A Year After Ranibizumab

Current efforts aim at building on the progress that has already been achieved.

INGRID U. SCOTT, M.D., M.P.H.

The approval of ranibizumab (Lucentis, Genentech), a pan-VEGF (vascular endothelial growth factor) inhibitor in June 2006 was hailed as a milestone event in the treatment of retinal disease and was greeted with great enthusiasm by both retina specialists and their patients. It marked the first time that retina specialists had at their disposal an approved treatment option for exudative age-related macular degeneration (AMD) which, in two pivotal phase 3 randomized controlled clinical trials (the MARINA and ANCHOR studies), was associated with visual improvement in about one-third of patients.^1,2

Many Questions Remain

Now, little more than 1 year after ranibizumab approval, however, many (if not most) retina specialists may not be managing their patients with exudative AMD according to the treatment protocol that led to the level 1 evidence supporting ranibizumab's use, and many questions regarding AMD treatment remain:

► Can we achieve the same efficacy results but reduce the frequency of intravitreal injections?
► Can we achieve the same results using off-label intravitreal bevacizumab (Avastin, Genentech) injections?
► Are there systemic and/or ocular safety differences among the various anti-VEGF agents currently being used intravitreally to treat AMD (pegaptanib [Macugen, OSI Pharmaceuticals], ranibizumab, bevacizumab)?
► What is the role of photodynamic therapy (PDT, Visudyne, QLT/Novartis) in the management of AMD?
► Are there combination treatment strategies that may offer greater advantages in terms of efficacy, safety and/or cost-effectiveness?

Additional Ranibizumab Studies

In both of the ranibizumab clinical trials^1,2 that supported the drug's approval by the Food and Drug Administration (the MARINA and the ANCHOR studies), ranibizumab was administered as an intravitreal injection into the study eye every month. In an effort to reduce the treatment burden and risks associated with monthly intravitreal ranibizumab injections, the PIER study was designed to investigate an alternative dosing regimen: three monthly intravitreal ranibizumab injections followed by one intravitreal ranibizumab injection every 3 months. Unfortunately, in the latter study, only 13% of treated patients achieved a greater than three-line gain in visual acuity (VA) at 1 year compared to 10% of control patients treated with sham injections.

A variable-dosing regimen (commonly known as the PrONTO study) has been reported in which patients received three consecutive monthly intravitreal ranibizumab injections followed by monthly visits, at which time retreatment was performed if one of the following changes was observed between visits: a loss of five letters in VA (refracted) in conjunction with fluid in the macula as detected by optical coherence tomography (OCT); an increase in OCT central retinal thickness of >100 μm; new-onset classic choroidal neovascularization (CNV); new macular hemorrhage or persistent macular fluid detected by OCT at least 1 month after the previous injection of ranibizumab.³ The efficacy results of this study at 1 year were similar to those of the MARINA and ANCHOR studies. In the PrONTO study, 33 of the 40 patients were reinjected with intravitreal ranibizumab (56% of these were reinjected within 3 months), and the average number of injections was 5.6. Of note, the PrONTO study was an open-label study that included 40 patients and had no control group. In addition, the treatment protocol required monthly office visits, OCT testing and visual acuity refractions.

Combination Therapies

Combination VEGF-inhibitor treatment strategies for exudative AMD have also been reported.^4-7 The rationale for this is to achieve the initial visual gains associated with pan-VEGF therapy, and then to maintain those results using, for example, isoform-specific pegaptanib⁸ (an anti-VEGF₁₆₅ aptamer). Pegaptanib may offer safety advantages due to its selectivity and it is a drug which, according to its labeled indication of exudative AMD, is injected intravitreally every 6 weeks rather than every 4 weeks as is indicated for ranibizumab.

A prospective study of 20 eyes treated with intravitreal bevacizumab induction followed by pegaptanib maintenance (with fluorescein angiography [FA]-guided retreatment with bevacizumab) demonstrated that at 1 year, the mean improvement in visual acuity was 2.4 Snellen lines, with 95% of eyes gaining at least 1 line of vision.⁴ In another study, 21 patients were treated with three monthly intravitreal ranibizumab injections followed by two maintenance injections of pegaptanib given 6 weeks apart.⁵ At 6 months, VA improved a mean of three lines, with 57% of patients having received a ranibizumab booster based on OCT criteria. In another series of patients, 88 patients were treated with intravitreal bevacizumab induction followed by pegaptanib maintenance; in this study, a gain in VA of more than three lines was achieved by 33% of patients, with mean acuity improving from 43.8 to 49.2 letters.⁶ Currently, the LEVEL study is evaluating the ability of pegaptanib to maintain initial visual gains provided by one to three previous AMD treatments.⁷

PDT and Anti-VEGF

Another combination treatment strategy currently being investigated is PDT combined with anti-VEGF therapy. The rationale for this is that PDT has been demonstrated to have the ability to close mature blood vessels, while anti-VEGF agents are believed to inhibit growth of new blood vessels but not affect existing mature pathological vessels.⁹ In addition, PDT has been reported to upregulate endogenous VEGF¹⁰ and inflammatory mediators,¹¹ which may contribute to angiogenesis and abnormal vascular permeability.

In a retrospective series of 24 eyes with juxtafoveal or subfoveal choroidal neovascularization associated with AMD, patients were treated with PDT and intravitreal bevacizumab (both treatments within a 14-day interval), with the need for retreatment based on persistent subretinal fluid on OCT or leakage on FA.¹² All retreatments consisted of combined PDT and intravitreal bevacizumab.

At the 7-month follow-up, 20 (83%) patients had stabilization of VA and 16 (67%) had improved VA (mean VA improvement was 2.04 lines), with no retreatment needed for 15 (63%) of eyes. Eight (33%) eyes were retreated with PDT and intravitreal bevacizumab, and 1 (4%) eye received two retreatments.

The DENALI study, a prospective, randomized clinical trial, is currently underway to compare standard fluence PDT plus intravitreal ranibizumab vs. half-fluence PDT plus intravitreal ranibizumab vs. intravitreal ranibizumab alone.

Triple Therapy Studies

Triple therapy refers to combined PDT/anti-VEGF therapy with an added steroid. The rationale for this strategy is that AMD has an inflammatory component as well as a vascular component,¹³ and the steroid may prevent PDT-induced upregulation of inflammatory factors.

In a prospective case series including 104 patients treated with reduced fluence PDT (42 joules/cm2 accomplished by a light delivery time of 70 seconds) followed 16 hours later by dexamethasone (800 μg) and bevacizumab (1.5 mg) injected intravitreally, five patients received a second triple treatment due to persistent CNV activity; 18 patients received an additional intravitreal injection of bevacizumab.¹⁴

With a mean follow-up of 40 weeks (with a range of 22 to 60 weeks), VA improved by a mean of 1.8 lines. Triple therapy is being investigated in ongoing randomized controlled clinical trials. The RADICAL study is currently enrolling patients randomized to one of the following four treatment arms for first-line treatment of exudative AMD:

► one-half fluence PDT plus intravitreal ranibizumab plus intravitreal dexamethasone
► one-quarter fluence PDT plus intravitreal ranibizumab plus intravitreal dexamethasone
► one-half fluence PDT plus intravitreal ranibizumab
► intravitreal ranibizumab alone.

The TAPER Study is currently enrolling patients considered to have failed previous treatment with intravitreal ranibizumab or intravitreal bevacizumab into one of the following two treatment arms: 1) one-half fluence PDT plus intravitreal ranibizumab plus intravitreal dexamethasone or 2) intravitreal ranibizumab alone (p.r.n. dosing).

Little more than 1 year after ranibizumab approval, there is hope for visual improvement for a substantial minority of patients with exudative AMD, and visual stabilization (within three lines of vision) is an achievable goal for most patients treated according to guidelines established by phase 3 clinical trials.

However, the optimal treatment regimen, one that maximizes efficacy while minimizing risks and treatment burden, is still unknown. In addition, the search continues for a treatment that may be associated with visual improvement in a greater proportion of patients with exudative AMD and a treatment (in addition to vitamin supplementation) for patients with nonexudative AMD. OM

References

1. Rosenfeld, PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432-1444.
3. Fung AE, Lalwani G, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J Ophthalmol. 2007;143:566-583.
4. Hughes MS, Sang DN. Safety and efficacy of intravitreal bevacizumab followed by pegaptanib maintenance as a treatment regimen for age-related macular degeneration. Ophth Surg Laser Imaging. 2006;37:446-454.
5. Sang DN, Hughes MS, Chin C. Induction/maintenance therapy with ranibizumab (Lucentis) followed by pegaptanib (Macugen) intravitreal injections in the treatment of age-related macular degeneration. Inves Ophthalmol Vis Sci. 2007;48 [ARVO e-abstract] nr. 1795.
6. Barnes CH. Efficacy and safety of intravitreal (IVT) bevacizumab induction and pegaptanib sodium maintenance in patients with neovascular age-related macular degeneration (NV-AMD). Invest Ophthalmol Vis Sci. 2007;48 [ARVO e-abstract] nr. 3371.
7. Friberg TR, LEVEL Study Group. Evaluation of efficacy and safety in maintaining visual acuity with sequential treatment of neovascular AMD: The LEVEL study. Invest Ophthalmol Vis Sci. 2007;48 [ARVO e-abstract] nr. 4568.
8. VEGF Inhibition Study in Ocular Neovascularization (VISION) Trial Group. Pegaptanib sodium for neovascular age-related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006;113:992-1001.
9. Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina. 2005;25:111-118.
10. Tatar O, Adam A, Shinoda K, et al. Expression of VEGF and PEDF in choroidal neovascular membranes following verteporfin photodynamic therapy. Am J Ophthalmol. 2006;142:95-104.
11. Visudyne [package insert]. East Hanover, N.J.: Novartis Pharmaceuticals Corp., 2005.
12. Dhalla MS, Shah GK, Blinder KJ, et al. Combined photodynamic therapy with verteporfin and intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration. Retina. 2006;26:988-993.
13. Spaide RF. Rationale for combination therapies therapies for choroidal neovascularization. Am J Ophthalmol. 2006;141:149-156.
14. Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration. Verteporfin PDT, bevacizumab, and dexamethasone. Retina. 2007;27:133-140.

Ingrid U. Scott, M.D., M.P.H., is professor of ophthalmology and public health sciences at the Pennsylvania State University College of Medicine. She is a consultant to Genentech, OSI/Eyetech and Pfizer. She can be reached via e-mail at iscott@psu.edu.