitreal bevacizumab (Avastin, Genentech) for neovascular AMD. However, the favorable short-term clinical efficacy was so apparent that use of intravitreal bevacizumab spread rapidly among the retina community,".
While there are no data that show the dominance of bevacizumab use to treat neovascular AMD, indirect evidence can be found in sales trends for other primary treatments that were in use in 2005 when bevacizumab first emerged.
"The cost differential between off-label bevacizumab and the other pharmacological treatments for neovascular AMD was striking," he said. From the time bevacizumab efficacy data were introduced by Philip J. Rosenfeld, MD, PhD, until the last quarter of 2006, pegaptanib sales fell 26% while verteporfin sales fell 63%. In addition, the approval of ranibizumab in July 2006 pushed verteporfin sales down 82% while pegaptanib sales fell 92%.
"The unprecedented growth of off-label bevacizumab as a primary therapy for AMD occurred in the setting of anecdotal reports, reports of non-randomized, non-controlled, small clinical series, and individual personal clinical experience," Dr. Williams said. "It has persisted in the setting of the availability of a highly efficacious, but expensive, [U.S. Food and Drug Administration-approved] product."
Dr. Williams pointed to four reasons for this growth: the value of evidence-based medicine, the value of mass clinical experience, pricing of FDA-approved drugs and the power of physician choice.
NEW TREATMENTS FOR AMD
VEGF Trap promising for neovascular AMD
VEGF Trap (Regeneron Pharmaceuticals) has been seen in two studies (CLEAR-IT AMD 1 and CLEAR-IT AMD 2) to be safe, bioefficacious, and tolerated in the eyes of patients with neovascular age-related macular degeneration. The 2- and 4-mg doses demonstrated more bioactivity than lower doses evaluated, according to Quan Dong Nguyen, MD.
The CLEAR-IT AMD 1 study evaluated six doses of VEGF Trap (0.05, 0.15, 0.5, 1, 2, or 4 mg) with each patient receiving one intravitreal injection of one dose and then followed for 6 weeks, reported Dr. Nguyen, assistant professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.
Twenty-eight patients then received one intravitreal injection of either 0.15 or 4 mg and were followed for 8 weeks. Investigators found that the injections in both parts of the study were well tolerated and no ocular inflammation developed. The retinal thickness decreased in the second part of the study, and the treatment duration was longer with administration of the higher dose, he said.
In the CLEAR-IT AMD 2 study, the patients were randomized into five groups and the following VEGF Trap doses were evaluated: 0.5 mg every 4 weeks, 2 mg every 4 weeks, 0.5 mg every 12 weeks, 2 mg every 12 weeks, and 4 mg every 12 weeks.
Analysis of 159 patients indicated that "overall there was a reduction in the central retinal thickness across all time points for 8, 12, and 16 weeks," Dr. Nguyen said. There was also a gain in visual acuity at all time points.
When the investigators evaluated the subgroups for efficacy, administration of 0.5 mg every 4 weeks and 2 mg every 4 weeks resulted in the greatest gains in visual acuity and the greatest reductions in the central retinal thickness at 12 weeks after treatment. Improvement continued at the 16-week evaluation. At week 12, there was no evidence of any ocular or systemic complications.
Dr. Nguyen concluded that VEGF may play a role in the armamentarium of therapy for choroidal neovascularization. He also noted that these results aided the design of the phase III trial in which 0.5 mg for 4 weeks, 2 mg for 4 weeks, 2 mg for 8 weeks, and 0.5 mg of ranibizumab (Lucentis, Genentech) for 4 weeks will be evaluated.
Topical therapy for CNV on the horizon
Topical therapy to treat posterior segment disease is possible despite the limitations of the blood-retinal barrier. The effective route of drug penetrance of topical therapy is either by the transcorneal route or by the transscleral/conjunctival route, said Baruch Kuppermann, MD, PhD, chief of the Retina Service, Department of Ophthalmology, University of California, Irvine.
A few such drugs are currently under development, and the hope is that they will eliminate the complications associated with intravitreal injections of drugs, he said.
• 801 kinase inhibitor (TargeGen) has activity against vascular endothelial growth factor (VEGF) receptor/PDGF receptor/Src family kinases and stops leakage, angiogenesis, and inflammation. In animal studies, the drug has been shown to have high concentrations in the anterior segment, lower effective concentrations in the posterior segment, very low concentrations in the aqueous and vitreous, and extremely low concentrations in the plasma.
• ATG2 (mecamylamine) (CoMentis) is a powerful nonselective nAChR antagonist that has reduced angiogenesis in animal models and inhibits VEGF synthesis/release and responses. Topical mecamylamine was seen to penetrate the retina-choroid in mice, probably by the transscleral-conjunctival route.
• OC-10X (Ocucure) is a nontoxic vascular targeting agent with selective tubulin inhibition. The agent is lipid soluble and crosses the human cornea; it achieves therapeutic concentrations at the retina-choroid. In rats, the drug, when given once every hour for 4 hours, achieved a corneal level of 100%, a lens/vitreous level of 11%, and a retina-choroid-sclera level of 83%.
• OT-551 (Othera) catalytic antioxidant has multiple modes of action, i.e., antioxidant, antiangiogenic, and anti-inflammatory. The agent penetrates the cornea and sclera and reaches the retina. It also suppresses photo-oxidative damage in the retinal pigment epithelium and photoreceptors. A phase II study is ongoing for geographic atrophy, neovascular age-related macular degeneration, and cataract.
• Pazopanib (Glaxo-Smith-Kline) has completed a phase I trial with 38 healthy volunteers. This compound has been in development to treat solid tumors, according to Dr. Kuppermann.
"Historically, we have never contemplated the use of topical therapy for posterior segment disease because of poor ocular penetrance," he said. "The small molecule drugs are being developed to meet this challenge. They have shown good posterior segment penetrance, safety, and efficacy."
New developments in posterior segment drug delivery
New extended delivery methods are under development and in the future should facilitate more effective administration of numerous types of ocular agents, said William F. Mieler, MD, professor and chairman, department of ophthalmology and visual science, University of Chicago.
Dr. Mieler said that new methods are needed to lessen the side effects and invasiveness of current methods as well as to reduce systemic side effects.
Listing delivery methods with potential to address these concerns, Dr. Mieler noted that several types of solid implants are on the market already, such as a fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb) and a ganciculovir intravitreal implant (Vitrasert, Bausch & Lomb). A subretinal implant system (I-vation, SurModics) has been tested in rabbits and appears to be capable of long-term sustained delivery.
Microspheres of biodegradable polymers are also being explored and could be a means of reducing toxicity during drug delivery, Dr. Mieler said. Studies are under way of delivering pegaptanib sodium (Macugen, OSI/Eyetech/Pfizer), and the feasibility of delivering other products by this route is also being investigated.
Thermoresponsive gels are another promising delivery method; one such product is currently on the market, although not for ophthalmic use, Dr. Mieler said.
At the University of Chicago and the Illinois Institute of Technology, investigators are studying thermoresponsive hydrogels and have developed one product that becomes a gel at body temperature in less than 1 minute. They hope to design a product that can be placed in a 27- to 30-gauge needle and delivered either intravitreally or in the juxtascleral space. The investigators are studying the delivery of bevacizumab (Avastin, Genentech) by this method.
Surgical-based delivery techniques include microcannulation of the suprachoroidal space. In addition, SurModics has developed a subretinal cannula (RetinaJect). A 25-gauge needle is used to transconjunctivally enter the vitreous; a 39-gauge cannula is then advanced to create the retinotomy.
Encapsulated cell technology (Neurotech SA) is also being tested as a novel means of drug delivery and has been shown to be safe and effective in early studies.
Finally, Ocular Surgery News interviewed Dr. Judah Folkman, who will give the keynote address during the opening session of the AAO meeting on November 11th.
Folkman: Angiogenesis research rooted in ophthalmology
By Matt Hasson, OSN Staff
The concept of anti-angiogenic agents, which has revolutionized cancer research, has led to the development of various ophthalmic therapies, according to a prominent medical researcher.
Angiogenic molecules include vascular endothelial growth factor, a protein contributing to age-related macular degeneration, diabetic retinopathy and other ocular diseases.
“The whole beginning of angiogenesis research for cancer started with ophthalmology,” Judah Folkman, MD, of Harvard Medical School and Children’s Hospital Boston, told Ocular Surgery News. “We always had ophthalmology in mind.”
Revolutionary findings
In a 1971 New England Journal of Medicine article, Dr. Folkman hypothesized that tumor growth depends on angiogenesis, or the growth of new blood vessels. His theory was criticized throughout the biomedical community, but early discoveries soon silenced the detractors.
Early angiogenesis experiments were performed in rabbit eyes, whose corneas were ideal for detecting new blood vessels, Dr. Folkman said.
“In order to prove that a tumor could make a protein that could diffuse from the tumor and stimulate new capillaries, the only way we could show that was in the eye,” he said.
The experiments demonstrated that proteins from the tumor triggered the growth of blood vessels. Before those experiments, the idea of such proteins existing was considered far-fetched, he said.
Dr. Folkman and fellow researchers later used tiny polymer implants that released angiogenic proteins into a rabbit cornea. After the implants were removed and diffusion of angiogenic proteins was halted, the corneal blood vessels gradually disappeared, he said.
New applications and drugs
In ophthalmology, angiogenesis research has reached new heights with the development of new drugs such as Lucentis (ranibizumab, Genentech), Dr. Folkman said.
“The demonstration of what Lucentis can do has brought many researchers and companies into the field, and they’re working now on other angiogenesis inhibitors including eye drops that may treat AMD,” he said. “Diabetic retinopathy is also beginning to be treated with Lucentis in clinical trials.”
First, some updates of on-going studies:
PRONTO (OSN, OT)
The 2-year results of the PrONTO Study, an exploratory open-label trial, indicated that intravitreal injection of ranibizumab (Lucentis, Genentech) produces rapid improvements in visual acuity and findings on optical coherence tomography (OCT) in patients treated for neovascular age-related macular degeneration, said Philip Rosenfeld, MD, PhD professor of ophthalmology, Bascom Palmer Eye Institute, University of Miami.
Forty patients underwent three consecutive monthly injections with 0.5-mg intravitreal ranibizumab during the first year and three patients withdrew during year 2. From months 3 to 24, OCT images were obtained monthly and fluorescein angiography images every 3 months with the goal of determining if OCT-guided regimens could be used over 2 years to maintain visual acuity improvements and OCT outcomes achieved after the three consecutive monthly doses of the drug.
"By day 1 after treatment, we saw about a 50-μm decrease in the central retinal thickness, a 190-μm decrease by 3 months, a 178-μm decrease by 12 months, and a 215-μm decrease by 24 [months]," Dr. Rosenfeld reported.
Patients each received an average of 10 injections during the study period. There was an increase in visual acuity (6 letters) by 14 days after the first treatment that continued to 3 months (11 letters). At 24 months, the mean improvement in visual acuity from baseline was 10.7 letters.
"The PrONTO Study showed that visual acuity and OCT changes appeared to be rapid after intravitreal ranibizumab," he concluded. "The OCT changes always preceded the visual acuity changes, whether for better or worse. OCT-guided treatment appears to preserve the benefits seen after three monthly doses of ranibizumab. A larger prospective study is necessary."
ANCHOR (OSN, OT)
Visual acuity endpoints in the ANCHOR Study showed that ranibizumab (Lucentis, Genentech) surpassed photodynamic therapy (PDT) with verteporfin, (Visudyne, Novartis Ophthalmics/QLT) for treating predominantly classic choroidal neovascularization lesions in age-related macular degeneration, reported Jeffrey Heier, MD, assistant professor ophthalmology, Tufts University School of Medicine, and clinical instructor in ophthalmology, Harvard Medical School, Boston.
"Ranibizumab was found to be a remarkably consistent therapy," said Dr. Heier, Analysis of subgroups in the 2-year ANCHOR Study indicated that the treatment effects of ranibizumab were consistent with all of the primary findings of the drug. Regarding age, the visual acuity results were consistent across all age groups, with the patients treated with PDT more likely to lose three or more lines of visual acuity.
"A gain of about three lines or more of vision was very likely in most age groups treated with ranibizumab," he said. "This finding was slightly less robust in the oldest patients."
Regarding baseline vision, the patients with better vision who were treated with PDT were more likely to lose three lines of vision, according to Dr. Heier. Patients treated with ranibizumab had very consistent results; the only patients who did not gain three lines or more were those with the highest baseline vision, he said.
Compared to PDT, ranibizumab showed a better gain in vision and a threefold greater decline in leakage. The overall treatment benefits were seen across all age groups and lesion sizes, he said.
The ANCHOR study was a multicenter, double-masked, controlled phase 3 study that randomly assigned 423 patients to either verteporfin PDT plus monthly sham or sham verteporfin PDT plus monthly intravitreal ranibizumab, dosed at either 0.3 mg or 0.5 mg.
"Ranibizumab remains a consistent and highly effective treatment," Dr. Heier concluded.
AVASTIN vs. LUCENTIS
Cost disparity between anti-VEGF agents raises economic, moral issues
The substantial difference in cost between ranibizumab, which has U.S. regulatory approval, and off-label bevacizumab presents an economic and moral dilemma for ophthalmologists, according to George A. Williams, MD.
"The retina world changed for better and forever" when bevacizumab (Avastin, Genentech) was introduced as a treatment for AMD [age-related macular degeneration]. He described its impact as "the bevacizumab tsunami, which continues today."
To conduct his economic analysis of the two drugs, Dr. Williams started with the assumption that ranibizumab and bevacizumab are equally effective and are used at the same frequencies. On a microeconomic level, he looked at the cost of each medication both to the physician and to the patient. On a macroeconomic level, he evaluated the cost of each drug to Medicare.
For the physician, bevacizumab costs $45 and ranibizumab costs $2,030.92 per injection; for the patient, Medicare co-pays are $9 and $406, respectively. Referring to delayed reimbursements, Dr. Williams called this the "no pay co-pay."
Dr. Williams estimated that ranibizumab is 44 times more expensive than bevacizumab, on a macroeconomic scale. The disparity raises the question of efficacy vs. cost effectiveness. If put to "the mother test" — referring to which drug surgeons would choose to administer to their mothers — bevacizumab might fail, even though it is cheaper.
He said the upcoming CATT study, the much-anticipated head-to-head comparison of the two drugs funded by the U.S. National Institutes of Health and the National Eye Institute, will hopefully shed more light on the efficacy and safety of both drugs.
Bevacizumab's impact felt despite lack of clinical data
Citing the downturn in sales of verteporfin and pegaptanib, David F. Williams, MD explained how bevacizumab has greatly impacted age-related macular degeneration treatment, despite the fact that is has not gained U.S. approval for treating the disease and the lack of clinical trial data to support its use.
"In 2005 and early 2006, mostly anecdotal reports existed regarding the efficacy of intravitreal bevacizumab (Avastin, Genentech) for neovascular AMD. However, the favorable short-term clinical efficacy was so apparent that use of intravitreal bevacizumab spread rapidly among the retina community,".
While there are no data that show the dominance of bevacizumab use to treat neovascular AMD, indirect evidence can be found in sales trends for other primary treatments that were in use in 2005 when bevacizumab first emerged.
"The cost differential between off-label bevacizumab and the other pharmacological treatments for neovascular AMD was striking," he said. From the time bevacizumab efficacy data were introduced by Philip J. Rosenfeld, MD, PhD, until the last quarter of 2006, pegaptanib sales fell 26% while verteporfin sales fell 63%. In addition, the approval of ranibizumab in July 2006 pushed verteporfin sales down 82% while pegaptanib sales fell 92%.
"The unprecedented growth of off-label bevacizumab as a primary therapy for AMD occurred in the setting of anecdotal reports, reports of non-randomized, non-controlled, small clinical series, and individual personal clinical experience," Dr. Williams said. "It has persisted in the setting of the availability of a highly efficacious, but expensive, [U.S. Food and Drug Administration-approved] product."
Dr. Williams pointed to four reasons for this growth: the value of evidence-based medicine, the value of mass clinical experience, pricing of FDA-approved drugs and the power of physician choice.
NEW TREATMENTS FOR AMD
VEGF Trap promising for neovascular AMD
VEGF Trap (Regeneron Pharmaceuticals) has been seen in two studies (CLEAR-IT AMD 1 and CLEAR-IT AMD 2) to be safe, bioefficacious, and tolerated in the eyes of patients with neovascular age-related macular degeneration. The 2- and 4-mg doses demonstrated more bioactivity than lower doses evaluated, according to Quan Dong Nguyen, MD.
The CLEAR-IT AMD 1 study evaluated six doses of VEGF Trap (0.05, 0.15, 0.5, 1, 2, or 4 mg) with each patient receiving one intravitreal injection of one dose and then followed for 6 weeks, reported Dr. Nguyen, assistant professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.
Twenty-eight patients then received one intravitreal injection of either 0.15 or 4 mg and were followed for 8 weeks. Investigators found that the injections in both parts of the study were well tolerated and no ocular inflammation developed. The retinal thickness decreased in the second part of the study, and the treatment duration was longer with administration of the higher dose, he said.
In the CLEAR-IT AMD 2 study, the patients were randomized into five groups and the following VEGF Trap doses were evaluated: 0.5 mg every 4 weeks, 2 mg every 4 weeks, 0.5 mg every 12 weeks, 2 mg every 12 weeks, and 4 mg every 12 weeks.
Analysis of 159 patients indicated that "overall there was a reduction in the central retinal thickness across all time points for 8, 12, and 16 weeks," Dr. Nguyen said. There was also a gain in visual acuity at all time points.
When the investigators evaluated the subgroups for efficacy, administration of 0.5 mg every 4 weeks and 2 mg every 4 weeks resulted in the greatest gains in visual acuity and the greatest reductions in the central retinal thickness at 12 weeks after treatment. Improvement continued at the 16-week evaluation. At week 12, there was no evidence of any ocular or systemic complications.
Dr. Nguyen concluded that VEGF may play a role in the armamentarium of therapy for choroidal neovascularization. He also noted that these results aided the design of the phase III trial in which 0.5 mg for 4 weeks, 2 mg for 4 weeks, 2 mg for 8 weeks, and 0.5 mg of ranibizumab (Lucentis, Genentech) for 4 weeks will be evaluated.
Topical therapy for CNV on the horizon
Topical therapy to treat posterior segment disease is possible despite the limitations of the blood-retinal barrier. The effective route of drug penetrance of topical therapy is either by the transcorneal route or by the transscleral/conjunctival route, said Baruch Kuppermann, MD, PhD, chief of the Retina Service, Department of Ophthalmology, University of California, Irvine.
A few such drugs are currently under development, and the hope is that they will eliminate the complications associated with intravitreal injections of drugs, he said.
• 801 kinase inhibitor (TargeGen) has activity against vascular endothelial growth factor (VEGF) receptor/PDGF receptor/Src family kinases and stops leakage, angiogenesis, and inflammation. In animal studies, the drug has been shown to have high concentrations in the anterior segment, lower effective concentrations in the posterior segment, very low concentrations in the aqueous and vitreous, and extremely low concentrations in the plasma.
• ATG2 (mecamylamine) (CoMentis) is a powerful nonselective nAChR antagonist that has reduced angiogenesis in animal models and inhibits VEGF synthesis/release and responses. Topical mecamylamine was seen to penetrate the retina-choroid in mice, probably by the transscleral-conjunctival route.
• OC-10X (Ocucure) is a nontoxic vascular targeting agent with selective tubulin inhibition. The agent is lipid soluble and crosses the human cornea; it achieves therapeutic concentrations at the retina-choroid. In rats, the drug, when given once every hour for 4 hours, achieved a corneal level of 100%, a lens/vitreous level of 11%, and a retina-choroid-sclera level of 83%.
• OT-551 (Othera) catalytic antioxidant has multiple modes of action, i.e., antioxidant, antiangiogenic, and anti-inflammatory. The agent penetrates the cornea and sclera and reaches the retina. It also suppresses photo-oxidative damage in the retinal pigment epithelium and photoreceptors. A phase II study is ongoing for geographic atrophy, neovascular age-related macular degeneration, and cataract.
• Pazopanib (Glaxo-Smith-Kline) has completed a phase I trial with 38 healthy volunteers. This compound has been in development to treat solid tumors, according to Dr. Kuppermann.
"Historically, we have never contemplated the use of topical therapy for posterior segment disease because of poor ocular penetrance," he said. "The small molecule drugs are being developed to meet this challenge. They have shown good posterior segment penetrance, safety, and efficacy."
New developments in posterior segment drug delivery
New extended delivery methods are under development and in the future should facilitate more effective administration of numerous types of ocular agents, said William F. Mieler, MD, professor and chairman, department of ophthalmology and visual science, University of Chicago.
Dr. Mieler said that new methods are needed to lessen the side effects and invasiveness of current methods as well as to reduce systemic side effects.
Listing delivery methods with potential to address these concerns, Dr. Mieler noted that several types of solid implants are on the market already, such as a fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb) and a ganciculovir intravitreal implant (Vitrasert, Bausch & Lomb). A subretinal implant system (I-vation, SurModics) has been tested in rabbits and appears to be capable of long-term sustained delivery.
Microspheres of biodegradable polymers are also being explored and could be a means of reducing toxicity during drug delivery, Dr. Mieler said. Studies are under way of delivering pegaptanib sodium (Macugen, OSI/Eyetech/Pfizer), and the feasibility of delivering other products by this route is also being investigated.
Thermoresponsive gels are another promising delivery method; one such product is currently on the market, although not for ophthalmic use, Dr. Mieler said.
At the University of Chicago and the Illinois Institute of Technology, investigators are studying thermoresponsive hydrogels and have developed one product that becomes a gel at body temperature in less than 1 minute. They hope to design a product that can be placed in a 27- to 30-gauge needle and delivered either intravitreally or in the juxtascleral space. The investigators are studying the delivery of bevacizumab (Avastin, Genentech) by this method.
Surgical-based delivery techniques include microcannulation of the suprachoroidal space. In addition, SurModics has developed a subretinal cannula (RetinaJect). A 25-gauge needle is used to transconjunctivally enter the vitreous; a 39-gauge cannula is then advanced to create the retinotomy.
Encapsulated cell technology (Neurotech SA) is also being tested as a novel means of drug delivery and has been shown to be safe and effective in early studies.
Finally, Ocular Surgery News interviewed Dr. Judah Folkman, who will give the keynote address during the opening session of the AAO meeting on November 11th.
Folkman: Angiogenesis research rooted in ophthalmology
By Matt Hasson, OSN Staff
The concept of anti-angiogenic agents, which has revolutionized cancer research, has led to the development of various ophthalmic therapies, according to a prominent medical researcher.
Angiogenic molecules include vascular endothelial growth factor, a protein contributing to age-related macular degeneration, diabetic retinopathy and other ocular diseases.
“The whole beginning of angiogenesis research for cancer started with ophthalmology,” Judah Folkman, MD, of Harvard Medical School and Children’s Hospital Boston, told Ocular Surgery News. “We always had ophthalmology in mind.”
Revolutionary findings
In a 1971 New England Journal of Medicine article, Dr. Folkman hypothesized that tumor growth depends on angiogenesis, or the growth of new blood vessels. His theory was criticized throughout the biomedical community, but early discoveries soon silenced the detractors.
Early angiogenesis experiments were performed in rabbit eyes, whose corneas were ideal for detecting new blood vessels, Dr. Folkman said.
“In order to prove that a tumor could make a protein that could diffuse from the tumor and stimulate new capillaries, the only way we could show that was in the eye,” he said.
The experiments demonstrated that proteins from the tumor triggered the growth of blood vessels. Before those experiments, the idea of such proteins existing was considered far-fetched, he said.
Dr. Folkman and fellow researchers later used tiny polymer implants that released angiogenic proteins into a rabbit cornea. After the implants were removed and diffusion of angiogenic proteins was halted, the corneal blood vessels gradually disappeared, he said.
New applications and drugs
In ophthalmology, angiogenesis research has reached new heights with the development of new drugs such as Lucentis (ranibizumab, Genentech), Dr. Folkman said.
“The demonstration of what Lucentis can do has brought many researchers and companies into the field, and they’re working now on other angiogenesis inhibitors including eye drops that may treat AMD,” he said. “Diabetic retinopathy is also beginning to be treated with Lucentis in clinical trials.”
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