anti-VEGF

Anti-VEGF Therapies and Retinal Disease

A look at how anti-VEGF therapy is shaping the management of AMD and other retinal diseases. Also, what advances lie beyond this therapy?

Frank Celia, Contributing Editor

Just a decade ago, many ophthalmologists specializing in retinal care measured the success of a therapy by whether their patients could differentiate light from dark.

Now, thanks largely to therapies that inhibit vascular endothelial growth factor (VEGF), this is no longer so. Today, a majority of patients with debilitating conditions, such as age-related macular degeneration (AMD) can expect disease control, and a significant portion will regain vision.

How popular have anti-VEGF therapies become since their introduction six years ago? According to the 2009 American Society of Retina Specialists “2009 Practices and Trends (PAT) Survey,” 91% of respondents manage wet AMD patients with anti-VEGF therapies. About 76% of doctors begin treatment with monthly anti-VEGF injections for three-to-four months, followed by treatment based on lesion activity and size. The other 15% of the respondents begin treatment with a single anti-VEGF injection, and then continue the injection based on lesion activity and size.

Although optometrists don't administer these drugs, they do help patients prepare for when retinal sub-specialists take over. During such cases, O.D.s also provide refractive solutions and observation. It's possible that optometry may soon play a greater role in the treatment of anti-VEGF patients with so-called “treat-and-extend” strategies, perhaps involving topical drops, sustained-release modalities or a combination of both (See “Are Topical Drops Imminent?” below.)

This article, drawn largely from material at the Retina Subspecialty Day at this year's American Academy of Ophthalmology (AAO) meeting, presents an overview of these drugs’ impact on eye care as well as a partial catalog of treatments and modalities in the pipeline.

Breakthrough treatment

The Food and Drug Adminstration (FDA) approved the curtain-raising drug pegaptanib (Macugen, Eyetech) for treating neovascular AMD in 2004. Ranibizumab (Lucentis, Genentech) was approved for AMD in 2006.

Yielding better outcomes, Lucentis quickly became the gold standard, with Macugen playing a secondary role. However, with a mechanism of action almost identical to Lucentis, bevacizumab (Avastin, Genentech), a cancer drug, arose as a popular off-label alternative to Lucentis.

Money concerns have driven this off-label usage: Lucentis costs about $2,000 a dose; Avastin costs about $50. Some insurers cover Lucentis, but others are reluctant; consequently, many retinal sub-specialists circumvent reimbursement uncertainties by favoring the less expensive drug.

Clinically and anecdotally, Lucentis has shown slightly better outcomes, but not enough to be statistically significant or to cause unease about the use of the off-label drug. Clinicians were initially concerned that Avastin — designed for systemic use — might pose risks, but no major adverse side effects have been detected. Retinal experts consider the drugs more or less evenly matched. (This could change, however, when results of the Comparison of AMD Treatments Trials: Lucentis-Avastin [CATT], become public in early 2011.)

“Patients occasionally ask me about Avastin vs. Lucentis for wet AMD,” says Joseph J. Pizzimenti, O.D., F.A.A.O., an associate professor at the College of Optometry at Nova Southeastern University in Ft. Lauderdale, Fla. and CEO of optometryboardcertified.com. “Much of (the decision) comes down to the patients’ health insurance status. Of course, we tell them that one treatment (Lucentis) is FDA-approved for wet AMD and the other is not. We don't currently have enough evidence to indicate that one is superior to the other.”

Dr. Pizzimenti says patients will likely be given the choice (by their retinal physician) and asked to sign an “informed consent” agreement if they choose Avastin over Lucentis.

Outcomes tend to be favorable with either Lucentis or Avastin. Presentations at this year's AAO meeting showed roughly 80% of treated AMD patients become stable, with 70% experiencing some degree of visual gain. About 30% to 40% of patients will achieve significant visual recovery, with “significant” being three lines of vision or better.

Beyond AMD

Such positive results sent investigators racing to test anti-VEGF therapy on other vascular retinal disorders, including:

► Diabetic macular edema (DME)
► Macular edema secondary to retinal venous occlusions (RVO)
► Choroidal neovascularization from non-AMD causes, such as degenerative myopia and angioid streaks
► Neovascular glaucoma
► Central serous chorioretinopathy

Conditions gaining the most recent attention are DME and RVO.

Regarding DME, several studies revealed that anti-VEGF therapy was effective at improving visual acuity in patients with this form of diabetic retinopathy. The READ-2, RESTORE trials, and results released by the Diabetic Retinopathy Clinical Research Network (http://drcrnet.jaeb.org) found Lucentis yielded better results than laser therapy alone, the previously care standard.^1,2 The RESTORE study showed that patients treated with Lucentis plus laser therapy regained 5.9 letters of visual acuity, and those treated with Lucentis alone gained 6.1 letters. By contrast, patients receiving only laser therapy gained 0.8 letters.²

Regarding RVO, Lucentis received FDA approval for this condition in summer 2010. The landmark BRAVO and CRUISE studies revealed that after six months of ranibizumab therapy, 55% to 61% of patients with branch retinal vein occlusion (BRVO) gained at least three lines of visual acuity, and about 47% of patients with central retinal vein occlusion (CRVO) gained at least three lines of visual acuity.^3,4 These results were particularly welcome because much RVO treatment has involved waiting to see whether the disease would resolve on its own. In fact, until anti-VEGF therapy, in CRVO — 20% of all RVO cases — no agreed-upon treatment existed.

Educating anxious patients

When educating patients about retinal disease, optometrists often must address a patient's anxieties regarding intravitreal injections.

“Patients are understandably uneasy about having a needle stuck in their eye,” Steven Ferrucci, O.D., F.A.A.O., chief of optometry at Sepulveda VA Ambulatory Care Center & Nursing Home, in Sepulveda, Calif., says. “It sounds horrible. But I tell them it sounds worse than it actually is. I've overheard experienced patients telling new ones in my waiting room that this is the case.”

Nevertheless, the monthly schedule of intravitreal injections can be burdensome to practitioners and patients, so a chief goal of experimental drugs is reduced dosage or a combination therapy with fewer injections. So far, injections of Avastin and Lucentis less than once a month appear to affect outcomes negatively, as does a six-month delay between diagnosis and treatment outset.⁵

Earlier this year, reports arose warning that anti-VEGF drugs might cause a very brief spike in intraocular pressure (IOP) immediately following injection, but this appeared not to be a widespread concern.

“We were really in tune with that [potential IOP spikes],” notes Dr. Ferrucci, who co-manages many AMD cases. “We checked IOPs immediately after every injection. But we did not find this to be a problem.”

Patients should know that 20% of them will be nonresponders or underresponders to anti-VEGF injections. That's when surgeons usually fall back on older strategies, such as thermal lasers, photodynamic therapy, anti-inflammatory drugs or some combination. No wide-spread agreement exists on what combination therapies work best.

Early detection

Anti-VEGF therapy has underscored the importance of early detection, as even brief delays in starting treatment can negatively affect visual outcomes.

The most prominent technology associated with the conditions discussed has been ocular coherence tomography (OCT), which has rivaled fluorescein angiography (FA) as the primary progress-tracking tool. OCT scans are quicker and less invasive. Many clinical trials in this field typically include OCT devices for tracking progress.

Although still widely distributed to at-risk patients, Amsler grids have also been eclipsed by new diagnostic devices. Preferential hyperacuity perimetry (PHP), for example, is a test designed to detect early conversion from nonexudative (“dry”) AMD to the neovascular (“wet”) form of the disease. Patients use a touch screen to identify flashing dots that have a deviating signal on distinct areas of the macula. Two such devices, the Foresee PHP (Reichert) and the PreView PHP (Carl Zeiss), are available.

Low macular pigment optical density (MPOD) may be associated with increased AMD risk. Heterochromatic flicker photometry (HFP) is a structural test that screens for low MPOD. It uses flickering blue and green light targets to yield an MPOD measurement in density units (du). Two versions of this technology exist: QuantifEYE (ZeaVision) and MacuScope (Marco).

Practices aiming to heighten their medical eyecare profile often start by acquiring one of these new diagnostic devices, optometrists say.

Retina beyond anti-VEGF

Anti-VEGF therapies’ success has galvanized drug manufacturers’ efforts to provide other treatments to supplant current drugs, or work with them to produce better outcomes. A vast mosaic of potential drugs and modalities is under development, some targeting vascular components of choroidal neovascularization, with others targeting extra-vascular components, too. Also, sources say that the makers of Lucentis and Macugen have sustained-release versions in the works. Other highlights follow.

► VEGF-Trap. Perhaps the most prominent drug in development, VEGF-Trap-Eye (Regeneron/Bayer), an anti-VEGF agent, may have more sustained effects than approved therapies. In a Phase 2 clinical study, 71% of patients experienced no vision loss progression or gained vision; and 30% gained three lines of vision or better, according to materials presented at the AAO meeting. Phase 3 studies will evaluate 4- and 8-week dosing schedules against Lucentis administered every four weeks.

► KH902. Another anti-VEGF agent, KH902 (Chengdu Kanghong Biotech), was well tolerated by human patients, 57% of whom gained three lines of vision or better. A study is evaluating once-every-two-month dosing.

► Gene therapy. The concept of viral vector therapy delivery holds great promise. In animal models, gene expression levels that impact VEGF production persist for a year in some cases. One company (Genzyme) has engineered an anti-VEGF protein that can be delivered by the adeno-associated virus (AAV) gene therapy vector.

► Radiation therapy. When zapped with the right amount of radiation, cells often lose the ability to replicate, but without undergoing necrosis. This could offer a noninvasive way to inhibit cells that promote choroidal neovascularization. In one such modality, a radiation source placed temporarily in the vitreous cavity delivers a controlled dose of radiation to the target tissue. (EpiRad, NeoVista).

► Anti-complement factors. The complement activation cascade can trigger local inflammation, tissue damage and up-regulation of angiogenic factors, such as VEGF. Complement factor inhibitors, such as POT-4 (Potentia Pharmaceuticals), might help slow this process in the eye.

► Fenretinide (RT-101). In a Phase 2 study, once-daily oral dosing of fenretinide (ReVision Therapeutics) has reduced neovascularization by about 50% in patients who have geographic atrophy (GA). This drug inhibits production of a toxin byproduct of vitamin A.

Some experts believe one or some of the therapies above might be combined with existing anti-VEGF agents to improve outcomes and/or reduce dosing schedules.

“The future might include several treatments up front to calm the disease down, then followed by some sort of eye drops or sustained-release injections,” says Jeffrey D. Gerson, O.D., F.A.A.O., of WestGlen Eyecare & Omni Eye Center of Kansas City, Mo. “VEGF-trap might be part of the answer.”

Dr. Gerson says he doesn't believe current anti-VEGF treatments will stand alone:

“The treatments might create an initial improvement, and then we'll maintain that improvement with another modality.”

All in all, advances in treatment have made it a much brighter future for your patients who suffer from sight-threatening retinal disease. OM

1. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in Diabetes (READ-2) study. Ophthalmology. Nov;117(11):2146-51.
2. Lang G. on behalf of the RESTORE study group. Safety and efficacy of ranibizumab as monotherapy or adjunctive to laser photocoagulation in diabetic macular edema: 12-month results of the RESTORE study. Late-breaker presentation at EASDec Meeting. May 22, 2010.
3. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010 Jun;117(6):1102-1112.
4. Brown DM, et al. Ranibizumab for macular edema following central retinal vein occlusion: six month primary end point results of a phase III study. Ophthalmology. 2010 Jun;117(6):1124-1133.
5. Regillo CD, Brown DM, Abraham P, et al. on behalf of the PIER Study Group: Randomized, double-masked, sham controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 1. Am J Ophthalmol. 2008;145:239-248.