Robert B Bhisitkul†1
`and Jay M Stewart1
`1Beckman Vision Center, University of
`California San Francisco, 10 Koret Way,
`K301, San Francisco, CA 94143, USA
`†Author for correspondence:
`Tel.: +1 415 476 8633
`bhisitkulr@vision.ucsf.edu
`
`Review
`
`Alternative anti-VEGF
`treatment regimens in
`exudative age-related
`macular degeneration
`
`Expert Rev. Ophthalmol. 5(6), 799–809 (2010)
`
`This article evaluates the currently used treatment regimens in ocular anti-VEGF therapy for
`exudative age-related macular degeneration. Anti-VEGF therapies using variable injection
`regimens and combination therapies have emerged as alternatives to standard monthly
`monotherapy to address drug costs, patient risks and indisposition, and office workload.
`Variable anti-VEGF regimens employ reduced-frequency intravitreal injections on an as-
`needed basis or a fixed intermittent schedule. Although high-level evidence available from
`randomized clinical trials generally indicates less favorable outcomes for variable anti-VEGF
`regimens, positive results from some prospective and retrospective studies support variable
`therapies. Combination anti-VEGF therapies most often incorporate verteporfin photodynamic
`therapy and/or intravitreal corticosteroids. High-level evidence is not yet published for
`combination therapies, but therapeutic success with reduced treatments has been reported
`in uncontrolled and retrospective studies. Evidence to establish relative efficacy will be derived
`from ongoing randomized clinical trials comparing alternative regimens to standard monthly
`anti-VEGF monotherapy.
`
`Keywords: age-related macular degeneration • bevacizumab • intravitreal corticosteroids • intravitreal injection
`• photodynamic therapy • ranibizumab
`
`Since intravitreal anti-VEGF agents became
`available for the treatment of exudative age-
`related macular degeneration (AMD), oph-
`thalmologists have been reconsidering standard
`monthly dosing strategies and exploring alter-
`native treatment approaches with these agents.
`These alternative anti-VEGF regimens can be
`broadly classified as:
`
`• Variable-dosing regimens, defined here as anti-
`VEGF monotherapies using intravitreal injec-
`tions less frequently than once a month and
`usually for less than 1–2 years’ duration;
`
`• Combination therapies, employing anti-VEGF
`agents in conjunction with other AMD treat-
`ment modalities, in particular verteporfin pho-
`todynamic therapy (PDT) and/or intravitreal
`corticosteroids.
`
`Treating physicians have several objec-
`tives when employing these alternative
`therapeutic regimens:
`
`• Foremost, to decrease the number and fre-
`quency of intravitreal injections, thereby
`reducing ocular risks (and theoretical systemic
`risks), drug and procedural costs, patient dis-
`comfort and indisposition, and office workload
`and resources;
`
`• To allow discontinuation of treatment upon
`cessation of disease activity, thereby attaining
`a therapeutic end point;
`
`• To seek improved visual outcomes relative to
`standard therapy by combining different
`therapies with distinct targets of action, and
` potentially achieving additive or synergistic
`effects.
`
`The use of alternative dosing regimens has
`been predicated on the clinical perception that
`their therapeutic benefits are equivalent to those
`achieved with standard monthly ranibizumab
`treatment as established in the MARINA and
`ANCHOR trials [1–3]. The answer to the question
`
`www.expert-reviews.com
`
`10.1586/EOP.10.71
`
`© 2010 Expert Reviews Ltd
`
`ISSN 1746-9899
`
`799
`
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`Review Bhisitkul & Stewart
`
`of relative therapeutic efficacy awaits completion of ongoing ran-
`domized clinical trials of these alternative regimens. In this article,
`we evaluate the relative efficacy of current alternative anti-VEGF
`treatment regimens in neovascular AMD on the basis of available
`preclinical and clinical evidence, and ongoing clinical trials.
`
`Current therapies in exudative AMD
`Approved & off-label therapies
`Currently, five pharmacologic therapies are used to treat exuda-
`tive AMD (Figure 1). Three therapies are approved by the US FDA
`for this indication: verteporfin PDT [4,5], pegaptanib sodium
`(Macugen®; OSI/Eyetech Pharmaceuticals, NY, USA) [6,7] and
`ranibizumab (Lucentis®; Genentech, Inc., CA, USA) [1,3,8].
`Intravitreal bevacizumab (Avastin®; Genentech, Inc.) and tri-
`amcinolone acetonide (and other injectable corticosteroids) are
`also widely used off-label for the treatment of exudative AMD.
`Ranibizumab, PDT and pegaptanib have been shown in large,
`randomized clinical trials to be safe and effective in the treatment
`of patients with exudative AMD [1,3,4,9]. Currently, ranibizumab
`
`Nonthermal laser
`
`Triamcinolone
`acetonide
`
`VEGF-A
`
`Bevacizumab
`
`Verteporfin
`
`Ranibizumab
`
`Choroidal
`neovascularization
`
`VEGF165
`
`Pegaptanib
`
`Figure 1. Mechanisms of action of current therapies in exudative age-related
`macular degeneration. Currently, five therapies are used in the treatment of exudative
`age-related macular degeneration, including verteporfin photodynamic therapy, the
`anti-VEGF aptamer pegaptanib sodium, which targets VEGF165, and the anti-VEGF
`monoclonal antibody fragment ranibizumab, which targets all isoforms of VEGF-A and its
`degradation products. Therapies used off-label include the corticosteroid triamcinolone
`acetonide and the anti-VEGF humanized monoclonal antibody bevacizumab.
`
`800
`
`and bevacizumab are the most widely used in neovascular AMD.
`Ranibizumab is an intravitreally injected humanized anti-VEGF-
`A antibody fragment that binds all VEGF-A isoforms and their
`biologically active degradation products [10]. Bevacizumab, derived
`from the same parent molecule as ranibizumab, is a humanized
`anti-VEGF-A antibody that also binds all VEGF-A isoforms and
`their biologically active degradation products [11]. Although beva-
`cizumab is FDA approved only for intravenous use in combination
`with chemotherapy for the treatment of colorectal, breast, lung
`and renal cell cancers, clinical experience with intravitreal beva-
`cizumab has shown that this agent is well tolerated and associated
`with improved vision and decreased retinal thickness in patients
`with exudative AMD [12–15]. Given its substantially lower cost
`than ranibizumab, bevacizumab has gained increasing popularity
`as an off-label AMD treatment.
`
`Therapies in development
`In addition to the aforementioned therapies currently in use,
`several therapies are in clinical development for the treatment
`of exudative AMD, including the ‘decoy
`receptor’ VEGF Trap-Eye (Regeneron,
`NY, USA), the radioisotope Epi-Rad90™
`Ophthalmic System (NeoVista, Inc.,
`CA, USA), siRNAs such as bevasiranib
`(Cand5; OPKO Health, Inc., FL, USA)
`and Sirna-027 (Sirna Therapeutics,
`CO, USA), the PDGF-targeted aptamer
`E10030 (Ophthotech Corp., NJ, USA).
`Many of these emerging agents are being
`investigated as some form of combination
`therapy in their development strategy,
`either as an adjunctive therapy (integrated
`with anti-VEGF drugs) or as a follow-
`on (maintenance) treatment after initial
`ranibizumab treatment. Alternative regi-
`mens using drugs in development will not
`be discussed further in this article.
`
`Rationale for variable-dosing
`regimens
`In clinical practice today, few retinal spe-
`cialists adhere to the strict schedule of
`regular monthly intravitreal injections for
`2 years as established by the MARINA
`and ANCHOR trials. A variety of vari-
`able treatment strategies have arisen, most
`of which utilize an initial series of several
`monthly injections followed by inter-
`mittent injections on either a fixed inter-
`mittent schedule (e.g., every 3 months) or
`on a pro re nata (PRN) basis. Although
`drug cost is a prime consideration in reduc-
`ing dosing frequency, variable treatment
`approaches prevail even with the use of the
`lower cost agent, bevacizumab.
`
`Expert Rev. Ophthalmol. 5(6), (2010)
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`Alternative anti-VEGF treatment regimens in exudative AMD
`
`Review
`
`The primary scientific rationale for variable therapy is to avoid
`treatment when it is not considered necessary, as when the mac-
`ula has become clinically dry after treatment. Reducing the fre-
`quency of injections while achieving equivalent outcomes aims
`to maximize the therapeutic efficiency. In PRN regimens, the
`clinician performs ongoing follow-up to reinstate therapy upon
`the re appearance of exudation; thus, these approaches rely on
`the reversibility of episodic visual declines during the course of
`treatment. Individualized treatment is another rationale for vari-
`able therapy, emphasizing the physician’s clinical judgment in the
`management of each patient, rather than rote retreatment on a
`monthly basis.
`On the other hand, the scientific rationale for standard continu-
`ous monthly therapy is based on VEGF biology, drug pharmaco-
`kinetics, and available Phase III clinical trial data. VEGF is con-
`tinuously expressed in the retina and retinal pigment epithelium
`(RPE) in normal adult nonhuman primates and rodents [16], with
`increased VEGF levels in choroidal neovascularization (CNV)
`membranes [17,18]. In humans, inferential evidence suggests that
`VEGF activity is sustained in exudative AMD; even chronic
`CNV membranes surgically removed from exudative AMD
`patients show strong VEGF labeling [19]. Furthermore, patients
`in the control arms of randomized clinical trials of anti-VEGF
`treatment for exudative AMD showed progressive visual decline
`for 2 or more years, again suggesting a role for chronic VEGF
`activity in the natural course of the disease [3,4,9].
`Monthly dosing has also been guided by the pharmacokinetics
`of ranibizumab and bevacizumab, both large-molecule biologics
`that are rapidly degraded and cleared from the eye. In the vitre-
`ous of rabbits and nonhuman primates, 0.5 mg of ranibizumab
`has a half-life of 2.9 and 2.6 days, respectively [20,21]. In human
`eyes, measurements of ranibizumab concentrations following
`intravitreal injection are consistent with a half-life of approxi-
`mately 3 days, with clearance below effective concentrations at
`4 weeks [22]. For bevacizumab, pharmacokinetic data show a vitre-
`ous half-life of approximately 4 days in rabbit eyes [23] and 6.7 days
`in human eyes [24].
`
`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 regi-
`men (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 let-
`ters 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 effi-
`cacy 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 injec-
`tions 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.
`
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`Review Bhisitkul & Stewart
`
`[32,104]
`
`[31,103]
`
`[29,102]
`
`[30,101]
`
`[8]
`
`[27,28]
`
`[3]
`
`[1]
`
`[2]
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`12
`
`NA
`
`NA
`
`0.5 mg T: 16.5
`0.3 mg T: 15.8;
`0.5 mg N: 19.3;
`0.3 mg N: 14.6;
`
`N: 2.0
`T: 2.0; XO: 3.0;
`
`0.5 mg T: +2.3
`0.3 mg T: +1.7;
`0.5 mg N: +2.3;
`+0.5;
`0.3 mg N:
`
`NA
`
`Ref.
`
`Outcomes (from baseline)
`
`sham: 49.2
`0.5 mg: 90.2;
`0.3 mg: 83.3;
`
`sham: 9.5
`0.5 mg: 13.1;
`0.3 mg: 11.7;
`
`sham: -16.3
`0.5 mg: -0.2;
`0.3 mg: -1.6;
`
`0.5 mg: 95
`
`0.5 mg: 35
`
`0.5 mg: +9.3
`
`sham: 52.9;
`0.5 mg: 90.0;
`0.3 mg: 92.0;
`
`sham: 62.2
`0.5 mg: 94.6;
`0.3 mg: 95.4;
`
`PDT: 65.7
`0.5 mg: 89.9;
`0.3 mg: 90.0;
`
`PDT: 64.3
`0.5 mg: 96.4;
`0.3 mg: 94.3;
`
`<3-line loss (%)
`
`sham: 3.8
`0.5 mg: 33.3;
`0.3 mg: 26.1;
`
`sham: 5.0
`0.5 mg: 33.8;
`0.3 mg: 24.8;
`
`sham: -14.9
`0.5 mg: +6.6;
`0.3 mg: +5.4;
`
`sham: -10.4
`0.5 mg: +7.2;
`0.3 mg: +6.5;
`
`PDT: 6.3
`0.5 mg: 41.0;
`0.3 mg: 34.3;
`
`PDT: -9.8
`0.5 mg: +10.7;
`0.3 mg: +8.1;
`
`PDT: 5.6
`0.5 mg: 40.3;
`0.3 mg: 35.7;
`
`PDT: -9.5
`0.5 mg: +11.3;
`0.3 mg: +8.5;
`
`(%)
`≥3-line gain
`
`in VA (letters)
`Mean change
`
`12
`
`24
`
`12
`
`24
`
`12
`
`(months)
`up
`Follow-
`
`Degeneration; SUSTAIN: Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration; T: Previously treated; XO: Crossover.
`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
`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
`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
`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
`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
`†Theoretical mean number of injections per year based on monthly dosing regimen.
`PRN
`Variable,
`
`(0.3 mg Ran)
`Phase III, open label
`
`SUSTAIN
`
`NA
`
`513
`
`12
`
`NA
`
`353
`
`monthly)
`Ran quarterly: 0.3 mg Ran
`(0.3 mg Ran quarterly: 0.5 mg
`Phase III, controlled 1:1:1
`
`EXCITE
`
`quarterly
`Variable,
`
`12
`
`12
`
`12
`
`NA
`
`NA
`
`6
`
`5.6
`
`(0.3 mg Ran:0.5 mg Ran)
`multicenter, single masked, 1:1
`
`2378
`
`SAILOR (cohort 1) Phase III, randomized,
`
`853
`
`(0.5 mg Ran)
`Phase III, multicenter, extension
`
`184
`
`Ran:0.5 mg Ran:sham)
`sham controlled, 1:1:1 (0.3 mg
`multicenter, double masked,
`Phase III, randomized,
`
`40
`
`center (0.5 mg Ran)
`Phase I/II, nonrandomized, single
`
`HORIZON
`
`PIER
`
`PrONTO
`
`PRN
`Variable,
`
`PRN
`Variable,
`
`quarterly
`Variable,
`
`PRN
`Variable,
`
`12†
`
`716
`
`Ran:0.5 mg Ran:sham)
`sham controlled, 1:1:1 (0.3 mg
`multicenter, double masked,
`Phase III, randomized,
`
`MARINA
`
`Monthly
`
`12†
`
`423
`
`per year (n)
`treatments
`Mean
`
`(n)
`Patients
`
`Ran:PDT)
`1:1:1 (0.3 mg Ran:0.5 mg
`sham controlled,
`multicenter, double masked,
`Phase III, randomized,
`
`ANCHOR
`
`Monthly
`
`Phase/design
`
`name
`Trial acronym/
`
`regimen
`Dosing
`
`age-related macular degeneration.
`Table 1. Summary of presented/published clinical trials of ranibizumab standard monthly and variable dosing regimens for exudative
`
`802
`
`Expert Rev. Ophthalmol. 5(6), (2010)
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`Alternative anti-VEGF treatment regimens in exudative AMD
`
`Review
`
`With Age-Related Macular Degeneration (FOCUS) trial (dis-
`cussed 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.
`The EXCITE study was a Phase IIIb, multicenter, active-con-
`trolled, double-masked clinical trial in which patients were ran-
`domized 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,
`
`ANCHOR (+11.3)
`
`PrONTO (+9.3)
`MARINA (+7.2)
`
`HORIZON (+4.1)
`SAILOR (+2.3)
`
`PIER (-0.2)
`
`3
`
`4
`
`5
`
`6
`Months
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`0
`
`1
`
`2
`
`15
`
`10
`
`5
`
`0
`
`-5
`
`Mean change in VA (letters)
`
`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 vari-
`able-dosing regimens in clinical practice [27]. The PrONTO regi-
`men consisted of 3-monthly ranibizumab (0.5 mg) injections fol-
`lowed 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 cen-
`tral 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 evaluat-
`ing a variable-dosing regimen of 3-monthly intravitreal ranibi-
`zumab (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, treat-
`ment-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 experi-
`enced 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 vari-
`able therapy. HORIZON was a Phase III
`open-label extension trial for patients who
`completed 2 years of ranibizumab or con-
`trol 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
`
`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.
`
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`Review Bhisitkul & Stewart
`
`multicenter, open-label, single-arm clinical trial) in which patients
`received 3-monthly loading doses of 0.3 mg ranibizumab fol-
`lowed 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 ranibi-
`zumab monotherapy under a monthly or variable dosing regimen
`are presented in Table 2.
`
`Combination therapies
`Rationale
`The clinical use of combination therapies is well established in
`other areas of medicine such as infectious disease and oncology.
`Since available treatments for exudative AMD have distinct
`mechanisms of action, combining these agents may provide
`synergistic or additive effects (Figure 1), which may translate into
`visual benefits superior to those achieved with anti-VEGF mono-
`therapy. As an example, adjuvant anti-VEGF therapy could off-
`set the increased VEGF expression that has been reported with
` verteporfin PDT therapy [33].
`Individualized treatment is also a rationale for combina-
`tion therapies; a patient’s incomplete response to any single
`treatment can be addressed by switching to or adding other
`modalities. Cessation of CNV activity, with the possibil-
`ity of permanent disease quiescence, is another goal of com-
`bination therapy. Furthermore, as with variable treatment
`
`monotherapies, combination therapies are aimed at reducing
`treatment frequency and attendant risks, financial costs and
`clinician workload.
`The data from evidence-based comparisons of anti-VEGF
`monotherapies versus combination therapies are limited at pres-
`ent. Data describing combination therapy with ocular anti-VEGF
`agents plus verteporfin PDT and/or intraocular corticosteroids
`have largely been reported as retrospective case series or small
`uncontrolled studies. Results are expected from clinical trials
`of various combination therapies for bevacizumab (Table 2) and
`ranibizumab (Table 3).
`
`PDT plus anti-VEGF therapy
`FOCUS was a Phase I/II multicenter, 2-year, randomized, single-
`masked, controlled study in which patients (n = 162) received
`PDT in combination with monthly intravitreal ranibizumab
`(0.5 mg) or sham injections. PDT was performed 7 days before
`initial ranibizumab or sham treatment and then quarterly as
`needed (standard of care at the time) [34,35]. At the 24-month
`follow-up, patients treated with ranibizumab plus PDT achieved a
`mean increase in VA of 4.6 letters compared with patients receiv-
`ing sham injections plus PDT, who experienced a mean decrease
`in VA of 7.8 letters [35].
`In case series and uncontrolled studies, combination therapy
`of verteporfin PDT with intravitreal bevacizumab has been
`reported to improve mean VA and reduce central macular
`thickness in patients with exudative AMD while also reduc-
`ing retreatment rates [36–38]. Randomized studies providing
`a direct comparison of anti-VEGF monotherapy to PDT-
`based combination therapy are forthcoming. The ongo-
`ing Verteporfin Photodynamic Therapy Administered in
`Conjunction with Ranibizumab in Patients with Subfoveal
`Choroidal Neovascularization Secondary to Age-Related
`Macular Degeneration (DENALI) and Efficacy/Safety
`
`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)
`
`Monotherapy (monthly/variable) CATT
`
`Monotherapy (monthly/variable) IVAN
`
`Monotherapy (monthly/variable) MANTA
`
`Monotherapy (monthly/variable) VIBERA
`
`Combination
`
`NA
`
`Randomized, multicenter, double-masked,
`controlled (Bev vs Ran)
`
`Randomized, multicenter, double-masked,
`controlled (Bev vs Ran)
`
`Randomized, multicenter, double-masked,
`controlled (Bev vs Ran)
`
`Randomized, multicenter, double-masked,
`controlled (Bev vs Ran)
`
`Randomized, single center, single-masked,
`controlled (Bev + PDT vs Bev + PDT
`+ triamcinolone)
`
`1208
`
`600†
`
`320†
`
`366†
`
`NA
`
`24
`
`24
`
`12
`
`24
`
`NA
`
`Ref.
`
`[105]
`
`[106]
`
`[107]
`
`[108]
`
`[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.
`
`804
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`Alternative anti-VEGF treatment regimens in exudative AMD
`
`Review
`
`[116]
`
`NA
`
`NA
`
`NA
`
`[115]
`
`[114]
`
`[113]
`
`[112]
`
`[111]
`
`[110]
`
`[35]
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`sham + PDT: 75
`Ran + PDT: 88;
`
`sham + PDT: 7
`Ran + PDT: 25;
`
`sham + PDT: -7.8
`Ran + PDT: 4.6;
`
`(%)
`<3-line loss
`
`(%)
`≥3-line gain
`
`in VA (letters)
`Mean change
`
`Ref.
`
`Outcomes (from baseline)
`
`12
`
`12
`
`12
`
`12
`
`~15
`
`24
`
`24
`
`24
`
`Degeneration; PDT: Photodynamic therapy; RADICAL: Reduced Fluence Visudyne-Anti-VEGF-Dexamethasone in Combination for AMD Lesions; Ran: Ranibizumab.
`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
`Ranibizumab Plus Dexamethasone Combination Therapy Versus Ranibizumab Monotherapy for Wet AMD; MONT BLANC: Efficacy/Safety of Verteporfin Photodynamic Therapy and Ranibizumab Compared with
`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
`DENALI: Verteporfin Photodynamic Therapy Administered in Conjunction with Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration;
`Bs: Bevasiranib sodium; CABERNET: A study of Strontium90 b Radiation With Lucentis to Treat Age-Related Macular Degeneration; CARBON: Combination of Bevasiranib and Lucentis Therapy in Wet AMD;
`†Theoretical mean number of injections per year based on monthly dosing regimen.
`monotherapy
`Triple therapy vs
`
`NA
`
`255
`
`masked, controlled (0.5 mg Ran + PDT vs Ran)
`Phase II/III, randomized, multicenter, double
`
`NA
`
`323
`
`masked, controlled (0.5 mg Ran + PDT vs Ran)
`Phase II/III, randomized, multicenter, double
`
`12†
`
`162
`
`2:1 (0.5 mg Ran + PDT vs sham + PDT)
`Phase I/II, randomized, single masked, controlled
`
`(months)
`Follow-up
`
`per year (n)
`treatments
`Mean
`
`(n)
`Patients
`
`Phase/design
`
`DENALI
`
`BLANC
`MONT
`
`FOCUS
`
`name
`acronym/
`Trial
`
`monotherapy
`Triple therapy vs
`
`monotherapy
`Combination vs
`
`Variable
`
`standard
`Monthly/
`
`variable
`Monthly/
`
`variable
`Monthly/
`
`standard
`Monthly/
`
`regimen
`Dosing
`
`NA
`
`60
`
`+ Ran vs Ran)
`Phase II randomized, single masked (PDT + Dex
`
`PDEX
`
`NA
`
`160
`
`(Ran + PDT vs Ran + PDT + Dex vs Ran)
`Phas