The resounding success of anti-VEGF therapies for AMD has sparked a race for the next generation of treatments.
When it comes to treating neovascular AMD, one groundbreaking invention has spawned the search for even more. “Over the last five to 10 years there have been tremendous advances,” said Jeffrey S. Heier, MD, partner at Ophthalmic Consultants of Boston and codirector of the OCB vitreoretinal fellowship. “At first, many involved in clinical research thought, ‘That’s it. Research will decrease dramatically,’” he said, referring to the discovery that anti-VEGF drugs—specifically, ranibizumab (Lucentis) and bevacizumab (Avastin)—control the advance of neovascularization and, in some cases, lead to visual improvement. “But success has bred more interest and more success,” Dr. Heier said.
Anti-VEGF therapy was just the beginning, agreed Allen C. Ho, MD, professor of ophthalmology at Wills Eye Institute and at Thomas Jefferson University. “We’ve made incredible strides to date, but we still need to remain hungry for better and more patient-friendly solutions to this problem. Despite the high efficacy of frequent ranibizumab injections, there’s still room to improve and raise the bar for our patients.”
SEARCHING FOR SYNERGY
A search at www.clinicaltrials.gov reveals no fewer than 130 wet AMD investigations, attesting to the push for better solutions. The studies involve different mechanisms of action, and they address different steps along the pathway that leads from early to late stages of the disease.
Some of these new pathway-based therapies involve molecules other than VEGF. Some employ radiation. Many are being tested in combination with the gold standard, Lucentis. Even the gold standard is being tested against itself.
The VEGF inhibitors are so good that they’re going to be hard to beat, said Mark S. Blumenkranz, MD, professor and chairman of ophthalmology at Stanford University. “Nothing matches up that well with Lucentis or Avastin. If you were to do a comparative trial, Lucentis would probably outperform most other compounds.” So the search is on for something synergistic, some super-therapy that will reduce the treatment burden and possibly improve visual acuity, he said. “Together they may be 300 percent better than either drug alone.”
David S. Boyer, MD, who has been involved in a number of the studies, said, “All these drugs are trying to improve upon, or be additive to [Lucentis or Avastin], in order to extend the time period between injections.” They will probably remain adjunctive because they lack the immediate punch of the anti-VEGF therapy. But once they kick in, the hope is that they will extend the time between treatments and perhaps lead to smaller central scotomas, better reading speeds and overall improvement of vision from baseline, he said.
It would be hard to improve on the number of patients who are stabilized with anti-VEGF therapy, said Dr. Boyer, clinical professor of ophthalmology at the University of Southern California and in private practice with Retina-Vitreous Associates Medical Group in Los Angeles. “One goal, whatever the drug, would be to improve the number of three-line gainers.”
Dr. Heier agreed. “We feel good that for the most part we’ve got treatments that are very effective at shutting down the exudative process.” He added, “We’d like to see greater efficacy. In clinical trials, we get some degree of improvement in upward of 70 to 80 percent of patients, but we get three-line gainers in roughly only one-third. Maybe that’s where a combination of these approaches will be most effective. Can we combine drugs, as in oncology, to get greater efficacy?”
TEN OPTIONS ON THE HORIZON
Many treatments are being tested, with many candidates within each class. Some are delivered orally, some topically, some intravitreally. It’s important to note that while some agents are in phase 3 testing, others are much further out in the pipeline. With that caveat in hand, here’s a brief overview of 10 of the most talked-about approaches:
Anti-VEGF Therapy. A number of investigations are piggybacking on the initial success of ranibizumab and bevacizumab:
VEGF Trap-Eye. Regeneron has developed VEGF Trap-Eye, an anti-VEGF molecule similar to ranibizumab and bevacizumab. VEGF Trap-Eye, which is given by intravitreal injection, is a fully human fusion protein that binds all forms of VEGF-A along with the related placental growth factors 1 and 2.
Preliminary phase 3 results showed that all regimens of VEGF Trap-Eye, including dosing every two months, compared favorably with ranibizumab 0.5 mg dosed monthly. Patients receiving Trap-Eye maintained vision at these rates: 96 percent receiving 0.5 percent Trap-Eye monthly; 95 percent receiving 2 mg monthly; and 95 percent receiving 2 mg every two months. With ranibizumab monotherapy, 94 percent achieved maintenance, Regeneron reported.
The most encouraging aspect of the results is that the bimonthly dose was comparable to Lucentis dosed monthly, said Dr. Heier, who chairs the steering committee for the phase 3 study. With Lucentis and Avastin, doctors have tried dosing on an as-needed basis, but monthly dosing appears to achieve a greater level of success, Dr. Heier said. “Whenever we try to deviate in terms of frequency, our results are often not as robust.” He conceded that this observation is anecdotal, and said the results from the CATT (Comparison of AMD Treatments Trial) study should yield a more definitive answer on dosing regimen.
The anticipated completion date of the Trap-Eye study is early 2012. “Durability is what we’re hoping for. We have the potential after a loading dose to dose half as frequently and still get the results,” Dr. Heier said.
Dr. Ho, who also is on the phase 3 steering committee, added, “It is not surprising that VEGF Trap-Eye compared favorably with ranibizumab in this phase 3 trial because VEGF Trap-Eye is a pan-VEGF inhibitor and is recognized to have the highest binding affinity for VEGF, even greater than ranibizumab.”
High-dose ranibizumab. Genentech is investigating the safety and efficacy of higher doses of Lucentis and evaluating alternative delivery technologies that have the potential to reduce the frequency of intravitreal injections. The ongoing phase 3 HARBOR trial has four arms: 0.5 mg of Lucentis monthly; 2 mg of Lucentis monthly; 0.5 mg of Lucentis administered on an as-needed basis; and 2 mg of Lucentis on an as-needed basis. The results are expected later this year.
“The results of HARBOR are highly anticipated, regardless of the results of the CATT study, as it will provide information on whether a higher dose of ranibizumab is well tolerated and whether we can raise the bar on efficacy for our patients,” said Dr. Ho, who is a member of the HARBOR steering committee. He noted that the 2-mg dose was well tolerated in the phase 1 trials, and all of the ranibizumab studies to date have demonstrated an efficacy advantage to the higher dose tested.
Visudyne + ranibizumab + dexamethasone. The power of combination therapy was tested in the RADICAL (Reduced Fluence Visudyne Anti-VEGF-Dexamethasone In Combination for AMD Lesions) trial. QLT evaluated three combinations of reduced fluence Visudyne (photodynamic therapy and verteporfin) plus Lucentis and, in two arms of the trial, intravitreal dexamethasone. These were compared with Lucentis alone to see whether combination therapy reduces the need for re-treatment.
Two-year, phase 2 results, released last June, showed that the combination approach led to significantly fewer visits at which re-treatments were applied. Best outcomes were achieved in the triple therapy half-fluence group, with a mean of 4.2 re-treatment visits, vs. 8.9 visits for Lucentis monotherapy, QLT reported.
“You can’t say that one is better than the other” in terms of visual outcome, said Dr. Ho, a lead investigator. “These are promising preliminary findings that would need confirmation by a larger clinical trial.” But the need for fewer visits is a welcome option for those elderly patients who often have trouble getting to the office, he said.
KH902. KH902 (recombinant human VEGF receptor-Fc fusion protein), developed by Chengdu Kanghong Biotech, is delivered by intravitreal injection. It is a gene fusion protein that can bind VEGF-A and other VEGF family members, including VEGF-B and placental growth factor (PlGF), and it is designed to inhibit the growth, migration and budding of vascular endothelial cells and neovascularization induced by VEGF. In a phase 1 study of 28 patients with CNV, the mean change in VA from baseline was a gain of 19.6 letters, with no patients losing 1 or more letters. In addition, the mean decrease in CNV area was 12.6 percent.1 A phase 2 clinical trial is under way.
Anti-Inflammatory Treatment. Allergan is testing dexamethasone in combination with ranibizumab. The two-year phase 2 trial, which started last August, has two arms: One is testing intravitreal injections of 700 µg ranibizumab and dexamethasone into the study eye; the other combines ranibizumab with sham injection.
In an earlier, six-month trial of 243 patients with CNV secondary to AMD, adjunctive therapy with the dexamethasone implant (Ozurdex) delayed the time to as-needed injections of 500 µg ranibizumab and reduced the need for repeated ranibizumab injections. 2
Radiation Therapy. Radiation has multiple effects in fighting AMD. It has the ability to destroy vascular tissue and inhibit new blood vessel growth. And radiation inhibits inflammatory response, which may play a role in VEGF expression. Two studies are testing radiation in combination with Lucentis:
Epi-Rad90 is being tested in the CABERNET (CNV Secondary to AMD Treated With Beta Radiation Epiretinal Therapy) study. NeoVista has enrolled 495 patients in this prospective, randomized, controlled pivotal phase 3 trial, which is evaluating the combined effects of epiretinal brachytherapy with strontium-90 and ranibizumab vs. ranibizumab monotherapy.
In an earlier safety and feasibility trial, researchers evaluated the Epi-Rad90 system with intravitreal bevacizumab in 34 patients. At 12 months, the mean change in BCVA was a gain of 8.9 letters, and 38 percent had gained 3 or more lines.3
The Epi-Rad90 system is similar to a phaco hand piece in size, shape and weight. An extension wire sits inside the device; the isotope is contained within a miniature housing located at the tip of the wire. Radiation exposure is limited to the area immediately surrounding the CNV lesion.
IRay is an external beam, low-energy x-ray radiation system designed to deliver precise doses of radiation at the macula. Oraya Therapeutics is recruiting 150 patients for a phase 2 study combining IRay at different doses with ranibizumab.
The phase 1 study of the device plus ranibizumab found no serious adverse results in either of the treatment arms (one group of patients received 16 Gy of radiation; the other received 24 Gy). It also found that VA stabilized and the need for re-treatment with Lucentis decreased in both groups.4
Vascular Stabilization. Ophthotech’s pegylated aptamer E10030 inhibits platelet-derived growth factor B (PDGF-B). This molecule regulates the recruitment of pericytes, which are necessary for vessel maturation. E10030 strips the pericytes from the neovascular tissue, which renders it highly sensitive to an anti-VEGF attack. In preclinical models, E10030, combined with anti-VEGF agents, induced neovascular regression.
In a phase 1, open-label clinical study, E10030 was well tolerated. And at 12 weeks, the combined treatment yielded improvement of three lines or better in 59 percent of patients. It also achieved a mean decrease of 86 percent in the area of CNV, Ophthotech reported. A phase 2 trial began April 2010.
One caveat, said Dr. Heier, is that all patients had classic lesions or large components of classic neovascularization. “However, regardless of lesion types, the results are encouraging.”
Complement Inhibition. Aberrant activation of the complement system is implicated in the pathogenesis of both forms of AMD. While complement inhibition has been regarded as a therapy for dry AMD, it looks promising for wet AMD as well.
Dr. Boyer said complement inhibition “may act to prevent progression of dry [to wet AMD].” However, he added, “I don’t think we have a place for it yet.” And Dr. Heier noted that the challenge with complement inhibition is the difficulty of identifying which components to block along the complement pathway. Compounds under investigation include:
ARC1905, an anti-C5 aptamer, selectively inhibits factor C5 of the complement cascade. Ophthotech reports that inhibition of the cascade at this level prevents the formation of the key terminal fragments responsible for tissue pathology, C5a and the membrane attack complex. The C5a fragment is proinflammatory, while the membrane attack complex initiates cell lysis and releases proangiogenic molecules such as PDGF and VEGF.
Two phase 1 studies are ongoing. One is evaluating ARC1905 in combination with Lucentis in patients with exudative AMD; the second is investigating the drug in patients with the nonexudative form of the disease. In both studies, ARC1905 is being administered by intravitreal injection. Results have not yet been reported.
Eculizumab is being tested as a complement inhibitor in a phase 2 trial at the University of Miami in patients with dry AMD. Under the proprietary name Soliris, eculizumab, which was developed by Alexion, is approved to block complement C5 and reduce hemolysis in patients with paroxysmal nocturnal hemoglobinuria. In the AMD study, it is being administered by intravenous infusion. Since the drug is FDA-approved, a phase 1 safety dose-escalation study for AMD was not necessary.
Tyrosine Kinase Inhibition. GlaxoSmithKline’s drug pazopanib is a small, orally bioavailable tyrosine kinase inhibitor that selectively inhibits multiple receptors, including VEGFR, PDGFR and c-kit. Approved for treatment of advanced renal cell carcinoma under the proprietary name Votrient, it is being tested as a monotherapy in AMD.
A phase 1, open-label study to evaluate pazopanib tablets was scheduled to end last October and a phase 2 test evaluating eye drops was completed in 2009. Results have not yet been reported.
A downside of kinase inhibitors is that there are many in the body, so systemic suppression will be a problem, Dr. Boyer said. “Systemic administration of drugs in older people is always a concern. I don’t know how they’d be able to handle it long-term.” A topical treatment could mitigate that effect, but topical delivery to the back of the eye is a challenge, Dr. Heier noted.
Nicotine Cholinergic Receptor Antagonist Therapy. Building on the theory that smoking is a risk factor for AMD, researchers at CoMentis (formerly Athenagen) are studying ATG003 (mecamylamine ophthalmic solution). Mecamylamine is a known nicotinic receptor antagonist; the antagonist molecule would abolish the proangiogenic effects of nicotine.
A phase 2 study comparing placebo eye drops to ATG003 drops was completed last year, but results have not yet been published. According to the company, the drops were well-tolerated in the phase 1 trial, which evaluated 80 patients in single and multiple dose-ascending regimens for up to 14 days.
Integrin Antagonist Therapy. Ophthotech’s alpha5beta1 integrin antagonist volociximab attacks a receptor that’s expressed on the cell membrane of new vessels. It interferes with endothelial cell survival and may result in an enhanced antiangiogenic response and neovascular regression. It inhibited CNV proliferation and reduced the degree of lesion formation in animal models when administered intravenously or intravitreally.
The company reports that a phase 1 open-label, multicenter study of volociximab plus Lucentis is ongoing in patients with exudative AMD; the drug is being given by intravitreal injection.
Gene Therapy. Genzyme’s experimental drug AAV2-sFLT01 uses a virus to transfer a gene into cells within the eye. The gene codes for a protein that is intended to diminish the growth of abnormal blood vessels under the retina. The duration of the gene’s effect is unknown, but it might last for years.
A phase 1 safety trial is under way. In the first part of the study, four different doses of the drug will be evaluated in four different groups of patients. The two highest doses that proved safe and well-tolerated will then be tested in part two of the study. The estimated primary completion date is December 2012.
Vascular Disruption. Unlike antiangiogenic therapies, which are designed to prevent formation of new blood vessels, vascular disrupting agents are intended to cause the vascular structure to collapse.
Oxigene’s VDA fosbretabulin (Zybrestat) is under investigation in several clinical trials, including studies of thyroid and ovarian cancer. Researchers also are studying Zybrestat’s use in ophthalmology and evaluating the drug in combination with Lucentis. The goal is to develop a topical formulation of Zybrestat for treating AMD; the formulation could be ready for testing this year, the company reports. However, a clinical trial has yet to be launched.
NOTES OF CAUTION
It will be some time before we know how any of these approaches will fare. And the experts offer two cautions:
Cost. As Dr. Boyer put it, “The wild card is, how much are these treatments going to cost?”
The cost of bringing new drugs to market is almost prohibitive, Dr. Blumenkranz noted. “Most drug companies are adding their drug to standard anti-VEGF therapy to show it’s better than the single drug alone.” However, because the FDA has tended to prefer head-to-head trials, it might be hard to organize a trial with a drug that has little effect on its own but might be highly synergistic with Lucentis.
In addition, the results of the CATT study are looming, he said. “If CATT shows that Avastin is equal to or better than Lucentis, on one hand, it will greatly reduce the cost of therapy. But it might have the unintended consequence of reducing the likelihood of other companies developing new molecules due to concerns about pricing.”
Efficacy. “At this point, the promise of superior efficacy from combination therapy is still unrealized,” Dr. Ho said. “Ranibizumab remains the gold standard of therapy. Its benchmark efficacy has been incredibly resilient in the face of challenges from other molecules or combination treatments.”
1 Zhang, M. et al. Ophthalmology Published online Dec. 9, 2010.
2 Loewenstein, A. et al. Invest Ophthalmol Vis Sci 2010;51:E-abstract 1255.
3 Avila, M. P. et al. Br J Ophthalmol 2009;93:305–309.
4 Kaiser, P. K. and V. Morales-Canton. Retina Today October 2010.
MEET THE EXPERTS
MARK S. BLUMENKRANZ, MD Professor and chairman of ophthalmology at Stanford University. Financial disclosure: He is an occasional ad hoc consultant to Genentech and has received research support from the company in the past. He also has been a consultant to Allergan and Neuron Systems and is a director and equity holder in Avalanche Biotechnologies.
DAVID S. BOYER, MD Clinical professor of ophthalmology at the University of Southern California and in private practice with Retina-Vitreous Associates Medical Group in Los Angeles. Financial disclosure: He is a consultant for Alcon, Allergan, Genentech, Novartis, Pfizer and Regeneron but has no equity interest in any of these companies.
JEFFREY S. HEIER, MD Partner at Ophthalmic Consultants of Boston and codirector of the OCB vitreoretinal fellowship. He is assistant professor of ophthalmology at Tufts and clinical instructor of ophthalmology at Harvard. Financial disclosure: He serves as a scientific advisor to numerous companies involved in the development of new treatments for AMD, but does not have equity in any of them. He chaired the phase 3 steering committee for Regeneron.
ALLEN C. HO, MD Professor of ophthalmology at Wills Eye Institute and at Thomas Jefferson University. Financial disclosure: He receives research funding from and is a scientific consultant for Genentech, QLT and Regeneron.
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