by Dan Roberts
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.
This is continually-updated information on notable anti-angiogenic research for wet AMD:
Macugen (pegaptanib sodium) [updated 10/22/04]
Lucentis (ranibizumab) [updated 2/23/08]
Tryptophanyl-tRNA synthetase (TrpRS) [1/02]
AdPEDF [updated 1/06]
EYLEA (formerly VEGF Trap-Eye) [updated 9/27/12]
AG-013958 [updated 7/06]
Avastin (bevacizumab) [updated 5/13/11]
TG100801 [updated 2/27/07]
ATG3 [updated 1/31/07]
Perceiva (originally sirolimus or rapamycin) [updated 2/19/10]
Squalamine (OHR-102) [updated 2/15/17]
OPT-302 [updated 5/5/16]
Macugen (pegaptanib sodium)
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 Diagnosed Patients 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.
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.
EYLEA (aflibercept injection, formerly VEGF Trap-Eye)
In August 2008, Regeneron Pharmaceuticals, Inc. and Bayer HealthCare AG announced that patients with wet AMD receiving EYLEA (aflibercept injection) 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 were no drug-related serious adverse events, and treatment was 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 supported Regeneron’s expectation that, with EYLEA treatment, patients’ visual acuity would 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 compared EYLEA and Lucentis. A phase 2 study in diabetic macular edema (DME) was also completed. EYLEA injected into the eye every two months was found to be as effective as monthly doses of Lucentis, and monthly monitoring of patients receiving EYLEA was not necessary.
On June 17, 2011, the Food and Drug Administration advisory panel voted unanimously to recommend EYLEA as a treatment for wet AMD. The advisers also said the injected drug could be given once every two months. This was an improvement upon the typical 4-6 week dosings of both Lucentis and Avastin.
Finally, on November 18, 2011, Regeneron announced that the FDA had approved EYLEA for treatment of patients with wet AMD. Recommended dose is 2 mg every four weeks for the first 12 weeks, followed by 2 mg every eight weeks. EYLEA offers less frequent injections than either Lucentis (4 weeks) or Avastin (6 weeks), and there are no monitoring requirements.
Since September 2012, Eylea has also gained approval in the U.S., Europe, and Japan for use in treating wet AMD, diabetic macular edema, and neovascular myopic degeneration. For more information, see www.regeneron.com.
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.
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 micrometers and no complications.
In May 2011, first year results of the Comparison of AMD Treatments Trial (CATT) were announced. The report focused on the relative safety and efficacy of Lucentis and Avastin. After one year, the two compounds have been found to be extremely similar in their improvement of mean visual acuity and the occurrence of adverse events. Five related trials were also undertaken in the UK and Europe.
At the end of the 2-year comparison study, The National Institutes of Health reported that both drugs improved vision when administered monthly or on an as needed basis. Patients receiving Lucentis, however, fully maintained first-year vision gains with an average 5.7 injections in the second year. In contrast, patients treated with Avastin experienced a greater decline in vision despite receiving significantly more injections over the two year period. In addition, secondary anatomical outcomes were significantly better with Lucentis. (Source: www.nih.gov/news/health/apr2012/nei-30a.htm)
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, initiated in April 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.
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.
Perceiva (originally sirolimus or rapamycin)
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 MacuSight’s phase 1 study of sirolimus in diabetic macular edema (DME) patients.
As of February 2010, Perceiva is being advanced in a broad Phase 2 clinical program across multiple large ocular indications including diabetic macular edema (DME), wet age-related macular degeneration (wet AMD), uveitis and dry age-related macular degeneration (dry AMD). Additionally, as part of this Phase 2 program, the company is using Perceiva to evaluate the potential role for sirolimus in the treatment of dry eye syndrome (DES).
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.
Researchers state that topical administration of pazopanib causes regression of already established CNV in patients with neovascular AMD. A 28 day safety study in February 2010 revealed no serious adverse events in the eye related to the drug. However, some mild to moderate symptoms were reported in some patients. A phase 3 trial is planned.
Squalamine (Ohr Pharmaceutical) is an anti-angiogenic small molecule that counteracts not only Vascular Endothelial Growth Factor (“VEGF”) but also other angiogenic growth factors such as Platelet Derived Growth Factor (“PDGF”) with high potency at nanomolar concentrations. Recent clinical evidence has shown PDGF to be an additional key target for the treatment of wet-AMD.
Using the intravenous formulation in over 250 patients in Phase 1 and Phase 2 trials for the treatment of wet-AMD, Squalamine demonstrated favorable biologic effect and maintained and improved visual acuity outcomes, with both early and advanced lesions responding. Ohr Pharmaceuticals has developed an eye drop formulation of Squalamine for the treatment of wet AMD designed for self-administration. Preclinical testing demonstrated that the eye drop formulation is both safe to ocular tissues and achieves in excess of target anti-angiogenic concentrations in the tissues of the back of the eye.
In May 2012, the Squalamine eye drop program was granted Fast Track Designation by the FDA, and the drug entered Phase 3 trials. Unfortunately, Ohr Pharmaceuticals had to temporarily suspend the study in February 2017 and stop further recruitment. Current subjects will still, however, continue to receive the treatment, since safety issues were not the reason for the suspension.
PAN-90806 is a topical eye drop for the treatment of neovascular AMD, diabetic retinopathy, and potentially diabetic macular edema (DME). It is being developed by Panoptica and began a phase 1 clinical trials in early 2014, a 2-month open-label study of approximately 30 patients at 15 to 20 sites in the U.S. More information.
OPT-302 is soluble receptor developed by Opthea Pty Ltd. It is a derivative of VGX-300 which has been optimised for local ocular administration. OPT-302 potently and specifically blocks VEGF-C and VEGF-D from binding and activating VEGFR-2 and VEGFR-3. Opthea is entering Phase 2A clinical trials.
The EMERGE study examined the hypothesis that a protein called Tissue Factor (TF), when out of control, initiates inflammation and angiogenesis, resulting in wet AMD. ICON-1 is thought to block the protein and reverse the progression of the disease, both alone and in combination with Lucentis.
RGX-314 differs from current therapeutics in that it includes a gene vector (NAV AAV8) which encodes an antibody fragment designed to neutralize VEGF (vascular endothelial growth factor) activity. This modifies the pathway for formation of new leaky blood vessels which lead to retinal fluid accumulation and vision loss.
Six leading retinal surgery centers across the United States are expected to participate in the Phase I trial of RGX-314. For further details on the trial, enrollment criteria and eligibility, contact email@example.com or visit https://clinicaltrials.gov/ct2/show/NCT03066258.