Healio
Healio
ByRajendra S. Apte, MD, PhD
December 01, 2006
6 min read
Save

Continuous dosing vs intermittent dosing of anti-VEGF agents

ByRajendra S. Apte, MD, PhD

The efficacy of pegaptanib sodium (Macugen, [OSI] Eyetech) in the treatment of neovascular, or wet, AMD was established in the VISION trial (Vascular Endothelial Growth Factor [VEGF] Inhibition Study in Ocular Neovascularization).1 Subsequently, clinical trials including ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) and MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) showed the effectiveness of ranibizumab (Lucentis, Genentech) in not only delaying the progression of AMD but also improving visual acuity in patients with AMD.2-3 A series of nonrandomized studies demonstrate similar visual acuity improvements in patients treated with intravitreal injections of bevacizumab (Avastin, Genentech).4 Subsequent trials have been designed to explore optimal therapeutic dosing regimens that consider cost-effectiveness, convenience and compliance in addition to efficacy. One dosing consideration is the use of intermittent therapy, which will increase the dosing interval, decrease drug administration and potentially lower the incidence of adverse events, lower overall drug cost and improve patient compliance.

Continuous therapy with pegaptanib sodium is effective in managing AMD

The VISION study encompasses results from two parallel phase 3 clinical trials in which AMD patients with any angiographic choroidal neovascularization (CNV) lesion composition were randomized to receive intravitreal pegaptanib sodium 0.3 mg, 1 mg or 3 mg or sham injection every 6 weeks for 54 weeks.1 Subsequent re-randomization extended the trial for an additional 48 weeks of treatment. Pegaptanib-treated patients lost a mean 9.4 letters compared with 17 letters lost by the sham group at 2 years. Visual acuity improved by three or more lines in less than 10% of pegaptanib-treated patients. A subgroup analysis demonstrated that patients with earlier manifestations of neovascular AMD responded better than did those with more advanced forms of the disease.2 The results from this study support the efficacy of pegaptanib sodium administered as part of a continuous regimen: 0.3 mg every 6 weeks for the long-term treatment of AMD.

MARINA and ANCHOR trials evaluate continuous therapy with ranibizumab

In the double-masked MARINA study, 716 patients with AMD and minimally classic or occult lesions were randomized to receive intravitreal sham or ranibizumab 0.3 mg or 0.5 mg monthly inject-ions for 24 months.3 Ranibizumab-treated patients had mean 6.5 letter (0.3-mg group) and 7.2-letter (0.5-mg group) improvements in visual acuity compared with baseline, but patients in the sham group experienced a 10.4-letter loss at month 24 (P<.001 for both treatment groups). In addition, at least 94.5% of ranibizumab-treated patients maintained vision (defined as a loss of fewer than 15 letters); 24.8% of patients in the 0.3-mg group and 33.8% in the 0.5-mg group had improved vision (defined as a gain of more than 15 letters) compared with 62.2% of patients in the sham group (P<.001 for both treatment groups). Results from the MARINA study (Figure 1) clearly demonstrate the efficacy of continuous therapy with ranibizumab.

Figure 1: Phase 3 MARINA trial results
Figure 1: Phase 3 MARINA trial results Mean change in visual acuity over 24 months in the MARINA trial.3

The ANCHOR study was a double-masked study in which 423 patients with predominantly classic wet AMD were randomized to receive monthly intravitreal injections of ranibizumab 0.3 mg or 0.5 mg or verteporfin photo-dynamic therapy every 3 months for 2 years. 4 One-year data demonstrated mean improvements of 18 letters for patients in the 0.3-mg group and 21 letters in the 0.5-mg group compared with the PDT group; furthermore, ranibizumab-treated patients gained an average of 8.5 and 11 letters, respectively, compared with baseline. Conversely, PDT was associated with a 9.5-letter loss. Overall, 94% of patients treated with 0.3 mg and 96% of patients treated with 0.5 mg maintained or gained vision, compared with 64% of patients in the PDT group.

Collectively, these results demonstrate for the first time that anti-VEGF agents have the capability to improve vision instead of simply stabilizing the disease when administered in continuous regimens.3-4 The next step in optimizing therapy is to simplify therapy if possible.

Intermittent therapy: Does it work?

Armed with positive results from the MARINA and ANCHOR phase 3 studies, Philip J. Rosenfeld, MD, PhD, and colleagues at the Bascom Palmer Institute conducted the PrONTO study (Prospective Optical Coherence Tomograph [OCT] Imaging of Patients with Neovascular AMD Treated with Intraocular Lucentis), which evaluated a variable-dosing regimen with ranibizumab. 6 Forty patients with AMD and visual acuities ranging from 20/40 to 20/400 received three consecutive monthly injections of ranibizumab 0.5 mg. Monitoring parameters included OCT, visual acuity as measured using the Early Treatment of Diabetic Retinopathy Study eye chart and fluorescein angiography. Follow-up ranibizumab was provided to patients who developed an increase in optical coherence tomography (OCT) thickness of 100 µm or more, experienced a loss of 5 letters with recurrent fluid as measured by OCT and those who developed new onset CNV or new macular hemorrhage. After three monthly injections, mean visual acuity score improved by 10 letters (P<.001) and mean central thickness decreased by 190 µm (P<.001) compared with baseline. At month 7, the average number of retreatments per eye was 0.2 (range 3-12 by month 12). The visual acuity improvement was maintained at 9 letters (P<.001) with the mean central thickness decreasing to 158 µm (P<.001). It should be noted, however, that there was no control arm and that response to intermittent therapy was variable. Almost half of the patients studied required re-treatment within 3 months of the initial three treatments. Researchers concluded that variable dosing was associated with improvements in visual acuity and OCT measurements that were similar to those attained with regular dosing.

Figure 2: Intermittent dosing in PIER Study
Figure 2: Intermittent dosing in PIER Study Initial vision gains were lost.7

Although the results from PrONTO were seemingly positive, a ranibizumab quarterly dosing schedule examined in the PIER study (Phase 3b, Multicenter, Randomized, Double-masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization with or without CNV Secondary to AMD) did not fare as well. 7 A total of 184 patients with predominantly classic, minimally classic or occult with no classic wet AMD were randomized to receive ranibizumab 0.3 mg or 0.5 mg or sham injections once a month for 3 months followed by a single dose every 3 months for a total of 24 months. After 3 months of monthly treatment, ranibizumab-treated patients demonstrated significant increases in mean visual acuity as demonstrated by a 2.9-letter gain in the 0.3-mg group and a 4.3-letter gain in the 0.5-mg group (Figure 2). These results were comparable in magnitude to the visual acuity improvements observed in the MARINA study.3 However, after the initiation of quarterly dosing, visual acuity returned to baseline by month 12 despite anatomical improvements as measured by OCT (Figure 3). Patients in the sham group lost an average of 16.3 letters at this time point. Although direct cross-study comparisons cannot be made, the data imply that quarterly dosing with ranibizumab may not be as effective in improving visual acuity outcomes compared with monthly dosing.

Figure 3: Intermittent dosing in the PIER Study
Figure 3: Intermittent dosing in the PIER Study Vision was not recovered despite OCT improvements at month 12.7

Further attempts to optimize anti-VEGF treatment regimens have re-shifted their focus on “as needed” regimens. In the ongoing SAILOR study (Safety Assessment of Intravitreal Lucentis for AMD), up to 5,000 AMD patients with CNV are undergoing treatment with three consecutive monthly doses of ranibizumab 0.5 mg followed by ranibizumab as needed for a total of 12 months.8 According to the study protocol, increased OCT thickness (at least 10 µm) and/or decreased visual acuity (loss of 5 letters or more) are the parameters that necessitate re-dosing. A potential problem with this model is that these markers have not been confirmed as effective monitoring tools in AMD.

The BRIDGE study (Bridging Industry and the National Eye Institute) is using combination therapy as a way to potentially decrease ranibizumab dosing and obtain visual outcomes equivalent to those in the MARINA and ANCHOR studies.8 According to the most recent protocol, patients in this study will receive anecortave acetate (Retaane, Alcon) 15 mg or sham at baseline in addition to ranibizumab 0.5 mg. They will subsequently receive either sham or anecortave acetate 15 mg every 3 or 6 months. All patients will receive ranibizumab as needed throughout the study.

Although the results from PrONTO are encouraging, they have not been duplicated in a randomized, controlled trial using an intermittent anti-VEGF regimen. The outcomes of the SAILOR and BRIDGE studies are yet to come. Perhaps in practice, ophthalmologists may be able to slowly decrease the dosing interval of anti-VEGF agents in some patients with improved vision and OCT measurements; however, these patients will require careful monitoring.

References
  1. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
  2. Schwartz SD. Macugen Anti-VEGF Therapy – The VISION Trials. Presented at: American Academy of Ophthalmology 2004 Annual Meeting; October 23-26, 2004; New Orleans, La.
  3. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355(14):1419-1431.
  4. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus vertepofrin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
  5. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112(6):1035-1047.
  6. Rosenfeld PJ, Fung AE, Lalwani 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 the annual meeting of the Association for Research in Vision and Ophthalmology; May 2, 2006; Fort Lauderdale, Florida.
  7. Brown D. PIER Study Presentation [Retinal Physician Website]. July 2006. Available at: http://www.healthcareconferencegroup.com/conferences/63/pier.htm. Accessed September 18, 2006.
  8. Kaiser P. Lucentis Update [Retinal Physician Website]. July 2006. Available at: http://www.healthcareconferencegroup.com/conferences/63/pier_pk.htm. Accessed September 18, 2006.