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Long-term AMD management: PRN or continuous dosing?
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A number of clinical trials have established the efficacy of treating patients with choroidal neovascularization in age-related macular degeneration with anti-angiogenic therapies in a regimented, continuous dosing schedule. More recently, trials now underway are investigating the use of these agents with a PRN, or as-needed, dosing schedule. This article evaluates the evidence to date on whether a continuous dosing schedule or a PRN dosing schedule is the best approach to treating CNV in AMD.
Vascular endothelial growth factor (VEGF) is an important factor in neovascularization, for inducing and maintaining CNV and for inducing vascular permeability. This is the case for all angiographic classes of CNV, whether classic, predominantly classic, minimally classic or occult with no classic component.
Regimented dosing
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In 2004, the first ophthalmic anti-VEGF therapy, pegaptanib sodium 0.3 mg, received approval from the Food and Drug Administration. Its approval was based largely on the results of the VISION (VEGF Inhibition Study In Ocular Neovascularization) clinical trial.1
The schematic in Figure 1 summarizes the treatment effect results of the VISION trial. Participants who were treated every 6 weeks for 2 years with pegaptanib lost significantly less visual acuity than those in a control group who received usual care.
Within the VISION trial, there was a hint of the effectiveness of a PRN dosing schedule for pegaptanib. In one arm of the study, pegaptanib was discontinued after 1 year in a small subgroup. In the second cohort, pegaptanib was continued every 6 weeks for the 2-year duration of the trial. In the group for whom treatment was discontinued after 1 year, more patients lost three or more lines of vision (15 letters or more) by the 2-year time point than in the group that received continuous therapy. This result suggests that continuous VEGF inhibition with the intravitreal aptamer pegaptanib is important for continued efficacy.
In 2006, results of two phase 3 clinical trials with another anti-VEGF agent, ranibizumab 0.5 mg, were announced. Ranibizumab, a modified human anti-VEGF antibody, was approved by the FDA in 2006 for treatment of CNV in AMD.
The MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody RhuFab V2 in the Treatment of Neovascular AMD) trial included patients with minimally classic or occult CNV lesions. 2 The ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) study included patients with predominantly classic lesions. 3
The primary end point in both trials was the percentage of patients losing fewer than 15 letters on the Early Treatment Diabetic Retinopathy Study VA chart at month 12. Key secondary end points were mean change in VA over time from baseline through 1 and 2 years; percentage of patients gaining 15 or more letters of VA at 1 and 2 years compared to baseline; and mean change in CNV leakage at 1 and 2 years compared to baseline. The 2-year results of MARINA and 1-year results of ANCHOR were published in October 2006.
In the MARINA trial, 716 patients with classic or occult with no classic lesions were randomly assigned to receive sham injections or monthly injections of one of two doses of ranibizumab, 0.3 mg or 0.5 mg. Because the 0.5-mg dose was approved by the FDA, the discussion of efficacy in this article is restricted to that dose.
At the 2-year time point, for the primary study end point of relative visual stabilization (fewer than 15 letters lost), 90% of patients in the 0.5-mg group achieved that end point, compared to 52.9% in the sham group.
For the secondary end point of mean change in ETDRS VA over time, at 2 years, the control group lost a mean of 15 letters, compared to an average gain of 6.6 letters in the 0.5-mg group.
Another secondary end point was the percentage of patients who gained 15 or more letters, or three or more lines on the ETDRS VA chart, compared to baseline. At the 2-year time point, 33.8% of patients in the 0.5-mg group gained three or more lines of vision compared to only the 3.8% in the sham group.
ANCHOR was similar in design to MARINA but included eyes with predominantly classic CNV lesions. The randomization differed from MARINA in that verteporfin photodynamic therapy, which had been approved by the FDA at the time of trial enrollment, was offered in the control arm in addition to sham injection. The 423 patients were randomly assigned to sham injection or one of two doses of ranibizumab. Again, discussion in this article is limited to the commercially available dose, 0.5 mg.
In the primary efficacy end point, 96% of patients lost fewer than 15 letters of ETDRS VA at the 1-year time point, as compared to 64.3% in the PDT arm. In the secondary end point of mean change in VA, the PDT group lost 9.5 letters and the 0.5-mg ranibizumab monthly injection group gained 11.3 letters at 1 year.
For the secondary end point of gain of 15 or more letters, 40.3% of patients in the 0.5-mg group gained that amount compared to 5% in the PDT group.
| Pegaptanib (0.3 mg) Treatment Effect Compared to Usual Care  Figure 1. The results of the VISION trial showed that patients treated with pegaptanib lost less visual acuity than patients who received usual care. Image: Apte RS |
PRN dosing
The studies above suggest that, with pegaptanib or ranibizumab therapy, regimented schedules of injections can provide efficacy in treating subfoveal CNV in AMD. But what is known about a PRN dosing schedule? Several studies currently underway may help ophthalmologists to evaluate whether this type of schedule can be a viable strategy.
PIER (Phase 3b, Multi-Center, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without Classic CNV Secondary to AMD) is a study of ranibizumab injections for subfoveal CNV in AMD. The 184 patients could have had any angiographic classification of subfoveal CNV, with or without a classic component. The three groups, similar in number, received sham or one of two doses of ranibizumab. Patients received injections at baseline and months 1 and 2. Evaluation was performed at month 3. Then there were quarterly injections at months 5, 8, and 11, a primary end point analysis at the 1-year time point and continuation of the study to the 2-year time point. The 1-year data have been released, and the 2-year data are being gathered.
The same end points measured in MARINA and ANCHOR were evaluated in PIER. For mean change in VA over time (Figure 2), at 1 year, the sham group lost 16.3 letters and the ranibizumab group lost 0.2 letters. Statistically, this end point demonstrates efficacy, but the efficacy in terms of mean VA was not as good at 12 months as it was at 3 months or as good as with ANCHOR or MARINA studies at 12 months. The change in VA is in the positive direction in the 0.5-mg treatment group up to the evaluation at month 3, and then there is a slow loss of efficacy back down to near baseline at the 1-year time point. This is in contrast to the MARINA and ANCHOR results, in which the efficacy was preserved at 1 and 2 years.
For the end point of preservation of VA, 90% of patients in the 0.5-mg treatment group lost fewer than 15 letters, vs. 49% in the sham group. For the end point of 15 or more letters gained from baseline, 13% of the 0.5-mg group gained that amount vs. 10% in the sham group.
Comparing these results historically with those of the MARINA and ANCHOR trials, there seems to be a loss in the percentage of patients who gained three lines of vision in PIER. PIER suggests, therefore, that there was partial loss of efficacy due to reducing the dosing regimen from a regimented monthly regimen to a quarterly regimen after the initial three monthly injections.
Another ongoing trial, a single-center uncontrolled study called PrONTO (Prospective Optical Coherence Tomography Imaging of Patients with Neovascular AMD Treated with Intraocular Lucentis) has taken a PRN approach.4
One-year results have been announced for 40 patients with subfoveal neovascular AMD with VA of 20/40 to 20/400 at baseline. Patients received three consecutive monthly injections with the 0.5-mg dose of ranibizumab. During subsequent follow-up, repeat injections would be given if certain criteria were met: if increased central retinal thickening of 100 µm or more was seen on optical coherence tomography (OCT) imaging; if VA loss of five letters or more was seen, with recurrent subretinal fluid on OCT; or if there was new onset classic CNV, macular hemorrhage or persistent fluid seen on OCT at 1 month after injection.
The mean number of injections per patient in the first year was 5.6, which was similar to the PIER study. Only the first three injections were needed by 17.7% of patients; 20% needed one additional injection. Only 5% needed the maximum of 12 injections in the first year.
At 1 year, the results reflect those of the MARINA and ANCHOR studies. Vision was stabilized (fewer than 15 letters lost) in 95% of patients; 35% of patients gained 15 or more letters; and the mean gain in VA was 9.3 letters. Also, the mean reduction in retinal thickening as measured by OCT was 158 µm.
The two studies, PIER and PrONTO, used different strategies to reduce the number of injections per year per patient, and they had slightly different results. So, ophthalmologists remain with the question of whether a reduced dosing regimen can be as efficacious as a regular regimen.
Another ongoing trial that may address this issue is the SAILOR (Safety Assessment of Intravitreal Lucentis for AMD) trial,5 a safety study of ranibizumab that was initiated before the drug was FDA approved for neovascular AMD. The trial is expected to yield data on 5,000 patients. The protocol calls for three monthly injections of 0.5 mg ranibizumab followed by PRN injections if evidence exists of disease activity, through an increase in retinal thickness of 100 µm or more on OCT, or a loss of five or more letters on VA, along with evidence of subretinal fluid or leakage on clinical examination.
Results from the SAILOR trial should be announced in 2007, and those results should give ophthalmologists more clues as to why the outcomes of PIER and PrONTO were so different.
| Mean Change in Visual Acuity Over Time  Figure 2. In the PIER trial, patients treated with ranibizumab lost fewer early treatment diabetic retinopathy study letters than patients who received usual care. Image: Apte RS |
Other studies
Other studies employ PRN dosing not as a monotherapy but as an attempt to reduce the number of intravitreal injections needed and therefore reduce the potential for complications of those injections, whether ocular or systemic.
One such study is the BRIDGE (Bridging Industry and the National Eye Institute) study. The protocol has been changed a number of times, but the regimen is basically a combination of anecortave acetate or sham juxtascleral depot at baseline and at 6 months, combined with injection of 0.5 mg of ranibizumab at baseline and subsequently PRN based on clinical and OCT criteria of disease reactivation or persistence. Results of the BRIDGE trial are not available.
Another study in which PRN dosing is used to reduce intravitreal injections is the LEVEL (Evaluation of Efficacy and Safety in Maintaining Visual Acuity with Sequential Treatment of Neovascular AMD) trial, more commonly known as the induction-maintenance trial. In this trial, patients are initially treated with a nonselective anti-VEGF agent, ranibizumab, bevacizumab or any combination of available therapies and then maintained for the rest of the trial with pegaptanib sodium. One aim of the study is to reduce the number of injections needed from every 4 weeks to every 6 weeks. Recruitment of an expected 1,000 patients is ongoing.
Conclusion
Sustained, continuous VEGF inhibition has achieved durable efficacy in randomized, double-masked clinical trials, both with ranibizumab and pegaptanib sodium. Regarding PRN dosing, some trials suggest that it is a viable strategy and others suggest that reduced dosing regimens seem less efficacious than continuous dosing. Whether a PRN regimen can be as good as continuous dosing is yet to be demonstrated. Results from the SAILOR trial, expected this year, will help ophthalmologists understand this issue more clearly.
References
- VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, D’Amico DJ, Masonson HN, et al. 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.
- Rosenfeld PJ, Brown DM, Heier JS. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419-1431.
- 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.
- Rosenfeld PJ, Fung AE, Lawani GA, Michels S, Venkatraman AS, Puliafito CA. Visual acuity outcomes following a variable-dosing regimen for ranibizumab (Lucentis) in neovascular AMD: The PrONTO study. Presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; May 2, 2006; Fort Lauderdale, Fla.
- Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am. 2006;19:361-372.