by Dan Roberts
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A substance in the body called Vascular Endothelial Growth Factor (VEGF) is responsible for the growth of new blood vessels. It promotes this growth by stimulating the endothelial cells, which form the walls of the vessels and transport nutrients and oxygen to the tissues. Evidence shows that when the retinal pigment epithelial (RPE) cells begin to wither from lack of nutrition (a condition called "ischemia"), the VEGF goes into action to create new vessels. This process is called "neovascularization," and it acts as a restorative function in other parts of the body. In the retina, however, the vessels do not form properly, and leaking results. This leakage causes scarring in the macula and eventual loss of central vision.
Antiangiogenic drugs prevent the VEGF from binding with the receptors on the surface of the endothelial cells. In most cases, the drugs are injected into the vitreous of the eyeball, then pass into the subretinal space, where the vessels proliferate. Neovascularization is then blocked, preventing bleeding into the retina.
Source: Martin A. Mainster, Ph.D., M.D., FRCOphth
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This is continually-updated information on all anti-angiogenic drugs for wet MD:
Macugen (pegaptanib sodium) [updated 10/22/04]
Lucentis (ranibizumab) [updated 9/6/07]
Tryptophanyl-tRNA synthetase (TrpRS) [1/02]
Retaane 15 mg (aka anecortave acetate) [updated 7/14/08]
Combretastatin A4 Prodrug (CA4P) [updated 2/15/07]
AdPEDF [updated 1/06]
VEGF-TRAP-EYE [updated 1/08]
AG-013958 [updated 7/06]
Avastin (bevacizumab) [updated 2/15/07]
JSM6427 [1/06]
TG100801 [updated 2/27/07]
ATG3 [updated 1/31/07]
Sirolumus (rapamycin) [10/31]
OT-551 [updated 4/8/09]
Endostatin [12/6/07]
Macugen, made by OSI EyeTech Pharmaceuticals, was the first antiangiogenic drug to gain FDA approval. Pegaptanib is a chemically synthesized strand of genetic material that bonds with VEGF cells to block replication. A large trial of Macugen on 1,196 patients at 117 centers around the world was completed in 2003. In November of that year, data presented to the American Academy of Ophthalmology (AAO) showed that Macugen stabilized or improved vision in 33% of the patients in the trials, while the same results occurred in 23% of a control group not given Macugen. As many as 71% of the patients given Macugen lost less than three lines of vision during the year, compared with 55% in the control group. The drug is injected directly into the eye every six weeks, or about nine times a year.
Working in conjunction with Pfizer Ophthalmics, Macugen gained FDA approval on December 17, 2004, and was ready for public use beginning in 2005.
On October 11, 2007, a retrospective study showed that results from Macugen treatment may be better than originally announced. The study, published in the September 2007 issue of Retina, found that overall, 90% of patients had responded to pegaptanib treatment at 9.1 months mean follow-up. Specifically, 18 patients (20%) gained three or more lines of vision, and vision stabilized in 63 patients (70%), which the authors defined as the prevention of a loss of three lines of vision.
Macugen is also being studied for expanded use in patients with diabetic macular edema and central retinal vein occlusion.
Genentech, Inc. announced on May 23, 2005 that a Phase III clinical study of the investigational drug Lucentis (ranibizumab) met its primary efficacy endpoint of maintaining vision in patients with wet AMD. Approximately 95 percent of patients maintained or improved vision (defined as a loss of less than 15 letters in visual acuity) at one year when treated with Lucentis injections compared to approximately 62 percent of those treated in the control arm. Vision improvement was an unexpected result that had not been seen at a significant level in other antiangiogenic drug trials. Lucentis is approved for use in the European Union, Switzerland, India, Canada and the United States. A regulatory decision in Australia is expected before the end of 2007.
On January 14, 2006, one-year data from the second pivotal Phase III study of Lucentis were presented at the Macula 2006 meeting in New York. Data showed that, for the second time in a large, Phase III study, Lucentis improved vision in patients with wet AMD.
On November 13, 2006, several new findings were presented at the 2006 AAO meeting:
Elias Reichel, M.D. reported that in the MARINA trials, there was improvement at all visual acuity levels, but there was not a big difference if the patient's baseline vision was either low or excellent. This "floor-to-ceiling" effect is not unusual with this kind of study, but it is useful information for patient communicating with patients about expectations.
Nancy Holekamp, M.D., discussed key anatomic endpoints in the MARINA trials, in particular, the total lesion area over time (no growth of the lesion area was noted in the treated patients), the mean area of leakage (the amount of decrease was statistically significant) and the mean foveal retinal thickness (treated eyes showed a significant thinning of the retina). The bottom line is that all anatomic outcomes from the trial favored Lucentis, and the treatment is so effective over a long period of time without any signs of toxicity, there is no indication that anything in lieu of Lucentis should be used to treat wet AMD.
Peter Kaiser, M.D., reported on subgroup analysis of Genentech's PIER study. The primary endpoint was met, showing a difference of 16 letters visual acuity between the treated group and the sham group. Further, the dosing regimen was effective, but the visual acuity benefit was not as robust when injections went from monthly to quarterly. The persistence of monthly injections may depend upon who has dry lesions and who has wet lesions at the 5th month. The dry lesion group did better than the wet lesion group with quarterly dosing. This data is pointing toward better prediction of dosage outcomes for individual patients.
On February 15, 2007, Dr. Kaiser reported two-year results of the Phase 3 ANCHOR trial comparing Lucentis with photodynamic therapy (PDT) for wet AMD. The study showed that Lucentis helps maintain vision, with few adverse effects, significantly better than PDT. 89.9% of patient randomised to Lucentis in a head-to-head comparison with Visudyne for photodynamic therapy (PDT) lost fewer than 15 letters on a visual acuity chart at 24 months compared to 65.7% of those treated with PDT. 78% of the Lucentis-treated group maintained their baseline visual acuity or gained letters, compared to only 29% of the PDT group.
Overall, patients randomised to Lucentis had a 20.5 letter benefit at 24 months (+10.7 EDTRS letters) compared to those treated with PDT (-9.8 letters). This was similar to visual acuity seen at 12 months (+11.3 letters with Lucentis vs -9.6 letters with PDT).
On February 23, 2008, the final results from Cohort 1 of the Phase IIIb SAILOR study of Lucentis in patients with wet AMD were presented on February 23, 2008 at the Bascom Palmer Eye Institute's Angiogenesis meeting by Dr. David Boyer (Retina-Vitreous Associates Medical Group, Los Angeles). The final, one-year data support the long-term safety and efficacy profile of Lucentis.
The study, titled "Ranibizumab (Lucentis) Safety in Previously Treated and Newly DiagnosedÊPatients with Neovascular Age-related Macular Degeneration (AMD): The SAILOR Study," was designed to evaluate the safety of two different doses of Lucentis (0.5 mg, the FDA-approved dose, and 0.3 mg) administered once a month for three months and thereafter as needed based on re-treatment criteria. Read the results here.
For more detail in all of these areas of study, see www.lucentis.com.
Tryptophanyl-tRNA synthetase (TrpRS)
Another potentially potent inhibitor of angiogenesis has been found by two scientists from The Scripps Research Institute (TSRI). As reported by Paul Schimmel, Ph.D., Ernest and Jean Hahnin, and Martin Friedlander, M.D., Ph.D. in the January 2002 issue of the journal Proceedings of the National Academy of Sciences, the antiangiogenesis activity of a fragment of the human protein tryptophanyl-tRNA synthetase (TrpRS) has many potential applications ranging from macular degeneration to cancer. In pre-clinical trials, the researchers have found that angiogenesis is completely stopped in 70% of cases. Also, since TrpRS is a naturally-occurring protein in the body, it may be more effective, because it would not bring toxicity and immune system problems into the treatment. Once the cells have been "taught" how to make the substance, the molecules could be delivered directly to the eye through gene- and cell-based vectors.
For more information and further updates about the TrpRS research, go to the Scripps Research Institute web site at www.scripps.edu.
Retaane 15 mg (anecortave acetate)
Alcon Research, Ltd. is conducting a clinical trial to evaluate the safety and effectiveness of treatment with the investigational drug anecortave acetate compared to a sham procedure. The purpose of the study was to evaluate the safety and effectiveness of anecortave acetate in stopping the progression of dry AMD to wet AMD.
Retaane 15 mg was injected around and behind the eye, rather than into the vitreous. There were no clinically relevent safety issues. Lead researcher Jason S. Slakter, M.D, however, announced in 2004 that a comparison of anecortave acetate with verteporfin PDT (in patients with predominantly classic subfoveal CNV) did not reach its primary endpoint. Two causal factors were identified, both of which had to do with the administration of the drug, and those protocols were later refined.
On July 14, 2008, Alcon announced termination of the development program. An interim analysis of studies C-02-60 A and B that was performed after 2,546 patients had completed the 24 month time point showed no effect on the primary or secondary endpoints. In addition to terminating studies C-02-60 A and B, the company also terminated two smaller studies with an identical design that were being conducted in Asia, C-04-30 and C-05-34.
The company continues to study anecortave acetate administered as an anterior juxtascleral depot to reduce intraocular pressure in patients with open-angle glaucoma.
For more information, go to the company's web site at www.alconinc.com.
Combretastatin A4 Prodrug (CA4P)
Oxigene, Inc., a biopharmaceutical company based in Waltham, Massachusetts, has been conducting clinical trials to assess the safety and effectiveness of its lead vascular targeting compound, Combretastatin A4 Prodrug (CA4P), as a treatment for wet age-related macular degeneration (ARMD).
The studies are being conducted at the Wilmer Eye Institute of the Johns Hopkins University School of Medicine with a research team led by Peter A. Campochiaro, M.D., and Quan Dong Nguyen, M.D. The human trials are based upon successful results in recent animal studies, which showed the ability of CA4P to suppress the development of choroidal neovascularization leading to retinal degenerative diseases such as AMD. These results were published in the July 2003 issue of Investigative Ophthalmology and Visual Science.
On February 15, 2007, Oxigene reported positive results from its Phase II, open label, dose ranging, international multi-centered study. This phase assessed the safety and efficacy of CA4P in the treatment of myopic macular degeneration. The primary efficacy endpoint of the study was maintenance of visual acuity (defined as less than a three line loss in visual acuity at 3 months) and 100% of the patients met this endpoint. Safety results were favorable and in line with expectations, with no drug related serious adverse events being reported.
The company also announced that it has completed a pre-IND meeting with the FDA regarding two topical ophthalmic formulations (eye drops and ocular mini-tabs) for CA4P in the treatment of age-related macular degeneration and intends to proceed with further development of topical formulations.
Promising results from GenVec's Phase 1, multi-center, open-label, dose-escalation study were presented in October 2004 at the Subspecialty Retina Day symposium of the first joint session of the American Academy of Ophthalmology and the European Ophthalmology Society in New Orleans, Louisiana.
AdPEDF is a protein produced naturally in the eye to promote survival of retinal and other nerve cells. It also regulates the growth of ocular blood vessels, as in patients with wet MD.
The PEDF (pigment epithelium-derived factor) gene produces the AdPEDF protein. By injecting the PEDF gene into the eye, the researchers are able to elevate the level of AdPEDF, thereby halting the development of blood vessels. The method of delivery is to use a virus to carry the gene into the cells. This is called a virus vector. That is a recent major accomplishment which has made gene therapy possible, and the process can be used in treating other diseases, as well.Clinical investigator Eric R. Holz, M.D. (Assistant Professor of Ophthalmology at the Baylor College of Medicine) reported that improvements in retinal appearance and stabilization of visual acuity in patients with very advanced disease were seen. Analysis of findings from the study is continuing so that plans for additional clinical testing of AdPEDF can be made.
The study was conducted at six sites nationwide including the Wilmer Eye Institute at Johns Hopkins University, Jules Stein Eye Institute at UCLA, the Kresge Eye Institute at Wayne State University, the Casey Eye Institute at Oregon Health & Science University, the University of Washington School of Medicine, and the Cullen Eye Institute/McPherson Retina Center at Baylor College of Medicine.
In January 2006, Researchers at Johns Hopkins University Medical Center announced that they were able to halt (at least temporarily) choroidal neovascularization (CNV) with single injections of the PEDF gene into the eyeballs of patients during a phase I clinical trial. For more information, see "Gene Therapy Successful in Halting CNV" on the MD Support site.
More information on the study may also be obtained at www.genvec.com.
An injectable protein that blocks growth of abnormal blood vessels associated with diabetic retinopathy may also be useful as a treatment for age-related macular degeneration.
VEGF Trap-Eye is a molecule which has been shown to block choroidal neovascularization in the retinas of mice. It was developed by researchers at the Johns Hopkins Wilmer Eye Institute and reported on in the June 2003 issue of the Journal of Cellular Physiology.
In August 2008, Regeneron Pharmaceuticals, Inc. and Bayer HealthCare AG announced that patients with wet AMD receiving VEGF Trap-Eye in a Phase 2 extension study on an "as needed" dosing schedule continued to show highly significant improvements in retinal thickness and vision gain at 52 weeks. There have been no drug-related serious adverse events, and treatment is generally well-tolerated.
For all dose cohorts combined, there was a 5.3 mean letter gain in visual acuity at the end of 52 weeks. The mean decrease in retinal thickness was 130 microns versus baseline. During weeks 12 to 52, patients from all dose groups combined received, on average, only two additional injections. This supports Regeneron's expectation that, with VEGF-Trap-Eye treatment, patients' visual acuity will improve over time without the need for monthly intravitreal injections.
A phase 3 study, VIEW 1, began enrolling patients in late 2007. The VIEW 1 study is comparing the VEGF Trap-Eye and Lucentis. A small pilot study in DME has also been completed, and Regeneron plans to conduct advanced studies of the VEGF Trap-Eye in DME. More information.
In early 2005, Pfizer Ophthalmics began recruitment to test the safety and efficacy (Phase I-II) of AG-013958 in subjects with subfoveal choroidal neovascularization associated with age-related macular degeneration. This was a randomized, masked, single and multiple-dose, sequential dose-escalation study of a drug that acts as an inhibitor of VEGF receptor-2.
The trials were halted in July 2006, as the drug was not providing the anticipated results.
Avastin (bevacizumab), has been shown in preliminary off-label studies to stop blood vessel growth and leakage in the retinas of patients with macular degeneration. Testing began in March 2005 at the Bascom Palmer Eye Institute in Miami under the leadership of Dr. Philip Rosenfeld. In July 2005, Dr. Peter Campochiaro followed with subjects at the Johns Hopkins Medical Center in Baltimore. Potential side effects, according to Rosenfeld, are increased risk of stroke or heart attack in patients taking chemotherapy, and elevation of blood pressure. Systemic infusions of Avastin, he said would be needed every few months.
Meanwhile, Genentech, Inc. (developers of Avastin for cancer treatment) announced that it was halting trials of the drug for patients with ovarian cancer after finding that it may cause perforation of the bowels. According to Dr. Rosenfeld, however, this has no affect on the trials for Avastin in treatment of AMD. "The adverse event of bowel perforation," he told MD Support, "is most likely the result of a tumor in the bowel. This was already described for the colorectal patients. We are using such low doses (400-500 fold lower drug) and less frequent dosing, that it would be very unlikely we would see this side effect. Remember, we gave high dose systemic Avastin to 18 patients and no one had this problem."
Genentech, Inc. is not involved in the trials testing Avastin for treatment of wet AMD. This is an off-label use that the company has so far declined to support. According to Dr. Susan Desmond-Hellmann, Genentech's president for product development, dividing Avastin into small lots for injection could introduce contamination, and the drug has never been tested for safety and efficacy as a treatment for macular degeneration. Also, Genentech is currently focusing on Lucentis as their flagship product (see above). They see simultaneous support of both trials as unnecessary, self-defeating and divisive. Some doctors, on the other hand, think this approach puts business first and is not advantageous to patients who might stand to benefit from a drug which they see as more effective and considerably less expensive than Lucentis. For more on this issue, see http://www.mdsupport.org/library/avastin.html
On February 15, 2007, Elias Reichel, M.D. reported to Hawaiian Eye/Retina 2007 that Avastin has shown good results in a small retrospective case series for treatment of neovascularization from myopic degeneration. 15 eyes studied showed a mean improvement in acuity of 3 lines, central foveal thickness decreased an average of 93 µm (micrometers) and no complications.
Jerini AG, a German biopharmaceutical company, has developed an antiangiogenic compound (JSM6427) that has shown positive results and offers a more convenient treatment protocol. It is a slow-release formulation delivered by an implanted osmotic pump, that would need to be administered every six months. Phase I clinical trials have begun.
On April 5, 2006, TargeGen, Inc. (San Diego) announced that topical (eye drop) administration of the prodrug, TG100801, may be effective for the treatment of retinal disease and may also be used in combination with approved products. TG100801 converts to the active drug TG100572 as it penetrates the eye. TG100572 was shown to stop neovascularization and to decrease inflammation, both of which are characteristics of wet macular degeneration.
On November 1, 2006, TargeGen announced the initiation of Phase I trials. According to their press release, "in published preclinical testing conducted by leading outside retinal disease experts, TG100801 demonstrated the ability to reduce VEGF-mediated retinal leakage, angiogenesis and inflammation after topical instillation." Dr. Shiyin Yee of TargeGen presented the preclinical data on TG100801 at The 6th International Symposium on Ocular Pharmacology and Therapeutics in Berlin, Germany (3/30/06 - 4/2/06). His presentation was titled "A novel first-in-class, non-invasively delivered, multi-targeted kinase inhibitor for the treatment of age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME)." Laboratories collaborating in the research were those of Dr. Martin Friedlander (Scripps Research Institute) and Dr. Peter Campochiaro (Johns Hopkins University School of Medicine).
On February 27, 2007, the company announced completion of the Phase I trial. Preliminary results suggested that TG100801 is well tolerated in humans at the low and high doses tested when applied topically twice daily for 14 days. Following these positive results, phase II clinical trials were begun on July 30, 2007.
On August 22, 2006, Athenagen, Inc. (now CoMentis) announced that it had begun human testing of its topical (eye drop) drug ATG3 for wet AMD. On January 31, 2007, the company announced successful completion of Phase I, and that "the eye drop therapy showed excellent ocular tolerability. There were no study medication-related systemic side effects, consistent with the very low levels of the compound found in the blood following eye drop application."
The company's Phase II clinical trial, expected to begin in the first quarter of 2007, is a placebo-controlled, double-masked, randomized dose-ranging study designed to evaluate both safety and efficacy in a larger sample of patients. The 330-patient study will be conducted at multiple centers worldwide. Interim (six month) efficacy data can be expected by mid-2008.
According to M. (Ken) Kengatharan, Ph.D., co-founder and VP of Pre-clinical R&D, data from pre-clinical efficacy studies show excellent penetration of the drug to the back of the eye. The eye drop formulation of mecamylamine, he said, "... enables delivery of drug to the retina and choroid with very little reaching the systemic blood circulation." The formulation was well tolerated in preclinical safety models at all doses now being used in human testing.
On October 31, 2006, MacuSight, Inc. announced the start of a Phase I study of sirolimus (rapamycin) for treatment of wet AMD. The randomized, open-label, dose-escalation study ran concurrent with a study of the same drug for treatment of diabetic retinopathy. Sirolimus is injected either subconjunctivally (just under the lining layer over the sclera) or intravitreally (into the back of the eye) for up to three months.
Developers say that sirolimus differs from other anti-angiogenic drugs in that it is "a highly-potent, broad-acting compound that has demonstrated the ability to combat disease through multiple mechanisms of action including immunosuppressive, anti-angiogenic, anti-migratory, anti-proliferative, anti-fibrotic and anti-permeability activity," and that it may, therefore, "serve as a potentially highly-efficacious therapeutic for a wide range of ocular diseases and conditions."
On February 25, 2008, MacuSight reported positive preliminary data from their phase 1 trial. Investigators found that the drug was well-tolerated at all doses for both administration methods tested, with no reported IOP elevations, inflammatory effects or indications of cataract progression. In addition, all patients showed improvements in visual acuity and reductions in retinal thickness. These results are similar to results from MacuSightÕs phase 1 study of sirolimus in diabetic macular edema (DME) patients. Based upon the positive findings, phase 2 trials will be initiated for both AMD and DME, as well as other ocular diseases and conditions.
On February 26, 2007, Othera Pharmaceuticals presented new preclinical data demonstrating the safety and effectiveness of OT-551, an antiangiogenic drug in eyedrop form. Results from the Phase I trials demonstrated that when the compound is added to either Lucentis or Avastin treatment there is a synergistic effect versus either treatment alone. According to Dr. Len Parver, Othera's Medical Director, "OT-551 could potentially improve the outcome of patients already on Lucentis by treating the underlying macular degeneration and decreasing the need for frequent Lucentis injections." Phase II trials are expected to begin in the second quarter of 2007. The results of Phase I were presented at the Angiogenesis 2007 Conference in Key Biscayne, FL, by Dr. Shaker Mousa, Professor of Pharmacology and Executive Vice President and Chairman of the Pharmaceutical Research Institute at Albany College of Pharmacy.
On April 8, 2009, Othera announced positive interim data results from its Phase 2 trial of OT-551. The 12-month findings from the 2-year trial suggest an emerging trend for reducing moderate vision loss (i.e. 15 letters or more on the ETDRS chart) in treated patients compared to the placebo group.
Endostatin is an experimental drug derived from type XVIII collagen. It is currently being tested to stop cancer in people by restricting the formation of abnormal blood vessels supplying blood to tumors. Past research (J Folkman, 2006) has shown that it may restrict the formation of abnormal blood vessels by interfering with growth factor proteins such as vascular endothelial growth factor (VEGF). This now appears to be making it a likely treatment for wet AMD.
In the December 2007 issue of the journal of the Federation of American Societies for Experimental Biology (FASEB), researchers described how giving endostatin to mice significantly reduces or eliminates abnormal blood vessel growth within the eye.
As reported by Alexander Marneros et al, mice without normally-occuring endostatin were about three times more likely to develop advanced AMD than normal mice. When endostatin was administered to both sets of mice, those lacking endostatin showed a reduction in the number of abnormal blood vessels. In control mice with normal levels of endostatin, the number of abnormal blood vessels was practically undetectable.
Endostatin can now be added to the growing list of antiangiogenic drugs being studied as potentially effective treatments for wet AMD.
For more information on clinical studies related to macular degeneration, see Clinical Trial Watch
For further explanation of the terms used in this article, see the MD Support Glossary and Eye Anatomy pages.