Anti-angiogenesis therapy for retinal disease is one of the biggest success stories in eye care. We now live in a world where millions who would otherwise have low vision or need service dogs enjoy robust visual acuity. Retina specialists, who within living memory often measured success by whether patients could tell if the lights were on in the room, now can offer the majority of their patients vision-saving treatments.

But time passes, fanfare fades, and yesterday’s miracle becomes today’s standard of care. Here at roughly the 10-year mark, anti-angiogenesis therapy’s focus has shifted from determining how well these treatments really work—and the astonishment that they actually do—to how to prolong their effects.

Prescribing Trends
Every year, the American Society of Retina Specialists (ASRS) surveys its members to determine their preferences and trends (PAT) in clinical practice. Some highlights from the 2013 PAT survey:  

• As in previous years, off-label Avastin remains the drug of first choice for AMD among a majority of ASRS members, with only 20% choosing the much more expensive Lucentis. However, both drugs lost ground last year to newer arrival Eylea, which 20% chose as their first-line therapy.

• More than 75% of US retina surgeons favor the treat-and-extend regimen for intraocular anti-VEGF injections. The second most common approach is monthly examinations and PRN treatment (a regimen more common overseas). Few physicians inject every month if it can be avoided.

• The practice of performing bilateral, same-day injections has increased, with slightly over half of respondents willing to do so. “This is the first year they’ve demonstrated such a willingness since we’ve followed this trend over the last five years,” notes Thomas W. Stone, MD, of Retina Associates of Kentucky, one of the survey’s editors. “It would suggest that safety concerns are lessening as experience develops with these treatments.”

There is a great need to maintain positive visual outcomes while giving patients, nearly all of them elderly, a break from schlepping to a doctor’s office for an unpleasant intraocular injection every few weeks for the rest of their lives.
A variety of strategies are under investigation, including combination therapies, sustained-release drug systems, topical eyedrop therapy and efforts to harness the genetic markers that predict clinical response. How these will play out remains to be seen, of course.

What does seem certain is optometry’s continued involvement comanaging retinal disease. Even under best-case scenarios, the patient deluge will not relent any time soon and experts predict an all-hands-on-deck environment for years to come.
Endless Injections
Most anti-VEGF literature suggests optimal outcomes hinge on frequent doses over the long term. It is well established that the best vision occurs when patients receive injections every month. When rates decline, vision tends to worsen rapidly. For example, two-year results in the landmark CATT trial showed that when patients were switched to as-needed dosing after receiving strict monthly dosing for one year, their vision fell back to nearly the same level as those who had received as-needed dosing from the outset of therapy.1

“Once follow-up becomes fixed and less frequent, results seem to suffer,” says Michael Colucciello, MD, a clinical associate professor at the University of Pennsylvania School of Medicine. “In the HORIZON, MARINA and ANCHOR extension study, less frequent follow-up and treatment resulted in loss of visual acuity gains achieved with monthly treatment during the initial phases of the ANCHOR and MARINA studies.”

Despite this, in practice very few retina specialists inject AMD patients every single month. Most employ what is known as the “treat-and-extend” approach. Patients receive three monthly doses, and if results are positive, the ophthalmologist slowly extends the period of time between shots one or two weeks at a time. This continues until subretinal fluid develops, at which point the MD reverts back to the most recent time interval between shots, and that becomes the de facto dosing schedule. Treat-and-extend lengthens dosing intervals a little, but most patients still require a shot every six or seven weeks, a schedule often burdensome for elderly patients––many of whom must rely on younger family members for transport to and from the physician’s office.

Approved in 2011, Eylea (aflibercept, Regeneron), the most recent anti-VEGF drug, was touted as a means of easing such burdens. Its two parallel Phase III trials—known as VIEW 1 and VIEW 2—which compared the newer drug to Lucentis (ranibizumab, Genentech), found both produced relatively similar visual outcomes.2

An integrated analysis also established that, during the two-year study period, Lucentis patients received about 17 injections while Eylea patients received about 11. Those six fewer injections generated much optimism for a reduced treatment burden with this modality.

However, because the VIEW trials did not include a group of Lucentis patients who received the drug every eight weeks, as it did with Eylea patients, the two drugs were never actually compared on an equal footing at that dosing schedule––a fact that puts those six fewer injections in a different light.

Furthermore, when the drugs did face off on equal, four-week schedules, Eylea only outperformed Lucentis when it held a fourfold greater dosing advantage in the VIEW 1 trial. In the VIEW 2 trial, when dosages were equal, Lucentis beat it. The bottom line: under equal dosing and scheduling conditions, aflibercept did not demonstrate a statistically significant advantage over ranibizumab in either VIEW trial. 

Evading the Needle
Recognizing the need to ease treatment burdens, pharmaceutical researchers continue to experiment with different ways of delivering therapies to the posterior segment. Recent developments in two popular strategies—sustained-release drug systems and topical drops—follow:

• A topical drop form of the anti-angiogenic agent Squalamine can reach the choroid in therapeutic levels, according to symposium data presented this year. Manufacturer Ohr Pharmaceutical recently announced enrollment of wet AMD patients in Phase II clinical trials for the drug, which achieved FDA fast-track approval status in 2012.

• Scientists at University College London found that formulations of nanoparticles loaded with Avastin could be delivered to the posterior segment in animal models.

• PanOptica recently received $45 million in series B venture capital financing for its experimental eye drop, PAN-90806, which is headed for Phase I trials in wet AMD.

• Genentech, maker of both Lucentis and Avastin, is developing a sustained-delivery device designed for surgical implantation in the pars plana beneath the conjunctiva. A 20-patient wet AMD trial of the device yielded outcomes similar to those achieved with anti-VEGF injection therapy, the company announced this spring.

• A new, bioerodible, sustained-release device called Tethadur, developed by Watertown, MA-based pSivida, can produce stable delivery of Avastin over a period of six months, according to the company. 

This came as a surprise, as models had predicted Eylea’s unique mechanism of action would yield a higher VEGF binding affinity than that of Lucentis.3 On the other hand, it should also be noted that many retina specialists do observe an anecdotal advantage with aflibercept, and it continues to gain popularity (see “Prescribing Trends”).

“I think Regeneron made some very smart moves in the way they positioned their clinical trials,” notes Alan J. Franklin, MD, PhD, of the Retinal Specialty Institute in Mobile, AL. Functionally, he says, he finds a bit of reduced treatment burden with Eylea, but not enough to cut in half the number of injections needed to maintain visual acuity gains. “If somebody is getting injections every six weeks, Eylea may stretch it to seven,” he says. “Having said that, if a patient is getting one less shot a year, well, those people will still really appreciate” the respite.

Group Therapy
Vascular endothelial growth factor is only one of countless chemical factors involved in angiogenesis. For all the effectiveness derived from suppressing VEGF, researchers believe there may be many other, perhaps more significant, therapeutic targets.

Hence the idea of combining anti-VEGF therapy with other suppressive elements. Fovista (E10030, Ophthotech)—which is nearing FDA approval and was recently licensed to Novartis for commercialization outside the US—combines Lucentis with an anti-platelet derived growth factor (PDGF) agent, and has been achieving impressive results. Suppressing PDGF is thought to slow the recruitment of pericyte cells during neovascularization. Pericytes protect the endothelial cells that comprise vascular walls.

A Phase IIb trial compared Fovista in combination with Lucentis to Lucentis monotherapy. Over six months, AMD patients receiving combination therapy gained a mean 10.6 letters of vision, while patients on monotherapy gained only 6.5 letters.
“I think the future of managing wet AMD is going to be combination therapy,” says Jay M. Haynie, OD, executive clinical director of Retina and Macular Specialists, a multi-site practice in Washington state. Not only will other anti-angiogenic agents be involved but probably steroids as well, he adds.

Years ago, Dr. Haynie comanaged AMD patients with a surgeon whose induction therapy consisted of Avastin (bevacizumab, Genentech), followed by Kenalog (triamcinolone acetonide), followed by another round of Avastin. “When we looked back at the data on these patients, we found they averaged three to five treatments a year, as opposed to 10 to 12. Looking at where AMD is going, I think we are going to see a resurgence of the anti-inflammatories,” he adds.
Varying drug delivery methods is another potential way to reduce treatment burden. Two lines of attack here include sustained-release drug systems and topical drops (see “Evading the Needle”).

Opinion differs as to which avenue seems more likely to prevail or yield greater benefit. “A topical therapeutic would offer an important alternative for the large wet AMD patient population currently being treated with frequent intravitreal injections,” says Jeffrey S. Heier, MD, director of the Vitreoretinal Service at Ophthalmic Consultants of Boston, in a statement released by Ohr Pharmaceutical, whose topical drop of the anti-angiogenic agent Squalamine recently began Phase II clinical trials. Interim results on the first 60 wet AMD patients will be released this month, according to the company.

Offering an alternate view of the future, David M. Brown, MD, FACS, of Retinal Consultants of Houston, believes sustained-release drugs represent eye care’s greatest hope. “Multiple topical formulations have been attempted, but it is quite difficult to get therapeutic levels of drugs into the posterior segment,” he notes. “And even if the drop did achieve adequate levels, we all know from glaucoma management that patient compliance often limits any potential gains.”

It’s only a matter of time before one of the several sustained delivery systems under investigation yields VEGF suppression for three to six months, or even longer, adds Dr. Brown. “Certainly, the patients could then be followed by OCT and clinical exams by their primary care doctors for any disease recurrence in the interim between ‘reloading’ or re-injecting the sustained formulation.”

Fickle Predictions
For drugs with such similar mechanisms of action, anti-VEGF therapies produce highly unique, patient-specific outcomes. Some respond immediately; others not at all. Initial responses sometimes fade, only to reappear when a different drug is substituted—which itself may then continue to work or weaken over time, depending on the patient. None of this seems to follow any discernible pattern.

“Currently, if I see a patient has very poor vision from wet AMD in one eye, and he or she gets the beginnings of wet AMD in the other eye, then I know to treat that patient very aggressively,” says Dr. Franklin. “But that is pretty much the only predictor we have right now: what the other eye looks like after treatment.”

With phenotypical clues lacking, genotypical ones would be welcome clinical tools, and Dr. Franklin has been active in the nascent field of AMD pharmacogenomics. “There has been linkages in terms of variable response to complement factor genes, to the ARMS2 gene, and most recently to one of the VEGF receptor genes,” he says, but larger studies are needed before definitive conclusions can be reached.

Should it prove successful, genetic testing’s potential payoffs would be enormous. “If you look at oncology, they do a lot of genetic testing to find out who’s going to respond better to what kind of treatment—so it’s not without precedent in other medical fields,” says Steven Ferrucci, OD, chief of optometry at the Sepulveda VA Ambulatory Care Center, who is preparing a lecture on the topic. “So, it seems logical to me that the genetics of macular degeneration may help guide future treatment.”

More to Come
The proven success of anti-angiogenesis therapy has spurred a large increase in experimental retinal drugs from biotech firms keen to enter a burgeoning market. Even if all the stratagems described above come to fruition, retina specialists in both optometry and ophthalmology will remain very busy for the foreseeable future.

“When I lecture, I often tell people: ‘My macular degeneration patients aren’t getting any younger and my diabetic patients aren’t getting any thinner,’” Dr. Franklin says of eye care’s ongoing workload.

But there is much cause for hope. Future breakthroughs await once again.

Mr. Celia is a freelance medical writer based in the Philadelphia area.

1. Comparison of Age-related Macular Degeneration Treatment Trials (CATT) Research Group; Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119:1388-98.
2. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Heier JS. Ophthalmology. 2012;119(12):2537-48.
3. Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal VEGF Trap. Br J Ophthalmol. 2008;92:667-8.
4. Davis BM, Normando EM, Guo L, et al. Topical delivery of Avastin to the posterior segment of the eye in vivo using annexin A5-associated liposomes. Small. 2014 Apr 24;10(8):1575-84.