Alternative Anti-VEGF Treatment Regimens in Exudative Age-related Macular Degeneration

Robert B Bhisitkul; Jay M Stewart

Expert Rev Ophthalmol. 2010;5(6):799-809.

Clinical Trial Evidence

Standard Dosing

MARINA and ANCHOR, two pivotal Phase III multicenter randomized, controlled clinical trials of intravitreal ranibizumab monotherapy, have established and quantified the therapeutic benefit associated with the continuous monthly injection regimen (Table 1). In both the MARINA trial of 716 patients with minimally classic and occult CNV^[3] and the ANCHOR trial of 423 patients with predominantly classic CNV,^[1] patients assigned to the ranibizumab treatment arms received monthly intravitreal injections (0.3 or 0.5 mg) for 2 years for a mean number of 21.9 and 21.4 injections per patient, respectively. At 12 months, patients in MARINA had a mean increase in visual acuity (VA) of 6.5 and 7.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the 0.3 and 0.5 mg ranibizumab cohorts, respectively, compared with a mean decrease of 10.4 letters in the sham cohort. In ANCHOR, at 12 months patients had a mean increase in VA of 8.5 and 11.3 letters in the 0.3 and 0.5 mg ranibizumab cohorts, respectively, compared with a mean decrease of 9.5 letters in the PDT cohort. In both MARINA and ANCHOR, visual function improvement was sustained through 24 months: at this time point, patients in MARINA had mean increases in VA of 5.4 and 6.6 letters in the 0.3 and 0.5 mg ranibizumab cohorts, respectively, compared with a decrease of 14.9 letters in the sham cohort. Patients in ANCHOR achieved a mean increase in VA of 8.1 and 10.7 letters in the 0.3 and 0.5 mg ranibizumab cohorts, respectively, compared with a decrease of 9.8 letters in patients receiving verteporfin PDT.

Variable Dosing

Six clinical studies (A Study of rhuFAB V2 [Ranibizumab] in Subjects with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration [PIER], Prospective Optical Coherence Tomography Imaging of Patients With Neovascular AMD Treated With Intra-Ocular Ranibizumab [Lucentis] [PrONTO], An Extension Study to Evaluate the Safety and Tolerability of Ranibizumab in Subjects with Choroidal Neovascularization Secondary to AMD or Macular Edema Secondary to RVO [HORIZON], A Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization [CNV] Secondary to Age-Related Macular Degeneration [SAILOR], Efficacy and Safety of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration [EXCITE], and Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration [SUSTAIN]) have evaluated the safety and efficacy of variable dosing of ranibizumab monotherapy (Table 1). Whereas the PIER and EXCITE studies used a variable regimen of fixed dosing intervals, the PrONTO, HORIZON, SUSTAIN and SAILOR studies used a PRN regimen (each with different protocols and retreatment criteria).

PIER was a Phase IIIb multicenter, double-masked, sham injection-controlled trial using a fixed variable injection protocol, in which AMD patients (n = 184) with predominantly or minimally classic, or occult (with no classic), CNV lesions were randomized to receive intravitreal ranibizumab (0.3 or 0.5 mg) or sham injections monthly for the first 3 months, followed by injections every 3 months.^[8] This alternative dosing regimen was selected based on earlier Phase I and II studies showing that the clinical effect of ranibizumab (0.3 and 0.5 mg) may last for 90 days.^[25,26] During the initial monthly injection phase, patients receiving ranibizumab showed a mean improvement in VA by the third month; however, in the subsequent phase of fixed quarterly injections, the mean VA declined to less than baseline VA at 12 months so that the overall mean change in VA was a decrease of 1.6 and 0.2 letters in the 0.3 and 0.5 mg ranibizumab cohorts, respectively, compared with a loss of 16.3 letters in the sham-injected cohort (p ≤ 0.0001). Although VA outcomes were statistically better with ranibizumab than with control injections, the visual outcomes were not as robust as those reported with continuous monthly ranibizumab therapy in the MARINA and ANCHOR trials.

The results of the investigator-sponsored PrONTO study, a Phase I/II prospective, open-label 2-year trial (n = 40 patients), have had a strong influence on the widespread adoption of variable-dosing regimens in clinical practice.^[27] The PrONTO regimen consisted of 3-monthly ranibizumab (0.5 mg) injections followed by selective dosing at monthly follow-up visits. Retreatment criteria were strict, including VA loss of five or more letters with evidence from optical coherence tomography of new macular fluid or persistent fluid following the last injection; an increase in central retinal thickness (CRT) of 100 µm or more; or new macular hemorrhage. Criteria during the second year were strengthened to include retreatment for any subjective evidence of macular fluid. Outcomes were favorable; 1-year data demonstrated that the PrONTO regimen reduced the number of injections to an average of 5.6 during the first year, with a mean improvement from baseline VA of 9.3 letters. At 2 years, the mean number of total injections was 9.9, with a mean visual improvement of 11.1 letters.^[27,28]

The SAILOR study, the largest trial in exudative AMD to date (n = 4307), was a Phase IIIb multicenter, 1-year study evaluating a variable-dosing regimen of 3-monthly intravitreal ranibizumab (0.3 or 0.5 mg) injections followed by PRN dosing in two patient cohorts. Follow-up visits were required every 3 months, and retreatment criteria included a VA loss of more than five letters compared with the patient's peak VA, or an increase in CRT (as measured by optical coherence tomography) of more than 100 µm with intraretinal or subretinal fluid, relative to the patient's best earlier measurements. Within the randomized, single-masked cohort 1 (n = 2378) at 1-year follow-up, treatment-naive patients experienced mean VA improvements of 0.5 and 2.3 letters in the 0.3 and 0.5 mg groups, respectively, while previously treated patients experienced mean VA improvements of 1.7 and 2.3, respectively.^[29] The visual outcomes achieved with the variable PRN regimen in the SAILOR trial compare unfavorably with those reported in the MARINA and ANCHOR trials, in which continuous monthly therapy was used. Moreover, the visual outcomes in SAILOR also compare unfavorably with those of the PrONTO study, although the studies differed with respect to the variable regimens and retreatment criteria employed.

The HORIZON study, although designed as an extension study, provides another assessment of the efficacy of variable therapy. HORIZON was a Phase III open-label extension trial for patients who completed 2 years of ranibizumab or control treatment in the Phase III ANCHOR and MARINA trials, or the Phase I/II Intravitreal Injections of rhuFab V2 in Combination With Visudyne in Subjects With Age-Related Macular Degeneration (FOCUS) trial (discussed in 'Combination therapies' section).^[30] On entering into HORIZON, patients were switched to a PRN regimen (dosing no more frequently than every 30 days) based on the discretion of the treating physician, with required patient visits every 3 months. Of 853 patients enrolled into HORIZON, 600 comprised the 'treated cohort' and had been in study groups previously treated with monthly ranibizumab injections. The remaining patients had previously received PDT or sham injections and were either in the ranibizumab crossover cohort (n = 168) or did not require further treatment (n = 85). Patients in the treated cohort showed a mean VA loss of 5.3 letters from study baseline, a reversal of the mean VA gains achieved (+9.4 letters) with their previous monthly treatments within the MARINA, ANCHOR and FOCUS trials. Patients in the crossover and untreated cohorts experienced a mean VA loss of 2.4 and 3.1 letters, respectively, from study baseline.

A comparison of mean changes in VA over 12 months for patients receiving 0.5 mg of ranibizumab as standard therapy or variable therapy is illustrated in Figure 2, although this should be interpreted with caution in light of the limitations of cross-trial comparisons.

(Enlarge Image)

Figure 2.

Visual acuity changes with ranibizumab. Mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) letters through 12-month follow-up with 0.5 mg ranibizumab for monthly (ANCHOR, MARINA) and variable-dosing regimens (HORIZON [treated cohort], SAILOR [cohort 1], PIER and PrONTO).
HORIZON: An Extension Study to Evaluate the Safety and Tolerability of Ranibizumab in Subjects with Choroidal Neovascularization Secondary to AMD or Macular Edema Secondary to RVO; PIER: A Study of rhuFAB V2 (Ranibizumab) in Subjects with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration; PrONTO: Prospective Optical Coherence Tomography Imaging of Patients With Neovascular AMD Treated With Intra-Ocular Ranibizumab (Lucentis); SAILOR: A Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization (CNV) Secondary to Age-Related Macular Degeneration; VA: Visual acuity.

The EXCITE study was a Phase IIIb, multicenter, active-controlled, double-masked clinical trial in which patients were randomized to 3-monthly loading doses of 0.3 or 0.5 mg ranibizumab followed by quarterly injections or 0.3 mg monthly injections through 12 months follow-up. Although data from the monthly dosing group have not yet been published, prelimary data suggest some clinical benefit of quarterly dosing through 12 months.^[31] Similarly, preliminary data from the SUSTAIN trial (a Phase IIIb, multicenter, open-label, single-arm clinical trial) in which patients received 3-monthly loading doses of 0.3 mg ranibizumab followed by PRN doses guided by changes in VA and CRT, have shown some clinical benefit of a PRN dosing regimen through 12 months.^[32]

The therapeutic benefits of standard monthly therapy versus variable treatment will be compared directly in upcoming large, randomized clinical trials. In the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT) study, currently enrolling 1200 patients, attention is focused on comparisons of bevacizumab and ranibizumab monotherapy. However, study arms in CATT will also allow for head-to-head comparisons of visual outcomes with standard monthly and variable regimens. Other head-to-head trials of bevacizumab compared with ranibizumab monotherapy under a monthly or variable dosing regimen are presented in Table 2.

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Table 1. Summary of presented/published clinical trials of ranibizumab standard monthly and variable dosing regimens for exudative age-related macular degeneration.
Dosing regimen	Trial acronym/name	Phase/design	Patients (n)	Mean treatments per year (n)	Follow-up (months)	Outcomes (from baseline)			Ref.
Dosing regimen	Trial acronym/name	Phase/design	Patients (n)	Mean treatments per year (n)	Follow-up (months)	Mean change in VA (letters)	≥3-line gain (%)	<3-line loss (%)	Ref.
Monthly	ANCHOR	Phase III, randomized, multicenter, double masked, sham controlled, 1:1:1 (0.3 mg Ran:0.5 mg Ran:PDT)	423	12^†	12	0.3 mg: +8.5; 0.5 mg: +11.3; PDT: -9.5	0.3 mg: 35.7; 0.5 mg: 40.3; PDT: 5.6	0.3 mg: 94.3; 0.5 mg: 96.4; PDT: 64.3	[2]
Monthly	ANCHOR		423	12^†	24	0.3 mg: +8.1; 0.5 mg: +10.7; PDT: -9.8	0.3 mg: 34.3; 0.5 mg: 41.0; PDT: 6.3	0.3 mg: 90.0; 0.5 mg: 89.9; PDT: 65.7	[1]
Monthly	MARINA	Phase III, randomized, multicenter, double masked, sham controlled, 1:1:1 (0.3 mg Ran:0.5 mg Ran:sham)	716	12^†	12	0.3 mg: +6.5; 0.5 mg: +7.2; sham: -10.4	0.3 mg: 24.8; 0.5 mg: 33.8; sham: 5.0	0.3 mg: 95.4; 0.5 mg: 94.6; sham: 62.2	[3]
Monthly	MARINA		716	12^†	24	0.3 mg: +5.4; 0.5 mg: +6.6; sham: -14.9	0.3 mg: 26.1; .5 mg: 33.3; sham: 3.8	0.3 mg: 92.0; 0.5 mg: 90.0; sham: 52.9;	[3]
Variable, PRN	PrONTO	Phase I/II, nonrandomized, single center (0.5 mg Ran)	40	5.6	12	0.5 mg: +9.3	0.5 mg: 35	0.5 mg: 95	[27,28]
Variable, quarterly	PIER	Phase III, randomized, multicenter, double masked, sham controlled, 1:1:1 (0.3 mg Ran:0.5 mg Ran:sham)	184	6	12	0.3 mg: -1.6; 0.5 mg: -0.2; sham: -16.3	0.3 mg: 11.7; 0.5 mg: 13.1; sham: 9.5	0.3 mg: 83.3; 0.5 mg: 90.2; sham: 49.2	[8]
Variable, PRN	HORIZON	Phase III, multicenter, extension (0.5 mg Ran)	853	NA	12	NA	T: 2.0; XO: 3.0; N: 2.0	NA	[30,101]
Variable, PRN	SAILOR (cohort 1)	Phase III, randomized, multicenter, single masked, 1:1 (0.3 mg Ran:0.5 mg Ran)	2378	NA	12	0.3 mg N: +0.5; 0.5 mg N: +2.3; 0.3 mg T: +1.7; 0.5 mg T: +2.3	0.3 mg N: 14.6; 0.5 mg N: 19.3; 0.3 mg T: 15.8; 0.5 mg T: 16.5	NA	[29,102]
Variable, quarterly	EXCITE	Phase III, controlled 1:1:1 (0.3 mg Ran quarterly: 0.5 mg Ran quarterly: 0.3 mg Ran monthly)	353	NA	12	NA	NA	NA	[31,103]
Variable, PRN	SUSTAIN	Phase III, open label (0.3 mg Ran)	513	NA	12	NA	NA	NA	[32,104]

^†Theoretical mean number of injections per year based on monthly dosing regimen.
AAO: American Academy of Ophthalmology; AMD: Age-related macular degeneration; ARVO: Association for Research in Vision and Ophthalmology; EXCITE: Efficacy and Safety of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration; HORIZON: An Extension Study to Evaluate the Safety and Tolerability of Ranibizumab in Subjects with Choroidal Neovascularization Secondary to AMD or Macular Edema Secondary to RVO; N: Not treated; NA: Not applicable; PDT: Photodynamic therapy; PIER: A Study of rhuFAB V2 (Ranibizumab) in Subjects with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration; PRN: Pro re nata; PrONTO: Prospective Optical Coherence Tomography Imaging of Patients With Neovascular AMD Treated With Intra-Ocular Ranibizumab (Lucentis); Ran: Ranibizumab; RS: Retina Society; SAILOR: A Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization (CNV) Secondary to Age-Related Macular Degeneration; SUSTAIN: Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration; T: Previously treated; XO: Crossover.

Table 2. Summary of ongoing Phase III clinical trials of bevacizumab in exudative age-related macular degeneration.
Dosing regimen	Trial acronym/name	Design	Patients (n)	Follow-up (months)	Ref.
Monotherapy (monthly/variable)	CATT	Randomized, multicenter, double-masked, controlled (Bev vs Ran)	1208	24	[105]
Monotherapy (monthly/variable)	IVAN	Randomized, multicenter, double-masked, controlled (Bev vs Ran)	600^†	24	[106]
Monotherapy (monthly/variable)	MANTA	Randomized, multicenter, double-masked, controlled (Bev vs Ran)	320^†	12	[107]
Monotherapy (monthly/variable)	VIBERA	Randomized, multicenter, double-masked, controlled (Bev vs Ran)	366^†	24	[108]
Combination	NA	Randomized, single center, single-masked, controlled (Bev + PDT vs Bev + PDT + triamcinolone)	NA	NA	[109]

^†Estimated patient enrollment.
AMD: Age-related macular degeneration; Bev: Bevacizumab; CATT: Comparison of Age-Related Macular Degeneration Treatment Trials; IVAN: A Randomized Controlled Trial of Alternative Treatments to Inhibit VEGF in Age-Related Choroidal Neovascularization; MANTA: Avastin Versus Lucentis in Age-Related Macular Degeneration; NA: Not available; PDT: Photodynamic therapy; Ran: Ranibizumab; VIBERA: Prevention of Vision Loss in Patients With Age-Related Macular Degeneration (AMD) by Intravitreal Injection of Bevacizumab and Ranibizumab.

Table 3. Summary of published and ongoing clinical trials of ranibizumab combination therapy in exudative age-related macular degeneration.
Dosing regimen	Trial acronym/name	Phase/design	Patients (n)	Mean treatments per year (n)	Follow-up (months)	Outcomes (from baseline)			Ref.
Dosing regimen	Trial acronym/name	Phase/design	Patients (n)	Mean treatments per year (n)	Follow-up (months)	Mean change in VA (letters)	≥3-line gain (%)	<3-line loss (%)	Ref.
Monthly/standard	FOCUS	Phase I/II, randomized, single masked, controlled 2:1 (0.5 mg Ran + PDT vs sham + PDT)	162	12^†	24	Ran + PDT: 4.6; sham + PDT: -7.8	Ran + PDT: 25; sham + PDT: 7	Ran + PDT: 88; sham + PDT: 75	[35]
Monthly/variable	MONT BLANC	Phase II/III, randomized, multicenter, double masked, controlled (0.5 mg Ran + PDT vs Ran)	323	NA	24	NA	NA	NA	[110]
Monthly/variable	DENALI	Phase II/III, randomized, multicenter, double masked, controlled (0.5 mg Ran + PDT vs Ran)	255	NA	24	NA	NA	NA	[111]
Monthly/standard	CARBON	Phase III, randomized, multicenter, double masked, controlled (Ran + Bs vs Ran)	496	12^†	~15	NA	NA	NA	[112]
Variable	CABERNET	Phase III, randomized, multicenter, controlled (0.5 mg Ran + EpiRad90)	450	NA	12	NA	NA	NA	[113]
Combination vs monotherapy	LuceDex	Phase I/II prospective (Ran + Dex vs Ran)	40	NA	12	NA	NA	NA	[114]
Triple therapy vs monotherapy	RADICAL	Phase II, randomized, multicenter, controlled (Ran + PDT vs Ran + PDT + Dex vs Ran)	160	NA	12	NA	NA	NA	[115]
Triple therapy vs monotherapy	PDEX	Phase II randomized, single masked (PDT + Dex + Ran vs Ran)	60	NA	12	NA	NA	NA	[116]

^†Theoretical mean number of injections per year based on monthly dosing regimen.
Bs: Bevasiranib sodium; CABERNET: A study of Strontium⁹⁰ β Radiation With Lucentis to Treat Age-Related Macular Degeneration; CARBON: Combination of Bevasiranib and Lucentis Therapy in Wet AMD; DENALI: Verteporfin Photodynamic Therapy Administered in Conjunction with Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration; Dex: Dexamethasone; FOCUS: Phase I/II Intravitreal Injections of rhuFab V2 in Combination with Visudyne in Subjects with Age-Related Macular Degeneration; LuceDex: A Prospective Study Comparing Ranibizumab Plus Dexamethasone Combination Therapy Versus Ranibizumab Monotherapy for Wet AMD; MONT BLANC: Efficacy/Safety of Verteporfin Photodynamic Therapy and Ranibizumab Compared with Ranibizumab in Patients with Subfoveal Choroidal Neovascularization; NA: Not applicable; PDEX: PDT Plus IVD and Intravitreal Ranibizumab Versus Lucentis Monotherapy to Treat Age-Related Macular Degeneration; PDT: Photodynamic therapy; RADICAL: Reduced Fluence Visudyne-Anti-VEGF-Dexamethasone in Combination for AMD Lesions; Ran: Ranibizumab.

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