ByDonald J. D’Amico, MD

May 01, 2006

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Pharmacotherapy with anti-VEGF agents: Implications for clinical practice

ByDonald J. D’Amico, MD

Treatment options for wet age-related macular degeneration are numerous. Selecting the right one depends not only on patient and physician considerations, but also on evaluation of clinical data.

Available therapies

Therapies that have the highest level of evidence for efficacy include laser photocoagulation, photodynamic therapy with verteporfin (Visudyne, Novartis) and intravitreal anti-vascular endothelial growth factor (VEGF) therapy with pegaptanib (Macugen, [OSI] Eyetech) and ranibizumab (Lucentis, Genentech). Beyond these proven therapies, however, physicians also use two additional therapies — PDT in combination with intravitreal triamcinolone, and intravitreal bevacizumab (Avastin, Genentech) — which, although lacking in randomized clinical trial evidence, have been adopted by popular acclaim. Anecortave acetate (Retaane, Alcon) is a potent inhibitor of angiogenesis in many animal models and has had positive results in AMD clinical trials but is not yet approved in the United States, although it was recently approved for the treatment of wet AMD in Australia. Anecortave acetate is unique in that it has an attractive extraocular delivery at convenient 6-month intervals and will probably be used in combination with other therapies.

New combination treatments are also becoming viable options, and data are beginning to accumulate on the treatment combinations now available, such as PDT plus pegaptanib, PDT plus ranibizumab, PDT plus bevacizumab and triple therapies. Sequential therapies such as ranibizumab or bevacizumab induction followed by pegaptanib maintenance have also been proposed. These combination and sequential therapies will undoubtedly be the therapies of the future, and the task at hand is to substantiate the efficacy of the therapies and to discover appropriate monitoring means, such as optical coherence tomography or fluorescein angiography, to adjust the various components of treatment.

Considerations

Deciding on an appropriate therapy requires consideration of a patient’s concerns. A patient wants the best option to maintain vision. A patient does not want to inconvenience his or her family and does not want to experience adverse effects or outcomes. Expense is also an issue, and a patient wants to limit medical expenses as much as possible.

Deciding on an appropriate therapy requires consideration of a patient’s concerns. A patient wants the best option to maintain vision.
– Donald J. D’Amico, MD

Ophthalmologists also have specific considerations related to individual treatments: They want to avoid treatment-related adverse effects and outcomes. Nonclinical considerations are also important. Ophthalmologists are concerned about how introducing a new treatment will affect office procedures, patient flow and staffing. Loss of income and the ongoing struggle to control costs will also play a role.

Ophthalmologists want to base their treatment selection and ongoing care decisions on clinical evidence. To date, in my opinion, most clinicians have been disappointed with early AMD treatment results. Various clinical trial designs, results and distinctions have created uncertainty among ophthalmologists.

Exploratory analyses

It may be useful to reexamine pivotal AMD trials, paying attention to subgroup analyses or extrapolating the available data.

In VISION (VEGF Inhibition Study in Ocular Neovascularization), pegaptanib led to significant improvements in vision change.¹ Thirty-three percent of patients who received 0.3 mg of pegaptanib maintained or gained visual acuity, compared with 23% of patients who received sham injections (P = .003). The risk of severe loss of visual acuity decreased from 22% in the sham-injection group to 10% in the pegaptanib group (P < .001).

Because the VISION trial was performed at a time when treatment for many of the eyes enrolled did not exist, a substantial number of the lesions included were older and perhaps less responsive to therapy. Since that time, ophthalmologists have been able to treat newer lesions. Randomized data on new lesion treatment do not exist, but VISION may provide answers. One may consider two distinct types of early lesions, which will be called type 1 or type 2. Type-1 lesions can be defined as lesion size less than 2 disc areas, in a patient with baseline visual acuity of at least 54 letters, no previous PDT/thermal laser and no scar/atrophy. Type-2 lesions can be defined as occult, in a patient with no lipid and in whom the study eye is first affected eye. In looking at the subgroups with type-1 lesions in the VISION trial, pegaptanib protected against moderate vision loss with 77% of 62 patients with type-1 lesions avoiding a 15-letter loss, compared with 50% of patients who received a sham injection plus PDT (Figure 1). PDT was also permitted in the pegaptanib arm. The rate of severe vision loss, defined as six or more lines, was 29% for patients who received usual care, compared with 3% for patients who received pegaptanib.

Enhanced Efficacy in Early Disease

Figure 1. Seventy-seven percent of 62 patients with type-1 lesions avoided a 15-letter loss when treated with pegaptanib.

Source: D’Amico DJ

Among patients with type-1 lesions, 12% who received pegaptanib gained three or more lines of visual acuity, compared with 4% of patients who received sham injections. Among 65 patients with type-2 lesions, 20% who received pegaptanib gained three or more lines, compared with none of the patients who received sham injections (Figure 2).

Exploratory analyses carry limitations of which ophthalmologists should be aware. The sample size is small, and it is impossible to control for all baseline, confounding characteristics. False negatives and positives may also occur.

Enhanced Efficacy in Early Disease

Figure 2. Twenty percent of 65 patients with type-2 lesions gained three or more lines of visual acuity when treated with pegaptanib.

Source: D’Amico DJ

Comparisons

With the subgroup analyses in mind, it is probable that the contemporary results with pegaptanib are substantially better than results available in the VISION trial, given the above consideration for treatment of earlier lesions. This leads to other questions. Is pegaptanib better than PDT alone? For occult and minimally classic lesions, the answer is yes. For classic lesions, the answer is almost certainly yes based on the exploratory analyses of the VISION data. A related question is whether pegaptanib plus PDT is better than pegaptanib alone. A 60% response rate with the combination in a phase-1b trial of 18 patients suggests that it may be, but an answer may need to wait for an ongoing trial.

Other anti-VEGF agents can be compared with pegaptanib. Ranibizumab appears to be more efficacious than pegaptanib.

Bevacizumab also appears to be more efficacious than pegaptanib.² One week after treatment, 55% of patients had more than10% reduction of baseline retinal thickness. Median vision improved from 20/200 to 20/80 at 4 weeks and at 8 weeks. Nevertheless, safety and liabilitity concerns are associated with bevacizumab use, and patients and physicians must consider many factors before selecting such an unapproved, off-label therapy.

Treatment decisions

While ophthalmologists wait for ongoing and future trials to provide definitive clinical data about how to best treat patients with wet AMD, I continue to treat all of my patients with wet AMD with pegaptanib. I would consider a bevacizumab booster for patients in whom pegaptanib has not stabilized the lesion or vision and for patients in whom vision is deteriorating, in clinically meaningful terms. For these patients, I am willing to offer bevacizumab, mindful of the safety/liability risks and informing the patients of a potential harm to their health. I am interested in new combination and sequential therapies, but will wait for clear data before adopting them.

References
Gragoudas ES, Adamis AP, Cunningham ET Jr, et al for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113;363-372.

Recent studies on anti-VEGF therapy

Anti-vascular endothelial growth factor (VEGF) therapy is emerging as a rapidly evolving field in the treatment of age-related macular degeneration. Studies have demonstrated that anti-VEGF agents inhibit vascular permeability and blood vessel growth. Recent studies exploring the safety and therapeutic effects of anti-VEGF agents ranibizumab, bevacizumab and pegaptanib are detailed below.

Ranibizumab

In a multicenter, controlled, open-label clinical trial, researchers evaluated the safety of repeatedly injecting ranibizumab intravitreally to treat neovascular AMD. In addition, changes in visual acuity and traits of AMD lesions were assessed.
In part 1 of the randomized study, 53 patients received monthly intravitreal ranibizumab for 3 months and 11 patients received usual care. Part 2 of the study allowed patients to continue the same care for 3 more months or switch to the other treatment method.
Sixty-two out of the 64 patients with subfoveal predominantly or minimally classic AMD-related CNV completed the two-part study. Forty-two patients receiving ranibizumab in part 1 continued that treatment in part 2, and nine patients receiving usual care in part 1 switched to ranibizumab treatment in part 2.
Results demonstrated adverse events with ranibizumab including reversible inflammation and minor injection-site hemorrhages, which were the most common, and iridocyclitis, endophthalmitis and central retinal vein occlusion, affecting one patient each. Some patients (22.6%) treated with ranibizumab in parts 1 and 2 experienced transient IOP increase. Visual acuity increased in patients treated with ranibizumab and decreased in patients treated with usual care. Areas of leakage and subretinal fluid decreased in ranibizumab patients.
Investigators concluded that repeated intravitreal injections of ranibizumab appeared safe and correlated with improved visual acuity. Additionally, patients with neovascular AMD experienced decreased leakage from CNV.

Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for treatment of neovascular age-related macular degeneration: A phase I/II multicenter, controlled, multidose study. Ophthalmology. 2006. In press.

Researchers performed a study on eight cynomolgus monkeys to assess the effect of intravitreal injection of ranibizumab combined with verteporfin PDT.
In each monkey, intravitreal ranibizumab was administered in one eye; placebo was administered in the other eye. Monkeys were treated weekly with verteporfin PDT in both eyes for 6 to 7 weeks.
Fluorescein angiography showed increased retinal pigment epithelial changes with window defects in both eyes of all monkeys. Complications were not attributed to ranibizumab. Eyes treated with PDT alone demonstrated reduced choriocapillaris density in the irradiated area.
Researchers concluded that, compared to PDT alone, there were no severe adverse effects with the combination treatment.

Kim IK, Husain D, Michaud N, et al. Effect of intravitreal injection of ranibizumab in combination with verteporfin PDT on normal primate retina and choroids. Invest Ophthalmol Vis Sci. 2006;47:357-363.

In an open-label, five-center, uncontrolled, prospective, dose-ranging, interventional case series study, researchers investigated the maximum tolerated dose of ranibizumab in one intravitreal injection.
Study participants included 27 patients with subfoveal CNV and BCVA of 20/100 or worse who were not eligible for laser photocoagulation or PDT.
Six escalating doses (50, 150, 300, 500, 1000 and 2000 µg) of a single intravitreal injection of ranibizumab were planned. Dosing at the next level would only occur after the lower dose was found safe and tolerable.
The dose limit was measured by intraocular inflammation, increased IOP, reduced visual acuity or hemorrhage within 90 days of injection.
Significant intraocular inflammation occurred with the 1000-µg dose of intravitreal injection of ranibizumab. Investigators concluded that 500 µg was the maximum tolerated single dose of ranibizumab.

Rosenfeld PJ, Schwartz SD, Blumenkranz MS, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology. 2005;112:1048-1053.

Bevacizumab

Investigators evaluated the retinal penetration and toxicity of bevacizumab in 10 albino rabbits.
In each rabbit, 0.1 mL of bevacizumab was injected intravitreally into one eye. Saline (0.1 mL) was administered in the other eye.
Electroretinogram responses of all eyes, recorded after 3 hours, 3 days and 1, 2 and 4 weeks, demonstrated similar amplitude and pattern. The experimental eyes showed normal pattern and amplitude with flash visual evoked potential. Additionally, full thickness retinal penetration was observed at 24 hours but absent at 4 weeks.
Researchers concluded that bevacizumab was nontoxic to rabbit retinas and that clinical effects of intravitreal bevacizumab are possibly due to full thickness retinal penetration.

Shahar J, Avery RL, Heilweil G, et al. Electrophysiologic and retinal penetration studies following intravitreal injection of bevacizumab (Avastin). Retina. 2006;26:262-269.

Investigators assessed the short-term electrophysiologic effects of intravitreal bevacizumab in the treatment of exudative AMD.
Prior to treatment with bevacizumab, nine patients were tested with multifocal electroretinography (mf-ERG) or Ganzfeld electroretinography (G-ERG). Five patients tested with G-ERG underwent repeated testing at 1 week after intravitreal bevacizumab. One month after treatment, the four patients tested with mf-ERG, as well as four of the five patients tested with G-ERG, were tested again with the same pretreatment protocol. A second intravitreal injection of bevacizumab was administered to one G-ERG patient 6 weeks after initial treatment. One month following this second dose, the patient underwent repeated testing
Results showed all mf-ERG patients had improved macular response at 1 month after treatment. No significant changes in electrophysiologic response were observed in G-ERG patients. At 1 month after treatment, central subfield thickness, as measured by optical coherence tomography, decreased. In addition, most patients experienced improved visual acuity.
Investigators showed that intravitreal bevacizumab improved mf-ERG macular function responses and maintained stable G-ERG responses. Treatment improves macular function, according to the macular electrophysiologic response. In addition, short-term use of intravitreal bevacizumab does not result in any significant measurable photoreceptor toxicity.

Maturi RK, Bleau LA, Wilson DL. Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina. 2006;26:270-274.

In an open-label, single-center, uncontrolled clinical study, researchers assessed the short-term safety of systemic bevacizumab in patients with neovascular AMD. They also evaluated the effects on visual acuity and subfoveal CNV.
At baseline, nine patients were treated with a 5-mg/kg infusion of bevacizumab. One or two additional doses were administered at 2-week intervals.
Researchers noted no serious ocular or systemic adverse events. Systolic blood pressure was mildly elevated by week 6 but was subsequently controlled by changing or initiating antihypertensive medication. The elevation of systolic blood pressure was not significant by week 12.
Results also showed significant visual acuity increases at week 1 in the study eyes. The median visual acuity letter scores increased by eight letters and the mean visual acuity letter scores increased by 12 letters by week 12. In addition, central retinal thickness measurements decreased.
At 12 weeks, the median visual acuity letter scores increased by 27 letters in the fellow eyes (mean increased by 16 letters), and central retinal thickness measurements decreased.
Significant reduction or absence of CNV leakage was observed in all eyes.
Researchers concluded that bevacizumab was well tolerated and that visual acuity, optical coherence tomography and angiographic outcomes improved.

Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112:1035-1047.

Pegaptanib

In a retrospective analysis of a randomized clinical trial that assessed pegaptanib treatment for diabetic macular edema, investigators evaluated the effects of intravitreal pegaptanib on retinal neovascularization.
Patients evaluated in this analysis had best corrected visual acuity letter scores between 68 and 25. At the outset of the study, at week 6 and week 12, patients received a sham injection or 0.3 mg, 1 mg or 3 mg of intravitreal pegaptanib. Additional injections and/or focal photocoagulation (a maximum of six therapies) were administered as needed throughout the study’s 18 weeks.
Nineteen patients with retinal neovascularization in the study eye at baseline were evaluated. After three excluded patients, 16 were evaluated.
Results showed 62% of the pegaptanib-treated patients had regression of neovascularization on fundus photographs and/or regression or absence of fluorescein leakage from neovascularization at week 36.
Researchers concluded that pegaptanib directly affects retinal neovascularization in patients with diabetes mellitus.

Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology. 2006;113:23-28.

Researchers performed a retrospective chart review to evaluate IOP after intravitreal injection of pegaptanib in the treatment of exudative AMD.
Pegaptanib’s short-term effect on IOP was evaluated in 79 patients who had 122 consecutive injections.
At baseline, the mean IOP was 15.73 6 3.41 mm Hg. Following pegaptanib injection, the mean IOP was 24.47 6 6.29 mm Hg. Thirty minutes after injection, the mean IOP changed 8.74 6 7.23 mm Hg. Normalized IOP was observed at the 5- to 7-day follow-up.
Regarding IOP, pegaptanib injection in this series exhibited short-term safety.

Hariprasad SM, Shah GK, Blinder KJ. Short-term intraocular pressure trends following intravitreal pegaptanib (Macugen) injection. Am J Ophthalmol. 2006;141:200-201.

Investigators concurrently performed two randomized, double-masked trials in 1,208 patients with exudative AMD and analyzed the data as a single study.
Patients received 0.3 mg of intravitreous pegaptanib or sham injections. Treatment was administered every 6 weeks for 48 weeks.
Seventy percent of pegaptanib patients lost less than 15 letters of visual acuity at 54 weeks, whereas only 55% of sham-injected patients lost less than 15 letters.
A 1-year trial extension showed that improved visual acuity with pegaptanib was maintained.
Researchers associate pegaptanib’s vision-improving effects to beneficial angiographic effects.
Results demonstrated that pegaptanib was well tolerated, and most ocular adverse events were mild to moderate and transient. Only 1.3% of pegaptanib patients experienced serious injection-related adverse events. In addition, researchers could not definitely attribute any systemic adverse events to pegaptanib.

Siddiqui MA, Keating GM. Pegaptanib: In exudative age-related macular degeneration. Drugs. 2005;65:1571-1577.