Clinical Medicine: Therapeutics
`
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`Exudative Age-Related Macular Degeneration: Current
`Therapies and Potential Treatments
`
`Polly A. Quiram1,2 and Yahui Song2
`1Vitreoretinal Surgery, PA Minneapolis, MN. 2University of Minnesota Medical School, Minneapolis, MN, USA.
`Email: pollyquiram@yahoo.com
`
`Abstract: Strategies for preventing vision loss in patients with neovascular age-related macular degeneration (ARMD) have evolved
`over the past decade. Whereas earlier treatments were based on thermal destruction of choroidal neovascularization (CNV), new
`therapies rely on targeted pharmacologic approaches to reduce the harmful effects of CNV treatment. For the first time in the history
`of neovascular ARMD treatment, anti-VEGF therapies have consistently improved visual acuity in a subset of patients. Clinical
`trials continue to investigate the optimal dosing strategies and combination therapies to better refine the treatment of this chronic and
`debilitating disease.
`
`Keywords: age related macular degeneration, anti-VEGF therapy
`
`Clinical Medicine: Therapeutics 2009:1 1003–1011
`
`This article is available from http://www.la-press.com.
`
`© Libertas Academica Ltd.
`
`This is an open access article distributed under the terms of the Creative Commons Attribution License
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`provided the original work is properly cited.
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`
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`Quiram and Song
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`Pathophysiology of ARMD
`Age-related macular degeneration (ARMD) is the
`leading cause of visual impairment in patients over
`the age 60 in Europe and North America and is the
`third leading cause of blindness worldwide.1,2 The
`number of patients with macular degeneration will
`dramatically increase over the next few decades
`due to the aging population. ARMD is classified
`by two forms: “dry” (nonexudative) and “wet”
`(neovascular, exudative). In most cases of dry
`ARMD, patients do not experience significant visual
`loss. A small percentage of dry ARMD patients
`(7%–10%) will progress to the “wet” form, which is
`characterized by significant visual loss. The hallmark
`of ARMD pathology is drusen formation, which is
`an insoluble lipid deposit that accumulates between
`Bruch’s membrane and retinal pigment epithelium
`(RPE).3 Whereas dry ARMD is characterized by
`atrophy of the macular RPE and degeneration of
`photoreceptors, wet ARMD is characterized by
`choroidal neovascularization (CNV) and loss of
`photoreceptors and the RPE. Vascular endothelial
`growth factor (VEGF) has been proven to be a
`key potent stimulator in CNV formation4 and is
`targeted in ARMD therapies. The risk factors for
`ARMD include: increased age, genetic markers and
`environmental factors (particularly smoking) with
`age being the strongest factor.5–7
`The precise molecular mechanisms of AMD
`remains unknown, however, accumulated data from
`pathobiological, biochemical and genetic studies have
`prompted an integrated model.8 This model states
`that aging is the primary factor with specific genetic
`variants exacerbating the pathogenesis along with
`environmental factors (smoking, etc). The initial step
`in ARMD pathogenesis is the natural aging process
`which causes oxidative stress and accumulation of
`drusen. Drusenoid material includes toxic substances
`that can trigger chronic inflammation and activate
`complement pathways. Chronic
`inflammation
`causes localized ischemia which stimulates VEGF
`production and resulting formation of choroidal
`neovascular membranes. Treatments
`to
`target
`pathogenic molecules (VEGF and inflammatory
`factors) are currently available and in the process of
`being developed.
`Inflammation as a pathologic process in ARMD
`is well documented by the discovery of complement
`
`1004
`
`factor H polymorphisms as a risk factor for ARMD.9,10
`Also, genome studies have identified a mitochondrial
`protein (ARMS2) which increases the susceptibility
`to ARMD.11,12 These studies support the role of
`genetic susceptibility and the variation of clinical
`presentation in different individuals and ethnic groups.
`In addition, environmental factors such as smoking,
`lack of an antioxidant-rich diet, hypertension and
`diminished immune system by chronic infection or
`inflammation, add another of layer of complexity to
`the pathogenesis of AMD.
`With the advances in the understanding of the
`pathogenesis of AMD on the molecular level, progress
`in ARMD treatment has evolved from laser therapy
`and surgical procedures to verteporfin photodynamic
`therapy and anti-VEGF based molecular therapies.
`This review will focus on anti-VEGF therapies
`with a brief introduction to upcoming innovative
`therapeutics.
`
`State of ARMD Therapy
`Significant progress in the treatment of neovascular
`ARMD has occurred since the introduction of
`thermal laser photocoagulation for subfoveal CNVM.
`Although a select number of non-subfoveal lesions
`can be successfully destroyed by thermal laser
`photocoagulation,
`recurrences and symptomatic
`scotomas can occur.13 Surgical removal of CNVM was
`investigated in the Submacular Surgery Trial (SST)
`and the findings showed poor visual and structural
`lesions.14 Fortunately,
`outcomes
`for subfoveal
`since the introduction of photodynamic therapy
`(PDT), therapeutic approaches have shifted from
`ablative to more pharmacotherapeutic.13,15 Targeted
`pharmacologic therapy began with the first anti-VEGF
`molecule, an RNA aptamer, Pegaptanib (Macugen,
`OSI Eyetech), which specifically inactivates the
`isoform. Treatment with
`pathologic VEGF165
`Pegaptanib allowed maintenance of vision without
`damage to the neurosensory retina.16 Clinical trials
`and retrospective reviews have revealed that treatment
`of CNV with ranibizumab (Lucentis, Genentech)
`and bevacizumab (Avastin, Genentech) not only
`maintains visual acuity, but improves visual acuity
`in a significant number of patients.17 The following
`sections summarize the pertinent data from ongoing
`clinical trials and review previous studies related to
`ARMD therapy.
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`Photodynamic Therapy
`The efficacy of verteporfin (photoexitable dye) for the
`treatment of CNV was established in several studies
`including the Treatment of Age-Related Macular
`Degeneration with Photodynamic Therapy (TAP)
`and the Verteporfin in Photodynamic Therapy (VIP)
`trials.15,18,19 In the TAP study, patients with some
`component of classic subfoveal CNV were treated
`with verteporfin or placebo. At one year, fewer eyes
`in the verteporfin group (39%) lost greater than 3 lines
`of vision (15 letters) than the placebo group (54%),
`(p (cid:12) 0.001, the primary endpoint of the study).
`At 2 years this beneficial effect was maintained.18
`When the data was subdivided into predominantly
`classic lesions, the beneficial effect was greater in
`the treated group (38% lost greater than 3 lines of
`vision) than the placebo group (61%). No beneficial
`effect was seen in patients with minimally classic
`((cid:12)50% classic) CNV.
`In the VIP study, patients with occult subfoveal
`CNV were treated with verteporfin or placebo. For
`the primary endpoint of loss of at least 15 letters,
`no difference was see between the verteporfin and
`placebo groups at 1 year. At two years, a beneficial
`effect was seen with 54% of verteporfin-treated
`patients losing 15 letters compared to 67% in the
`placebo group (p (cid:29) 0.023).19 Further analysis of
`the TAP and VIP data revealed that smaller lesions
`((cid:12)4 disc areas) lost less vision than larger CVN
`lesions. These studies concluded that small lesions
`size was a better predictor of visual acuity than lesion
`composition.15 The most common adverse events
`associated with verteporfin therapy included back
`pain, injection site reaction, photosensitivity reaction
`and visual disturbance. Acute decreases in visual
`acuity (losing greater than 20 letters within 7 days of
`treatment) were reported in 0.7% of patients in the
`TAP trial and 4.4% of patients in the VIP trial.20
`Pegaptanib
`Pegaptanib was introduced in 2004 as the first
`intravitreally administered anti-VEGF agent.3
`Pegaptanib
`is an anti-VEGF RNA aptamer
` isoform
`the VEGF165
`that primarily
`targets
`to
`reduce vascular permeability and
`retinal
`neovascularization.21 The VEGF Inhibition Study in
`Ocular Neovascularization (VISION) determined the
`efficacy and tolerability of pegaptanib. Patients were
`
`Clinical Medicine: Therapeutics 2009:1
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`Treatment of ARMD
`
`randomized to receive 0.3 mg, 1 mg or 3 mg of
`pegaptanib or sham injection every 6 weeks for
`48 weeks. The results showed that all 3 doses of
`pegaptanib were significantly more effective than
`sham in achieving the primary endpoint (loss of fewer
`than 15 letters). Loss of less than 15 letters occurred
`in 70% of eyes treated with ranibizumab (0.3 mg)
`compared to 55% of sham eyes. Pegaptanib was found
`to be effective in maintaining vision, but only 6% of
`eyes gained 15 or more letters. This pivotal study
`showed that repeated intravitreal injections could be
`performed to maintain visual acuity in neovascular
`ARMD. Injection related adverse events were rare
`with endophthalmitis occurring in 1.3% of patients
`and traumatic injuries to lens or retina occurring in
`0.6% of patients.
`Bevacizumab (Avastin)
`and Ranibizumab (Lucentis)
`To date, bevacizumab and ranibizumab are the
`most affective treatments for ARMD. These anti-
`VEGF antibodies provide pan- VEGF blockage
`rather than binding a single isoform of VEGF. In
`recent studies, the full-length monoclonal anti-
`VEGF antibody (bevacizumab) and antigen binding
`fragment (Fab) active site fragment (ranibizumab)
`have been shown to be highly effective at reducing
`vision loss. Results of the phase III clinical trials
`(ANCHOR, MARINA) for ranibizumab (Lucentis,
`Genentech) have shown stabilization or improvement
`of vision in 95% of patients, and improvement of
`(cid:4)3 lines of vision in 40% of patients.22 Off-label use
`of intravitreal bevacizumab (Avastin, Genentech)
`has been shown to significantly improve vision in
`several studies.23–25 A recent survey of practicing
`retinal specialist by the American Society of Retinal
`Specialists (ASRS) (Preferences and Trends, 2007)
`show that 50% of retinal specialist use ranibizumab
`as first line therapy and 50% use bevacizumab as first
`line therapy for treatment of CNV lesions (ASRS
`2007 Preferences and Trends, Membership Survey,
`R. Mittra).
`Ranibizumab and Pivotal Clinical Trials
`Marina
`is a humanized antigen binding
`Ranibizumab
`fragment (Fab) designed to block all active forms of
`VEGF.26 In 2006, ranibizumab was approved for the
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`Quiram and Song
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`treatment of subfoveal CNVM. MARINA (Minimally
`Classic/Occult Trial of the Anti-VEGF Antibody
`Ranibizumab in the Treatment of Neovascular AMD)
`enrolled patients with minimally classic or occult
`(lesions with presumed recent disease progression.17
`Patients were randomized to sham or ranibizumab
`intravitreal injection (0.3 mg or 0.5 mg) every 4 weeks
`for 24 months. The primary outcome was loss of less
`
`than 15 letters. At one year, the results showed that
`95% of eyes treated with ranibizumab (0.3 mg and
`0.5 mg) lost less than 15 letters compared to 63%
`of sham eyes (Fig. 1). In addition to maintenance of
`visual acuity, treatment with ranibizumab showed
`significant gains in visual acuity with 25%–34% of
`eyes (0.3 mg and 0.5 mg doses) gaining 15 letters
`at 12 months. The mean gain in visual acuity at
`
`Sham injection
`(n = 238)
`
`0.3 mg of ranibizumab
`(n = 238)
`
`0.5 mg of ranibizumab
`(n = 240)
`
`Gained > 15 letters
`
`33.8
`
`24.8
`
`33.3
`
`26.1
`
`5.0
`
`3.8
`
`12 Months
`
`24 Months
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Increase of (cid:41) 15 Letters (%)
`
`Lost < 15 letters
`
`94.5
`
`94.6
`
`92.0
`
`90.0
`
`62.2
`
`52.9
`
`12 Months
`
`24 Months
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Loss of < 15 Letters (%)
`
`0.5 mg of ranibizumab
`0.3 mg of ranibizumab
`
`Sham injection
`
`15
`
`18
`
`21
`
`24
`
`12
`Month
`
`0
`
`3
`
`6
`
`9
`
`10
`
`5
`
`0
`
`−5
`
`−10
`
`−15
`
`Mean change in visual acuity
`
`(no. of letters)
`
`Mean Change from
`Baseline
`0.5 mg of ranibizumab
`0.3 mg of ranibizumab
`Sham injection
`
`(day 7)
`+2.6
`+2.3
`+0.6
`
`+5.9
`+5.1
`−3.7
`
`+6.5
`+5.6
`−6.6
`
`+7.2
`+5.9
`−9.1
`
`+7.2
`+6.5
`−10.4
`
`+7.4
`+6.9
`−11.8
`
`+6.8
`+6.1
`−13.6
`
`+6.7
`+6.2
`−15.0
`
`+6.6
`+5.4
`−14.9
`
`Figure 1. Data from MARINA trial. Top: Percentage of patients in each group who lost less than 15 letters (left) or gained 15 or more letters (right).
`Bottom: Mean change from baseline visual acuity during a 24 month period. Comparison between the ranibizumab groups (0.3 mg and 0.5 mg) and
`sham is shown below chart.
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`12 months was 7.2 letters compared to a loss of
`10 letters in the sham group. At 24 months, this
`effect was maintained in the ranibizumab group with
`an average gain of 6 letters compared to a 15 letters
`loss in the sham group (difference of 21.5 letters)17
`(Fig. 1). Adverse events including endophthalmitis
`and retinal detachment were rare. Systemic adverse
`events were no different in ranibizumab and sham
`groups including hypertension, death, myocardial
`infarction and cerebrovascular events.
`Anchor
`ANCHOR (Anti-VEGF Antibody for the Treatment of
`Predominantly Classis Choroidal Neovascularization
`in AMD) enrolled patients with predominantly
`classic CNV for randomization into 3 groups: PDT
`with sham injection of ranibizumab, sham PDT with
`ranibizumab 0.3 mg or sham PDT with ranibuzumab
`0.5 mg. The primary outcome was loss of less than
`15 letters at 12 months. The study found that 94%–96%
`of ranibizumab injected eyes (0.3 mg and 0.5 mg,
`respectively) lost less than 15 letter compared to 64%
`of eyes treated with PDT alone (p (cid:12) 0.0001).27 A gain
`of (cid:14)15 letters was present in 40.3% of eyes receiving
`ranibizumab and 5.6% of eyes receiving PDT
`(Fig. 2). The mean change in visual acuity was an
`11 letters gain with ranibizumab compared to a 9.5 letter
`loss with PDT treatment at 12 months (20.8 letter
`difference). Subgroup analyses showed that the
`benefit of ranibizumab over PDT for predominately
`classic lesion was present regardless of patients’
`age, visual acuity or lesion size.28
`Alterante Dosing Strategy:
`PrONTO Study
`The PrONTO study (Prospective OCT Imaging of
`Patients with Neovascular AMD Treated with Intraocular
`Ranibizumab) is a 2-year, open-label, prospective study
`to evaluate an OCT guided dosing regimen.29 The study
`enrolled patients to receive 0.5 mg of ranibizumab
`monthly for 3 months with additional reinjection if:
`loss of (cid:14)5 letters, OCT evidence of fluid defined
`as subretinal fluid or retinal cysts, increase in OCT
`thickness of (cid:14)100 microns, new macular hemorrhage,
`or new CVN. Reinjection also occurred if fluid persisted
`following a previous injection. Major endpoints examined
`were changes in visual acuity and OCT thickness
`from baseline after treatment and the number of injections
`
`Clinical Medicine: Therapeutics 2009:1
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`Treatment of ARMD
`
`required over 12 months. Other endpoints included the
`number of consecutive monthly injections to achieve a
`fluid free macula and the time to next injection due to
`fluid recurrence.
`The most common criteria for reinjection was vision
`loss, a fluid increase of (cid:14)100 microns on OCT and
`persistent fluid following the last injection. Of the
`40 eyes enrolled, 7 eyes did not require another injection
`after the initial 3 injections and 8 eyes required only
`4 injections. The mean number of injections was 5.6 in
`12 months. Visual outcomes were similar to those seen
`in the MARINA and ANCHOR trials (Fig. 3). Of the
`40 patients, 95% lost (cid:12)15 letters and 35% gained
`15 or more letters (mean 9.3 letters). OCT outcomes
`resulted
`in a mean reduction
`in
`thickness of
`178 microns. The authors found that development of
`any of the retreatment criteria was preceded by OCT
`changes suggestive of early fluid. Although these
`results are comparable to MARINA and ANCHOR,
`this study was smaller, nonrandomized, open-label,
`and unmasked.
`Clinical Trial Data Provides
`“Guidelines”
`Dosing strategies
`Two dosing strategies have been proposed using
`clinical trial data and ancillary testing data to
`monitoring efficacy and guide decision-making.
`“Strategy A” adheres to the clinical trial protocol with
`“automatic” monthly injections for 24 months without
`the use of FA or OCT to guide retreatment decisions.
`FA and OCT are only obtained to evaluate adverse
`events if unexplained vision loss occurs. Pitfalls of
`this approach include the potential for overtreament
`considering the known risks of intravitreal injection,
`patient discomfort and
`inconvenience, possible
`toxicity by blocking the neurotrophic effects of VEGF
`with prolonged VEGF blockade and societal costs.
`“Strategy B” is a tailored, more labor intense approach
`that requires synthesis of all available data (exam, FA
`and OCT). Monthly injections are performed for 3
`months (similar to MARINA, ANCHOR, PrONTO),
`followed by monthly imaging studies which are used
`to guide the need for retreatment until the lesion
`is considered inactive. Once considered inactive,
`patients are then closely monitored with clinical
`exams, FA and OCT imaging. Pitfalls include possible
`undertreatment, the difficulty of determining when a
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`Gained > 15 letters
`
`35.7
`
`40.3
`
`5.6
`
`Verteporfin
`(N = 143)
`
`0.3 mg of
`Ranibizumab
`(N = 140)
`
`0.5 mg of
`Ranibizumab
`(N = 139)
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Gain of (cid:41)(cid:2)15 Letters (%)
`
`Lost < 15 letters
`
`94.3
`
`96.4
`
`64.3
`
`Verteporfin
`(N = 143)
`
`0.3 mg of
`Ranibizumab
`(N = 140)
`
`0.5 mg of
`Ranibizumab
`(N = 139)
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Loss of < 15 Letters (%)
`
`Quiram and Song
`
`0.5 mg of ranibizumab
`
`0.3 mg of ranibizumab
`
`Verteporfin
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`Month
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`15
`
`10
`
`5
`
`0
`
`−5
`
`−10
`
`−15
`
`Mean change in visual acuity
`
`(no. of letters)
`
`Mean Change from Baseline
`0.5 mg of ranibizumab
`0.3 mg of ranibizumab
`Verteporfin
`
`(day 7)
`+4.6
`+8.4
`+2.9 +5.9
`+3.9
`+0.5
`
`+9.8 +10.0 +9.9 +10.2 +10.6 +10.2 +10.9 +11.4 +10.9 +11.1 +11.3
`+6.4 +6.8
`+7.2 +7.4 +7.9
`+8.2
`+7.7
`+8.1
`+7.8
`+8.6 +8.5
`−1.8 −2.5
`−3.1 −4.1 −5.6 −6.8 −7.1 −7.1
`−8.3
`−9.1
`−9.5
`
`Figure 2. Data from ANCHOR trial. Top: Percentage of patients in each group who lost less than 15 letters (left) or gained 15 or more letters (right).
`Bottom: Mean change from baseline visual acuity during a 12 month period. Comparison between the ranibizumab groups (0.3 mg and 0.5 mg) and sham
`is shown below chart.
`
`lesion is completely inactive, and the “off label” use
`of the prescribed medication.
`
`CATT Trial
`Bevacizumab (Avastin) and Ranibizumab (Lucentis)
`appear to be similarly effective, and currently the CATT
`clinical trial (Comparison of AMD Treatment Trial) is a
`multicenter trial sponsored by the National Eye Institute
`
`which directly compares the effectiveness of Avastin
`and FDA approved Lucentis. Monthly dosing and “as
`needed” dosing will be compared in this 2-year study.
`We are currently awaiting the results of the study.
`
`Future Treatments
`intravitreal
`Because of
`the need for repeated
`injection in the above treatments, newer therapeutic
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`Treatment of ARMD
`
`injection. Results showed improvements in excess
`foveal thickness and median improvement of three
`letters.33 Patients tolerated the injection and the results
`demonstrated bioactivities of VEGF Trap-Eye. Testing
`with repeated injections for longer-term will be the
`next step in evaluating its potential as a therapeutic
`agent for ARMD.
`NT-501 (Neurotech pharmaceuticals, inc.)
`NT-501 is an intraocular polymeric implantable device
`containing modified human retinal pigment epithelium
`cells transfected with modified ciliary neurotrophic
`factor (CNTF) gene.34 The semipermeable membrane
`of the transplant allows diffusion of the CNTF
`protein to the intraocular space, while allowing the
`exchange of nutrients and waste products to sustain
`the viability of the cells. This delivery device
`circumvents the blood-retina barrier and the immune
`attack on implanted cells. The phase II clinical trial
`in 51 subjects with progressive geographic atrophy
`revealed stabilization of visual acuity of 97% of
`patients compared to 70% of controls at 12 months.
`Fenretidine
`Fenretidine inhibits of vitamin A delivery to the
`eye by displacing retinal-binding protein in the
`blood.35 It has been undergoing phase II clinical trials
`for dry ARMD. This trial is based on an original
`study that fenretinide can block the formation of
`lipofusion pigments in the retinal pigment epithelium in
`recessive retinitis pigmentosa knockout mice model.36,37
`Fenretidine is an oral agent that is used for the
`treatment of certain cancers and its role as a treatment
`for macular degeneration is being investigated.
`Other investigational therapies
`Sirolimus (rapamycin) is an immunosuppressive
`agent that inhibits the response of IL-2. The efficacy
`of this molecule in the treatment of exudative
`ARMD is being investigated in a Phase II study of
`ocular Sirolimus in combination with Ranibizumab
`(EMERALD study). “Double” and “triple” therapies
`using a combination of anti-VEGF agents, low fluence
`photodynamic therapy, intravitreal dexamethasone
`and external beam radiation have shown promise.39,40
`Conclusion
`Age-related macular degeneration is a chronic,
`vision threatening and increasingly prevalent disease.
`
`1009
`
`16
`14
`12
`10
`8
`6
`4
`2
`0
`
`Mean
`Median
`
`0
`
`1
`
`2
`
`3
`
`4
`6
`5
`9 10 11 12
`8
`7
`Months since intial injection
`
`Months since intial injection
`9 10 11 12
`8
`6
`5
`4
`7
`
`3
`
`1
`
`2
`
`0
`
`0
`
`Mean
`Median
`
`−40
`
`−80
`
`−120
`
`−160
`
`−200
`
`−240
`
`Number of letters gained
`
`Change in central retinal thickness
`
`Figure 3. Data from PrONTO trial. Top: Mean and median change in
`visual acuity through 12 months. Bottom: Mean and median change
`in the optical coherence tomography (OCT) central thickness through
`12 months.
`
`agents with longer half-life, high potency, minimal
`systemic side effects, and less invasive administration
`are being investigated. The following is a brief
`introduction to a few promising new agents.
`
`VEGF Trap (Regeneron pharmaceuticals, inc)
`VEGF Trap-Eye is a recombinant fusion protein of
`the Fc domain of human IgG1combined with a VEGF
`binding domain of human VEGF receptors 1 and 2.30
`Similar to bevacizumab and ranibizumab, it binds to
`all isoforms of VEGF. The key feature is a very high
`binding constant for VEGF, which is even higher than
`native VEGF receptors. This property leads to high
`potency and longer duration of action, suggested to
`last for 10 weeks.31 Although repeated intravitreal
`injections are required for administration, the longer
`duration of action is favorable. Systemic administration
`has been show to cause multiple side effects,32
`which have not been observed following intravitreal
`injection. In a recent phase I trial, 5 patients with
`diabetic macular edema received one-time intravitreal
`
`Clinical Medicine: Therapeutics 2009:1
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`Quiram and Song
`
`Although current therapies have dramatically changed
`visual outcomes of patients with this disease, future
`clinical trials and new therapies are necessary to
`address prevention and better refine early treatment
`of this chronic and debilitating disease.
`Disclosure
`The authors report no conflicts of interest.
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`
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