Many posters and papers presented at this years ARVO meeting discussed the safety and efficacy of anti-VEGF therapyparticularly Avastin (bevacizumab, Genentech)for a variety of purposes. Others involved anti-VEGF therapy in combination with photodynamic therapy. Researchers also discussed anti-VEGF therapy in a topical drop, new predictive data from the Age-Related Eye Disease Study (AREDS) and the use of spectral domain ocular coherence tomography (SD-OCT) for retinal imaging.

 

Anti-VEGF Safety, Frequency

Controversy has been brewing over the off-label use of Avastin for the treatment of age-related macular degeneration (AMD). First, the manufacturer threatened to limit the supply of Avastin for off-label use. Then, after outcries from ophthalmic surgeons, retinal specialists and at least one senator, Genentech reversed that decision. But, the company continued to recommend its other anti-VEGF product, Lucentis (ranibizumab), because it is specifically designed, FDA approved and manufactured for intraocular delivery for the treatment of wet AMD.

Several presentations this year provided research on the use of Avastin in comparison to Lucentis.

Researchers at the Indiana School of Medicine retrospectively reviewed 50 eyes treated with Avastin and 25 eyes treated with Lucentis for neovascular AMD, to compare systemic and ocular complications.316/D637

Acuity generally improved in both groups, although there was no statistical difference in acuity change between the two groups. Both demonstrated significant decreases in central foveal thickness, but again, there was no statistical difference between the two. No intraocular or systemic complications were reported in either group. Researchers concluded that intravitreal Avastin is as safe as Lucentis for the treatment of wet AMD, though a large clinical trial is needed to confirm these findings.

Given that Lucentis is safe and approved for the treatment of neovascular AMD, how frequently should it be administered?

Researchers in Switzerland evaluated data from three large Phase III, randomized, double-masked trials to compare gains in visual acuity (VA) with monthly vs. quarterly injections of 0.5mg of Lucentis.2883 In MARINA, 716 patients were treated monthly for two years. In ANCHOR, 423 patients were treated monthly with Lucentis or quarterly with verteporfin photodynamic therapy (PDT) for two years. In PIER, 184 patients were treated monthly with Lucentis for three months and then once every three months for two years.

Monthly treatment resulted in greater gains than quarterly treatment; 33% of MARINA patients and 41% of ANCHOR patients gained 15 or more letters after two years, compared with 8% of PIER patients. But, the proportion of VA gain was maintained over two years of treatment in all three trials.

 

Lucentis + PDT

Research has shown that Lucentis with PDT results in better visual outcomes for AMD patients than PDT alone. But, is Lucentis with PDT better than Lucentis alone?

Different presentations investigated this questionand they didnt exactly agree. New York researchers took data from several studies (ANCHOR, MARINA, FOCUS, TAP and VIP) and confirmed that Lucentis combined with PDT is better than PDT alone, but that Lucentis alone leads to better VA scores.1171 Randomized controlled studies of Lucentis vs. Lucentis plus PDT are warranted, they say.

To that end, researchers from Switzerland and Austria presented results from a one-year, phase III, randomized, double-masked study of Lucentis 0.3mg vs. Lucentis 0.3mg and verteporfin PDT.1170 Acuity improved in both groups; however, the combination group had slightly less improvement. Both showed reduced central retinal thickness, intraretinal edema and subretinal fluid, but pigment epithelial detachment was increased in the monotherapy group and decreased in the combination group. Also, the combination therapy may reduce lesions better, resulting in less retreatment.

Researchers at the University of West Virginia also found that Lucentis and PDT combined was more efficient in reducing re-treatments.560/A528 Eyes with poor early closure of choroidal neovascularization (CNV) lost an average of five letters of vision after the second and third injections. But, eyes that had progressively better early closure of CNV gained an average of 23 letters. This could provide an early way to predict which eyes may not respond to Lucentis monotherapy.

Triple Therapy

If PDT plus an anti-VEGF agent is good, is adding another therapy even better? Such appears to be the case when dexamethasone is added to verteporfin PDT and Avastin. Researchers in Germany observed 104 patients given one cycle of triple therapy.1167 Acuity improved an average of 1.78 lines, and retinal thickness decreased an average of 171m. Triple therapy offers a good safety profile and potentially lower cost to patients with CNV secondary to AMD, researchers concluded.

 

Anti-VEGF in a Drop?

A topical anti-edema, anti-angiogenic kinase inhibitor is being studied to target CNV in AMD patients.3771 Administration in rodents achieved therapeutic levels in the posterior pole. A Phase I study in humans showed no toxicity in twice-a-day instillation for two weeks, and a Phase II study is underway.

 

New AREDS Data

AREDS researchers reviewed 10 years worth of data to create probability estimates of progression to neovascular AMD and central geographic atrophy (CGA).5065 They reviewed the data of 4,642 participants of AREDS, and they constructed a 10-year risk model to estimate the probability of progression to neovascular AMD or GCA. Researchers accounted for age, gender, smoking status and treatment. For example, the probability of progression of a male non-smoker, aged 55 to 84 years, with advanced AMD in the fellow eye, on placebo therapy, is 42.3%. By comparison, the risk for a similar participant on active treatment is 35.4%. These estimations may be useful in discussing risks with patients, the researchers concluded. 

In other AREDS research, investigators questioned if statins are associated with a greater risk for devel- oping neovascular AMD.3772 In a cohort of 1,266 participants, they found statin use to be associated with advanced AMD development; but, researchers noted that previous studies found inconsistent associations with cardiovascular risk factors.

New AREDS Data: 10-Year Risk of AMD Progression 5065
	% with event at 10 years
Baseline Drusen Status	Neovascular AMD	GCA	Advanced AMD
Small or no drusen O.U.	1.1%	0.1%	1.21%
Intermediate drusen in one eye.	3.1%	0.5%	3.6%
Intermediate drusen O.U.	9.4%	2.4%	11.6%
Large drusen in one eye.	9.7%	3.1%	12.4%
Large drusen O.U.	30.9%	9.3%	35.8%
Advanced AMD in fellow eye.	38.8%	23.1%	53.1%

Other Avastin Applications

Chicago researchers retrospectively analyized 75 eyes given intravitreal injections of Avastin.2736/A517 Patients had proliferative diabetic retinopathy with vitreous hemorrhage and/or iris neovascularization that was not amenable to panretinal photocoagulation. Eleven eyes received a second Avastin injection. Neovascularization improved in 97% of eyes. Hemorrhage improved in 85%, which then allowed panretinal photocoagulation. No adverse events were seen during follow-up.

Avastin has also been used to treat cases of macular edema due to central retinal vein occlusion or branch retinal vein occlusion (BRVO). Researchers in Germany retrospectively studied 48 eyes treated with an average of 2.18 Avastin injections.2709/A490 Edema decreased and VA improved, and average macular retinal thickness decreased from 497m to 379m. Average VA improved from 20/125 to 20/100; 15 patients gained more than three lines of vision. But, seven patients got worse; most of these had an ischemic retinal vein occlusion.

Retinal Imaging

The advantages of SD-OCT over standard time domain OCT are faster speed, better registration and higher resolution. So, SD-OCT is preferred for use in infants and children. But, the instrument is just too big. So, researchers at Duke University customized a hand-held system for infant imaging.5044 Researchers note its use in the assessment, management and documentation of shaken baby syndrome.

Researchers in Austria compared two SD-OCT systems by scanning 10 patients with AMD, 10 patients with BRVO, and 10 patients with central serous chorioretinitis.928/D758 Both SD-OCT systems enabled better differentiation of details and retinal layers compared with radial scans of time domain OCT.

Dr. Dunbar is director of optometric services and optometry residency supervisor at Bascom Palmer Eye Institute, in Miami, and is the author of Reviews Retina Quiz.

 

316/D637. Cosgrove FM, Province W, Peracha MO, Gao H. Comparison of intravitreal bevacizumab vs. ranibizumab for neovascular age-related macular degeneration (AMD).

2883. Wolf S. Visual acuity gain with ranibizumab therapy: Two-year data from the MARINA, ANCHOR, and PIER trials in patients with neovascular AMD.

1171. Del Priore LV, Shah AR. Combination therapy of ranibizumab + PDT is not superior to ranibizumab alone: A meta analysis using Lineweaver-Burke plots.

1170. Hatz KB, Schneider U, Sacu S, et al. Randomized double-masked study comparing ranibzumab monotherapy and PDT combined with ranibizumab in patients with exudative AMD: BCVA and morphological results.

560/A528. Jabbour NM, Odom JV. Comparison of treatment using intravitreal ranibizumab alone with combination treatment using intravitreal ranibizumab and verteporfin photodynamic therapy in neovascular age-related macular degeneration.

1167. Augustin AJ, Offermann I. Triple therapy for the treatment of wet AMD.

3771. Freeman WR, Leese P, Khan J, et al. A topical (eye drop) multi-kinase inhibitor for treatment of choroidal neovascularization in age-related macular degeneration: rationale and results of early clinical trials.

5065. Chew EW, Cohen G, Clemons T, Milton R, AREDS Research Group. Ten-year estimated progression rates to neovascular AMD and central geographic atrophy from AREDS.

3772. Cukras CA, Agron E, SanGiovanni JP, et al. The use of statins and the development of AMD in AREDS.

2736/A517. Tsai PL, Riaz KM, Kamat KK, et al. Efficacy of intravitreal bevacizumab (Avastin) in patients with proliferative diabetic retinopathy.

2709/A490. Kraus J, Gamulescu M, Helbig H. Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to retinal vein occlusion.

5044. Scott AW, Farsiu S, Toth CA. Novel techniques to evaluate the infant retina with portable handheld spectral domain optical coherence tomography.
928/D758. Sayegh RG, Ahlers C, Golbaz I, et al. Three-dimensional analysis of macular edema using two different spectral domain OCT systems.