While bevacizumab is not a cure, the use of bevacizumab in combination with chemotherapy did prolong survival. One theory for this was that as tumor vasculature was deprived of oxygen and nutrients, tumor growth and metastasis were limited. Another hy­pothesis is that anti-angiogenic drugs like bevacizumab may tran­sient­­ly “normalize” the abnormal arch­i­tecture associated with neovascularization, improving the delivery of the drug and oxygen, thereby increasing the efficiency of conventional che­mo­therapy.7 Whatever the mechanism of action, an anti-VEGF drug like bevaci­z­u­mab may be beneficial for any ocu­lar disease in which neovascularization and edema play a major role, particularly diseases like neovascular AMD, diabetic retinopathy, vein occlusions, neovascular glaucoma and re­ti­no­pathy of prematurity.

Systemic Bevacizumab

The role of VEGF in neovascular AMD has now been confirmed as the result of the Phase III clinical trial of the anti-VEGF drug pegaptanib sodium (Macugen, Eyetech).8 Pe­gap­ta­nib sodium is now approved for the treatment of all neovascular AMD; however, the average pegaptanib-treated patient still continues to lose vision while receiving therapy.8 Another anti-VEGF drug known as ranibizumab (Lu­­centis, Genentech) was shown to im­prove visual acuity, angiographic and optical coherence tomography out­comes in open-label, uncontrolled Phase I/II studies. Genentech’s one-year, Phase III results confirm earlier studies in AMD pa­tients. Patients with predominantly oc­cult macular neovascularization treated with ra­ni­biz­u­mab had an overall vision improvement and statistically significant better outcomes than the sham-injected controls.

Ranibizumab is a humanized, antibody fragment against VEGF and is derived from one of the binding arms of a full-length murine monoclonal antibody. The same monoclonal antibody was as precursor for bevacizumab.9 When we observed the beneficial responses in our patients receiving the ra­nibizumab during the Phase I/II studies, we proposed that bevaciz­u­mab, the full-length antibody against VEGF, could also be used as a treatment for neovascular AMD. One po­tential advantage is the use of intrave­nous injection, which avoids the discomfort and risks associated with an intraocular injection. In addition, a single systemic dose can treat both eyes. The disadvantages of systemic therapy, however, include systemic exposure to an antiangiogenic drug at therapeutic levels, resulting in a higher risk of systemic adverse events compared to intravenous injection.

SANA

In the spring of 2004, we initiated the Systemic Avastin for Neovascular AMD (SANA) study at the Bascom Palmer Eye Institute. In this study we offered systemic bevacizumab as salvage therapy for patients who were not candidates for verteporfin photodynamic therapy or who refused PDT. Pe­gaptanib sodium was not yet commercially available. Unlike the re­gi­mens used in cancer therapy, we proposed treating patients only two or three times followed by a period of close observation, with retreatment pos­sible if the leakage from the neovascularization recurred. The full de­tails of this study and the preliminary results from the first nine subjects followed for 12 weeks were published in the June issue of Oph­thal­mo­logy.10 Since this article was published, a total of 18 patients have been followed for at least 24 weeks, and the 24-week results confirm and improve upon the pre­liminary results observed at 12 weeks (submitted for publication). Of the 18 patients, nine initially received three treatments, and 11 received only two treatments. The majority of pa­tients did not require another treatment through 24 weeks.

With improvement in visual acuity, OCT and angiographic outcomes, the systemic use of bevacizumab ap­peared to be both effective and du­rable. Moreover, the cost of intrave­nous bevacizumab therapy is comparable to the cost of pegaptanib therapy. The average drug cost for bevacizumab is $2,200 per infusion, and the cost for the 24 weeks of therapy is $4,400 for most patients, roughly equi­­valent to four intravitreal injections of pegaptanib over 24 weeks.

The only significant adverse event ob­served in our study group was a mild elevation of blood pressure that was easily controlled with anti­hy­per­ten­sive medication. There were no thromboembolic events in our study group; however, we have far too few patients, and our follow-up has been far too short for us to know the true in­cidence of adverse events.

It must be noted that in the earlier can­cer trials of bevacizumab, there were serious, life-threatening ad­verse events attributable to the drug, and the most significant serious ad­verse event was doubling of throm­bembolic risk from 1.9 percent to 4.4 percent. The FDA and Ge­nen­tech is­sued warning let­ters regarding this adverse event in August 2004 and again in January 2005. Most other sig­nificant ad­verse events identified were probably related to the type and lo­­cation of the malignancy being treated.

We suspect that the increased risk of thromboembolic events observed in the cancer population treated with che­motherapy and bevacizumab every two weeks for months or years will not necessarily be the same risk in our AMD patients receiving three or four bevacizumab treatments over a year. We continue to be extremely vigilant in our selection and monitoring of pa­tients in the study.

Despite the impressive results in a small number of patients with neovascular AMD, a large, multicenter clinical trial of systemic bevacizumab ap­pears unlikely. Neither Genentech nor the Na­tional Eye Institute seems likely to fund such a trial, and few unfunded cli­nical sites would be willing to treat and coordinate the number of patients necessary to make a large trial possible. We calculate that a study with a power of 95 percent to detect a doubling of thromboembolic events in our AMD population would require 420 par­ticipants.

Intravitreal Bevacizumab

Bevacizumab was used as an in­tra­vit­real injection in humans in any of the early clinical studies. The preclinical data in primates suggested that intravitreal bevacizumab would be too large to penetrate the retina and re­sult in any therapeutic effect, but be­va­ciz­u­mab was never tested in an animal model of macular neovascularization to see if this assumption was correct.11 Once we observed the dramatic results of systemic intravenous be­va­cizumab in patients with neovascular AMD, we proposed that a much lower dose of bevacizumab injected into the eye could result in a similar benefit while reducing the risk of systemic ad­verse events. We calculated that a dose of about 1 to 1.5 mg of bevaciz­u­­mab would be ap­prox­­imately 400-fold less than the sys­temic dose of bev­­acizumab used in the SANA study.

Another appealing feature of in­tra­vitreal bevacizumab is its low cost. Com­­­pared with the cost of pegaptanib sodium, an intravitreal dose of beva­ciz­­­umab would be a bargain. While a dose of pegaptanib (0.3 mg) is ap­prox­imately $1,000 or $3,300 per mg, the proposed 1-mg dose of beva­ciz­­u­mab would cost $5.50. Moreover, a dose of 1 to 1.25 mg could be conveniently injected using 0.04 ml to 0.05 ml of the commercially supplied be­va­c­­­iz­umab, which is not known to contain preservatives or additives that may be toxic to the retina. At the Bas­com Palmer Eye Institute, we have of­fered off-label intravitreal bevacizumab to patients as a salvage treatment for those who continue to lose vision as­­sociated with neovascular lesions and worsening OCT profiles despite treatment with approved therapies. In our first report of a patient receiving in­travitreal bevacizumab, we observed improvement in angio­graph­ic and OCT outcomes after one injection, near­ly identical to the outcomes we ob­served following systemic bevaci­zumab and intravitreal ranibizumab. The patient’s vision remained stable over four weeks, and this patient has remained stable through six months and has not required another injection.12

Since this first patient was injected, our clinical, anecdotal experience with intravitreal bevacizumab has grown, and the positive outcomes we ob­served in this first patient have been re­liably reproduced in other patients. It is now obvious that a large, prospective clinical study must be initiated to de­termine the safety and efficacy of intravitreal bevacizumab. With an in­tra­vitreal half-life that may be twice as long as ranibizumab,13 we may be able to dose less frequently than ra­ni­biz­umab, perhaps every eight weeks or 12 weeks. If intravitreal be­va­ciz­u­mab proves to be safe and ef­fective for the treatment of neovascularization and macular edema from a wide range of ocular diseases, then intravitreal bevacizumab would have immediate global impact because of its low cost and worldwide availability.

Dr. Rosenfeld is an associate professor of ophthalmology at Bascom Palmer Eye Institute.

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2. Hurwitz H, Fehrenbacher L, Novotny W, et al. Be­vacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350(23):2335-2342.

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4. Kabbinavar FF, Hembleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin im­proves survival in patients with metastatic colorectal cancer. J Clin Oncol 2005;23(16):3706-3712.

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Lucentis Trials Show Promise in Halting Choroidal Neovascularization Ranibizumab (Lucentis, Genentech) is a recombinant, humanized fragment antigen binding of a monoclonal antibody against human endothelial growth factor. In three Phase I and open label multicenter Phase I/II studies in patients with primary or recurrent subfoveal neovascular AMD, intravitreal injections of ranibizumab ap­­peared to be safe and well-tolerated for treatment periods up to seven months. In these studies, ranibizumab demonstrated improvements in visual acuity, decreases in total area of leakage by fluorescein angiography, and decreases in retinal thickness by optical coherence to­mo­graphy. Additional trials are evaluating the clinical benefit of ranibizumab in patients with predominantly classic or minimally classic/occult CNV. Their status as reported at this year’s American Academy of Oph­thal­mo­logy meeting:  • MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neo­vas­cular AMD). This Phase III multicenter, randomized, double-masked, sham injection-controlled trial included 716 patients with minimally classic/occult CNV secondary to AMD. Eligible patients had not previously received subfoveal laser treatment, verteporfin (Visudyne) photodynamic therapy, or experimental treatments for their AMD in the study eye. Patients were randomized 1:1:1 to sham injection or to ranibizumab (0.3 mg or 0.5 mg) injected intravitreally monthly for 24 months. The primary efficacy endpoint is the proportion of subjects losing less than 15 ETDRS letters at one year. Approximately one-third of the patients had minimally classic CNV and two-thirds had occult CNV. Preliminary analysis of one-year MARINA data revealed that approximately 95 percent of patients treated with ran­i­­bizumab lost fewer than 15 letters at one year, compared to approximately 62 percent in the control group (p<.0001). On average, the patients treated with rani­biz­u­mab had a significant visual acuity improvement compared to baseline, while the control group experienced a substantial decrease from baseline in mean VA. Ocular adverse events were similar to those of earlier trials, and no increase in the serious non-ocular adverse events relative to the control group was noted. The incidences of uveitis and endophthalmitis were each less than 1 percent.  • FOCUS (RhuFab V2 Ocular Treatment Combining the Use of Visudyne to Evaluate Safety) is a randomized, single-masked, Phase I/II trial investigating safety, tolerability and efficacy of ranibizumab 0.5 mg in combination with verteporfin PDT versus verteporfin PDT alone in patients with subfoveal predominantly classic CNV due to AMD. One week before the first administration of either intravitreal ranibizumab or sham injection to the study eye, patients are treated with verteporfin PDT, with as many as 23 additional monthly injections with rani­bizumab or sham injection. Patients may continue to receive verteporfin PDT at the investigators’ discretion and in accord with product labeling. The primary efficacy endpoint is the proportion of subjects losing fewer than 15 letters of VA at one year. The study enrolled 162 patients. The study has met its primary endpoint based on one-year data: Approximately 90 percent of patients treated with the combination therapy had stable or improved vis­ual acuity, compared with approximately 68 percent of patients in the control arm of PDT alone (p=.0003). Pa­tients treated with combination therapy had significantly improved average VA compared to baseline; mean VA in the PDT-alone control group decreased from baseline. There was an increased risk of uveitis in combination the­ra­py patients compared with those treated with PDT alone. The study protocol was amended after data safety monitoring identified this imbalance. Endophthalmitis was the next  most common ocular serious adverse event oc­curring in ranibizumab-treated patients. The frequency of cerebral vascular events was slightly higher in patients treated with ranibizumab, whereas myocardial infarctions were slightly more frequent in the PDT-alone arm; the differences between these groups was not statistically significant.  • ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) is a multicenter, randomized, double-masked, active-treatment controlled Phase III trial evaluating the safety and efficacy of ranibizumab in 423 subjects with predominantly classic subfoveal CNV, with sites in the United States, Europe and Australia. Inclusion criteria were the same as those of the MARINA study. Patients in this trial are being randomized 1:1:1 to either verteporfin PDT plus sham injection or to placebo PDT plus ran­i­bizumab (0.3 mg or 0.5 mg) monthly for 24 months. Patients in the ANCHOR trial are being evaluated by fluorescein angiography every three months to determine the need for additional PDT or placebo PDT. The study is ongoing.