PHARMACOLOGIC THERAPIES

Pharmacotherapy to Amenable Diseases Retinal • 3 section

-Age chapteNeovascular• 18

Degeneration Macular related

<20/50.16 The treatment strategy that was tested was “treat if there is leaking” on the angiogram. The studies were conducted before optical coherence tomography was available. Over 90% of patients required retreatment at 3 months; however, by year 5 of follow-up, patients were requiring less than one treatment per year. Subjects required about three treatments in the first year and two in the second. In contrast to MPS-style therapy, acute severe vision loss was uncommon, with less than a 4.4% incidence in both the TAP and VIP.

PEGAPTANIB

Pegaptanib is the first FDA-approved therapy for neovascular AMD to target VEGF specifically. A pegylated oligonucleotide aptamer, it was designed to have a high binding specificity for only the VEGF165 isoform which is known to stimulate pathologic neovascularization in the eye while not being required for physiologic vascularization. The VEGF Inhibition Study In Ocular Neovascularization (VISION) trials22,23 consisted of two multicenter controlled replicate trials that randomized a total of 1190 patients regardless of angiographic lesion subtype to receive one of three doses of pegaptanib or sham injection every 6 weeks for 54 weeks. Patients were then re-randomized to continue sham treatments, discontinue sham treatments, or be assigned to two of the three pegaptanib doses every 6 weeks for an additional 54 weeks. All doses were well tolerated and, at 54 weeks, 70% of patients receiving 0.3 mg pegaptanib lost fewer than 15 letters of visual acuity compared to 55% in the sham group (P < 0.001).23 At 102 weeks, patients who continued pegaptanib were half as likely to lose >15 letters of visual acuity than patients who discontinued pegaptanib.22 Pegaptanib outcomes are similar to PDT outcomes except the drug appears to be helpful for all CNV compositions so a wider range of subjects can be treated.

RANIBIZUMAB

It has been hypothesized that pegaptanib’s unique specificity for VEGF165 isoform may actually have been its downfall. Its successor, ranibizumab, was developed as a recombinant, humanized monoclonal antibody Fab fragment that binds all active isoforms of VEGF-A with high affinity. Approved by the US FDA in 2006 for the treatment of all angiographic subtypes of subfoveal neovascular AMD, ranibizumab is the first treatment for neovascular AMD that has afforded patients a significant chance for improvement in visual acuity.

The safety and efficacy of ranibizumab in minimally classic and occult subfoveal CNV were evaluated in a 2-year, prospective, randomized, double-masked, sham-controlled trial. The Minimally classic/ occult trial of the Anti-VEGF antibody Ranibizumab in the treatment of neovascular Age-related macular degeneration (MARINA) trial24 randomized 716 patients to receive one of two doses of intravitreal ranibizumab or sham injections every month for 24 months. At 12 months, 95% of patients receiving ranibizumab lost < 15 letters (about 3 lines) of visual acuity compared to 65% of subjects receiving sham injections (P < 0.001) (Figure 18.1). At 24 months, this difference was maintained, with 92% and 90% of patients receiving 0.5 mg and 0.3 mg of ranibizumab losing < 15 letters of visual acuity (compared to 52.9% of control subjects). Further, 34% and 25% of patients receiving 0.5 mg or 0.3 mg of ranibizumab gained 15 letters of visual acuity, compared to 5% of control subjects (P < 0.001).24

The Anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization in AMD (ANCHOR) trial,25 another 2-year, randomized, prospective double-masked study, reported similar results for the treatment of predominantly classic CNV with ranibizumab. A total of 423 patients were randomized in a 1 : 1 : 1 ratio to receive either monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) or verteporfin PDT on study entry and every 3 months thereafter according to accepted guidelines. At 12 months, 94.3% of patients receiving 0.3 mg of ranibizumab and 96.4% of patients receiving 0.5 mg of ranibizumab lost < 15 letters of visual acuity, compared with 64.3% of controls (P < 0.001) (Figure 18.1). Further, 35.7% of the 0.3-mg group

Figure 18.1  Percentage of subjects losing fewer than 15 letters of visual acuity at 12 and 24 months in the Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab in the treatment of neovascular Age-related macular degeneration (MARINA) trial and at 12 months in the Anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization in AMD (ANCHOR) trial. 24-month outcomes have not been published for

the ANCHOR trial. *P < 0.001; PDT, photodynamic therapy; 0.3 mg, 0.5 mg, dose of intravitreal ranibizumab.

and 40.3% of the 0.5-mg group gained 15 letters of visual acuity compared to 5.6% of the verteporfin PDT group (P < 0.001).25

The RhuFab V2 Ocular treatment Combining the Use of Visudyne to evaluate Safety (FOCUS) trial26 established the superior efficacy of treatment with the combination ranibizumab and verteporfin PDT over treatment with PDT alone. Because the primary goal was the evaluation of treatment safety, patients who were previously treated with PDT were not excluded. All 162 patients received PDT initially then quarterly as needed for 24 months; however patients were also randomized in a roughly 2 : 1 ratio to receive monthly 0.5-mg ranibizumab injections or sham injections. The study found a distinct benefit of adding bevacizumab, with 90% and 88% of patients receiving bevacizumab losing < 15 letters of VA at month 12 and 24, compared to 68% and 75% for PDT alone (P < 0.001, P < 0.05) (Figure 18.2). At 24 months, 25% of patients in the bevacizumab + PDT group gained 15 letters, compared to 7% for PDT alone (P < 0.05).26

Despite the unprecedented consistent efficacy of ranibizumab, the requirement for monthly injections administered for an indefinite period and cost of the drug pose a significant treatment burden.

Several studies have attempted to define alternative dosing strategies for anti-VEGF therapies that decrease dosing frequency without compromising efficacy. The Phase IIIb, multi-center, randomized, doublemasked, sham-Injection-controlled study of the Efficacy and safety of Ranibizumab (PIER) study randomized 184 patients with subfoveal CNV of any lesion subtype to receive either sham injections or 0.5 mg ranibizumab monthly for 3 months followed by quarterly dosing for a total of 24 months. For the first 3 months, visual acuity and ocular coherence tomography (OCT) improvements mirrored that observed in the ANCHOR and MARINA trials; however, after 12 months, the mean change in visual acuity from baseline was a loss of 1.6 letters.27 Thus, scheduled dosing of ranibizumab every 3 months was judged to be inferior to monthly dosing.

Monthly intravitreal ranibizumab for the first 3 months, followed by pro re nata (PRN) OCT-guided therapy, is an alternate dosing strategy for which data appear more promising. The Prospective OCT imaging of patients with Neovascular age-related macular degeneration Treated with intra-Ocular Lucentis (PrONTO) trial28 treated as such with retreatment decisions based on increase in central retinal thickness (CRT) of at least 100 m, visual loss associated with edema on OCT, presence of new classic CNV on fluorescein angiography, and presence of new hemorrhage or persistent fluid on OCT. Patients on average received 5.6 injections over the course of the 12-month study period. Further, mean retinal thickness had decreased by 178 m and visual

Figure 18.2  Percentage of subjects losing fewer than 15 letters of visual acuity at 12 and 24 months in the RhuFab V2 Ocular treatment Combining the Use of Visudyne to evaluate Safety (FOCUS) trial. *P < 0.001, **P < 0.05; PDT, photodynamic therapy; 0.5 mg, dose of intravitreal ranibizumab.

acuity had improved by 9.3 letters, with 35% gaining >15 letters.28 The ongoing Sustain trial will provide data on the safety and efficacy of ranibizumab administered as three consecutive monthly loading doses followed by retreatment based on visual acuity loss of >5 letters or increase in CRT > 100 m on OCT. Interim analysis revealed that, of the 531 patients enrolled, the first 69 ranibizumab-naïve patients to complete the 12-month study required a mean (± sd) of 5.3 (±2.2) injections and gained approximately 7 letters of acuity.29

BEVACIZUMAB

Around the time that ranibizumab was in phase I/II clinical trials, another nonselective VEGF-A inhibitor, bevacizumab, was approved by the FDA for treatment of metastatic colon cancer. Due to concern about the ability of this large molecule to gain access to CNV by diffusion through retina, it was not initially suggested as therapy for neovascular AMD. However, after animal studies showed leakage of fluorescein-conjugated bevacizumab from laser-induced CNV, Michels et al.30 initiated a small-scale investigation of off-label intravenous bevacizumab for subfoveal CNV. Twelve-week data showed good tolerability (aside from a 12-mmHg mean increase in systolic blood pressure) and marked improvement in visual acuity, OCT, and angiographic outcomes. Subsequently, several small series of intravitreal administration of bevacizumab31 echoed the initial favorable reports of safety and efficacy.

Bevacizumab costs physicians approximately $45 per injection while ranibizumab costs approximately $2030. In the USA, the co-pay for Medicare-insured patients is $9 and $406, respectively. In addition to a price ratio of 39 : 1 with respect to bevacizumab, ranibizumab may also pose the disadvantage of decreased durability per treatment. The intravitreal half-life of bevacizumab and ranibizumab determined in animal studies is 4.32 and 2.88 days.32 Remission intervals (time until retreatment as indicated by OCT) accordingly were found to be longer for bevacizumab (141 days) compared to ranibizumab (102 days).33 On the other hand, a longer half-life may have drawbacks with regards to systemic side-effects and toxicity. The reader is referred to Section 4 for additional discussion of the safety of bevacizumab for intravitreal injection.

To date, there have been no randomized double-blinded clinical trials to compare ranibizumab and bevacizumab. However, the Comparison of Age-Related Macular Degeneration Treatments Trial (CATT)34 which began enrollment in early 2008 will determine which of the following four regimens should be used as the standard of comparison for subsequent clinical trials: bevacizumab or ranibizumab on a fixed dosing schedule of every 4 weeks, or bevacizumab or ranibizumab on a variable (PRN) dosing schedule. A total of 1200 patients with AMD and active subfoveal CNV (without previous treatment) will be enrolled and followed every 4 weeks for 2 years.

COMBINATION THERAPY

While intravitreal anti-VEGF monotherapies offer unprecedented benefit with regard to visual outcome, therapy with monthly intravitreal injection administered for a prolonged period poses significant drawbacks, including additional safety risk, financial burden, and the inconvenience of monthly visits to the ophthalmologist. There is also the theoretical risk of upregulation of VEGF receptors or compensatory upregulation of VEGF production in the setting of long-term use of anti-VEGF therapy. Further, unlike verteporfin PDT, which exerts its effect through a unique angio-occlusive mechanism, anti-VEGF agents fail to destroy existing CNV. Combined therapy with ranibizumab or bevacizumab and PDT offers the potential for a synergistic effect through concomitant elimination of existing CNV and prevention of new CNV. Combination therapy with PDT may also allow for decreased frequency of anti-VEGF therapy.

Augustin et al.35 reported visual and OCT outcomes for a prospective interventional case series of 104 patients who received one cycle of triple therapy (reduced fluence PDT followed 16 hours later by intravitreal dexamethasone and bevacizumab). Only 5 patients required a second round of triple therapy due to ongoing CNV activity over mean followup of 40 weeks (range 22–60 weeks). Further, mean increase in visual acuity was 1.8 lines and mean decrease in retinal thickness was 182 m.35 A more recent pilot study of intravitreal triamcinolone acetonide (IVTA) as an adjunct to PDT provides additional support for the role of corticosteroids in the treatment of neovascular AMD. Thirty patients with occult and minimally classic CNV secondary to AMD were randomized to receive either PDT or PDT followed by 12 mg IVTA, with both groups receiving additional PDT as needed quarterly for a year. The difference in visual acuity did not achieve statistical significance at 1 year; however, the mean number of PDT treatments for the IVTA + PDT group (1.13 treatments) was significantly lower than for the PDT alone group (3.6 treatments; P < 0.001).36 However, 40% of patients in the IVTA group required topical glaucoma therapy for intraocular pressure control.

The ongoing Denali trial and its European counterpart, the Mont Blanc trial, are the first large-scale randomized studies to compare ranibizumab monotherapy with ranibizumab combination therapy (with standard or reduced fluence PDT). Approximately 300 patients will be followed for 2 years in order to determine whether combination therapy reduces the frequency of treatments. Primary endpoints will measure the proportion of patients with a treatment-free interval of at least 3 months and best corrected visual acuity at 12 months using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol.

TREATMENTS UNDER INVESTIGATION

Several new pharmacotherapies aim to halt the angiogenic effects of VEGF by inhibiting the production of either VEGF (bevasiranib) or its receptor (AGN211745). Other potential mechanisms include upregulation of the antiangiogenic factor, PEDF (AdPEDF.11), or blockade of the tyrosine kinase cascade (vatalanib, pazopanib) downstream from the VEGF receptor. VEGF-Trap, which binds existing VEGF like ranibizumab and bevacizumab, is emerging as a potentially important therapy. A recent dose escalation trial (n = 157) reported no ocular adverse events, a 160-m decrease in CRT, and a 9.3-letter gain at 12 weeks following monthly 0.5-mg intravitreal VEGF-Trap.37 These and other emerging therapies will be discussed in greater detail in Section 4.

Another newer technique for use in conjunction with ranibizumab involves intraocular application of 24 Gy beta-irradiation directly to CNV via a 20-gauge cannula fitted with a small strand of strontium-90. The low-level radiation preferentially targets the CNV, leaving overlying healthy retina unaffected. Used in combination with ranibizumab, preliminary results have been promising and a prospective randomized trial is under way. Focal radiotherapy combined with ranibizumab both postoperatively and either intraoperatively (n = 22) or preoperatively (n = 12) showed an average 11.4-letter gain in acuity at 9 months for both groups combined. In all, 93% of patients lost less than 15 letters at

Pharmacotherapy to Amenable Diseases Retinal • 3 section