therapeutics

Retinal Therapeutics: The Year in Review

2011 marked another busy year for this rapidly advancing field — and there's more to come, experts say.

By Frank Celia, Contributing Editor

Anti-vascular endothelial grow factor (VEGF) therapy continued its successful run this year, changing the retina sub-specialty into one of the most talked about and studied fields in medicine. In addition to FDA approval of yet another anti-VEGF agent for the treatment of age-related macular degeneration (AMD), aflibercept (Eylea, Regeneron), 2011 saw the publication of a landmark study that validated a popular off-label drug, bevacizumab (Avastin, Genentech); a Congressional hearing on retina care's soaring Medicare budget; and an endophthalmitis outbreak that made national headlines and impacted government policy.

All this occurred against a backdrop of hundreds of thousands of new patients inundating retina practices as often as once a month, plus an unremitting tide of venture capital-funded new drug trials, with all the players hoping to replicate or surpass anti-VEGF's success.

A new approval

Researchers understand that many patients using anti-VEGF medications often require transport to and from office visits, a burdensome task that frequently falls to family members, who tend to juggle work and family obligations. This, plus the obvious stresses on practice facilities and patients' wallets, have prompted researchers to seek ways to curtail the therapy's frequent injection schedule.

Eylea, previously known as VEGF Trap-Eye, which gained FDA approval last month, could accomplish this goal. In two clinical trials, researchers found Eylea injected every eight weeks was effective.

“Eylea has an [enhanced] affinity for capturing more of the VEGF proteins, in addition to related proteins like placental growth factor,” says Derek N. Cunningham, O.D., director of optometry at Dell Laser Consultants in Austin, Texas. “It's not really expected to be groundbreaking or revolutionary …, but it'll be helpful having a third option for patients unresponsive to the other two treatments.”

Although ranibizumab (Lucentis, Genentech) was originally designed for once-per-month dosage, through the years surgeons have extended regimens for some patients as far as every two months on average without significant outcome detriment. So, there is hope Eylea dosing can be safely extended further than two months, according to Alan Franklin, M.D., Ph.D., of the Retina Specialty Institute in Mobile, Ala., who has comanaged AMD cases with Dr. Cunningham in the past. “That's the big question everyone has,” he says. “Can we push VEGF Trap to every three months? Because if we just stay at two months, then it's not much better than what we were getting with Lucentis.”

CATT provides results and raises questions

Unveiled this spring, the Comparison of AMD Treatments Trial (CATT) proved Avastin as effective as Lucentis at preserving and improving visual acuity.¹ Though not powered to assess Avastin's systemic safety, the study measured adverse events as a secondary endpoint and found serious risks failed to emerge statistically among 1,200 patients after one year of treatment.

For several years, retinal subspecialists have treated patients with the off-label Avastin, a cancer drug, which is priced significantly lower than its sibling Lucentis (both are manufactured by Genentech). Though pilot studies had proven Avastin as effective, the large-scale, rigorous CATT study was greeted as a welcome validation of the popular, affordable drug.

Pioneering as it is, the data nonetheless contain caveats that have caused perhaps even greater anticipation of the CATT team's forthcoming two-year results, due for a spring 2012 release. For starters, physicians expressed surprise at the extent to which Lucentis outperformed Avastin in drying and thinning retinas. Maculas receiving Lucentis were thinner by a statically significant 32µm. Monthly Lucentis also produced the highest percentage of retinas with no trace of fluid at one year, as well as the highest percentage of retinas with no leakage seen on fluorescein angiography. Physicians worry such discrepancies — though not significant at one year — could threaten Avastin-treated eyesight over the long term.

The perception of parity achieved by CATT seemed jeopardized late this summer when a rash of infections among Avastin patients made national news.² More than a dozen patients developed endophthalmitis at around the same time in Florida, Tennessee and California, several after treatment at Veteran's Affairs (VA) hospitals. Though suspicion fell mainly on the compounding pharmacies where the shots were created, an ongoing investigation by the FDA has not ruled out the possibility of manufacturer or physician error. Moreover, the outbreak may only have been a highly regrettable statistical anomaly. Whatever the cause, the infections had a serious effect. To date, the most significant result has been the VA health system's decision to switch its clinics exclusively to Lucentis pending further investigation.

Cost concerns

The price discrepancy between Lucentis and Avastin has drawn the attention of the federal government. A Department of Health and Human Services (HHS) report estimated that between 2008 and 2009 Medicare paid $40 million for 936,382 Avastin injections and $1.1 billion for 696,927 Lucentis injections. Had physicians relied exclusively on Avastin during those years, Medicare would have saved $1.1 billion and patients pocketed $275 million in co-payments, said the report.

Government officials are keenly aware of the substantial sums of money at stake. This summer, Senator Herb Kohl (D-Wisconsin) chaired a Special Committee on Aging that focused on the CATT results and the potential cost savings of Avastin.

Though the HHS report stopped short of calling for Medicare to drop Lucentis coverage, it did ask the Centers for Medicare & Medicaid Services (CMS) to “evaluate its current authorities and seek additional authorities as necessary to control Part B drug and biological expenditures more effectively.”

Other modalities: anti-VEGF and beyond

Invasive intravitreal injections may prove as only one of several ways to administer forthcoming retinal therapeutics.

“Bevacizumab injected subconjunctivally seems to be efficiently transported into intraocular tissues,” notes Andrew S. Gurwood, O.D., professor of clinical sciences at the Pennsylvania College of Optometry at Salus University in Elkins Park, Pa. “Bevacizumab has even been shown to be distributed into the intraocular tissues of fellow eyes via a systemic circulation, adding what might be a protective effect to uninjured eyes.”

Also, recent studies show topical administration altered neovascular growth in newly forming vessels in rabbit corneas.³

“Novel uses like this may open the door for the consideration of topical administration for cases exhibiting anterior segment neovascularization where only panretinal laser photocoagulation was available before,” adds Dr. Gurwood.

Additionally, pazopanib (Votrient, GlaxoSmithKline), a small orally bioavailable tyrosine kinase inhibitor, continues to offer the potential of a topical drop for neovascular AMD. A 2011 German study revealed topical pazopanib has anti-angiogenic effects in rats.⁴

“In my mind, a topical drop therapy would be the biggest change that I have seen in my career,” says David H. Kisling, O.D., a private practitioner in Fort Collings, Colo. He says he feels confident drops will eventually make it to the market. If O.D.s could treat neovascular AMD with topical drops and monitor the patient's progress with ocular coherence tomography (OCT), it would “open up a whole new realm for us, one optometry has never been able to touch before,” says Dr. Kisling.

The opportunity would represent a “win” for both doctors and patients, says Dr. Kisling. “Ophthalmology is going to get a whole lot more referrals, and patients are going to get diagnosed and treated a whole lot earlier than they ever did,” he explains.

Raising the bar

In many patients, the early and intermediate stages of dry AMD can last for years, even decades.

“Less than 20% of these patients go on to develop the advanced form of AMD,” says Diana L. Shechtman, O.D., F.A.A.O., associate professor, Nova Southeastern University College of Optometry, Fort Lauderdale, Fla. “In the early or even moderate stage of the disease, so long as the optometrist has the capabilities and instruments, we can certainly followup [with] these patients and play a critical role in their management by making the proper nutritional supplementation recommendations and educating them about lifestyle modification.”

Dr. Shechtman continues: “I had a case just recently of an intermediate AMD patient with a history of 20/40 vision. She returned to the clinic for follow up with a BCVA of 20/50+. The OCT macular cube showed a subtle change in retinal thickness and the mild subretinal edema, and thus, we suspected the beginnings of wet AMD, which was confirmed later by fluorescein angiography. Given the early diagnosis, the patient's prognosis following treatment was excellent.”

Hence, primary eyecare exams now have a new kind of patient to diagnose, she says. “With the advent of new treatment options and diagnostic modalities, the bar has been raised. Furthermore, catching a patient with AMD and a BCVA of 20/400 is no longer acceptable.” OM

1. Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19; 364 (20):1897-908. Epub 2011 Apr 28.
2. The New York Times. Health: Avastin Injections Are Reported to Cause Blindness. www.nytimes.com/2011/08/31/health/31drug.html?_r=1&scp=1&sq=Andrew%20Pollack%20+%20Avastin%20Injections%20are%20reported%20to%20cause%20blindness&st=cse (Accessed Nov. 30, 2011.)
3. Perez-Santonia JJ, et al. Inhibition of corneal neovascularization by topical bevacizumab (Anti-VEGF) and Sunitinib (Anti-VEGF and Anti-PDGF) in an animal model. Am J Ophthalmol. 2010 Oct; 150(4):519-528.
4. Yafai Y, et al. Anti-angiogenic effects of the receptor tyrosine kinase inhibitor, pazopanib, on choroidal neovascularization in rats. Eur J Pharmacol. 2011 Sep;666(1-3):12-18.