The revelation that anti-vascular endothelial growth factor agents could be effective against choroidal neovascularization in exudative age-related macular degeneration was just the start of several investigations into the usefulness of these drugs. At this year’s ARVO meeting, researchers demonstrate how anti-VEGF therapy can be useful in diabetes, vein occlusion and in combination with other approaches. Here’s a look at their latest findings.

(Unless stated otherwise, the researchers have no financial interest in the techniques or technology discussed in their abstracts.)

Macular Edema

At this year’s meeting, researchers and scientists for Genentech will share the six- and 12-month results from the CRUISE and BRAVO studies of the anti-VEGF agent ranibizumab in patients suffering from macular edema secondary to central retinal vein occlusion (CRUISE) or branch retinal vein occlusion (BRAVO).

CRUISE is a Phase III, double-masked study in which patients with macular edema (central subfield thickness of at least 250 µm) were randomized to receive six monthly intravitreal injections of 0.3-mg (n: 132) or 0.5-mg (n: 130) ranibizumab or sham injections (n: 130) followed by observation with p.r.n. therapy to one year. Enrollment numbers were similar in BRAVO, with 132 receiving sham injections, 134 receiving 0.3-mg doses and 131 receiving 0.5-mg doses.

During the observation period (six to 11 months), all patients could receive monthly ranibizumab if prespecified criteria were met: Snellen- equivalent study eye best-corrected visual acuity 20/40 or worse or mean central foveal thickness ≥250 µm. If either criterion was met, the 0.3 mg and 0.5 mg groups received their assigned dose and sham group received 0.5 mg ranibizumab. The primary efficacy endpoint was mean change from baseline BCVA letter score at six months. Secondary endpoints at one year included the mean change from baseline BCVA letter score and mean change from baseline central foveal thickness over time. In CRUISE, the 0.3-mg patients received an average of 5.8 injections during the treatment period and 3.8 during observation. The 0.5-mg patients received 5.6 during treatment and 3.3 during observation, and sham patients got 3.7 during observation.

In CRUISE at one year, the CFT change from baseline was -427.2 ±305.1 µm for sham vs. -452.8 ±269.3 µm for 0.3-mg patients and -462.1 ± 283.1 µm for 0.5-mg patients.

In terms of acuity in the CRUISE study, in the 0.3-mg group patients gained an average of 13.9 letters at a year. In the 0.5-mg group, they also gained an average of 13.9 letters.

The sham group gained 7.3 at a year. Forty-seven percent of the 0.3-mg group and 50.8 percent of the 0.5-mg group gained 15 or more letters, vs. 33 percent for sham.

In the BRAVO study, the 0.3-mg patients received an average of 5.7 injections during the treatment period and 2.8 during observation. The 0.5-mg group got an average of 5.7 injections during treatment and 2.7 during observation. Sham patients got 3.6 during the observation period.

In BRAVO at one year, the CFT change from baseline was -273.7 ±236.9 µm for sham vs. -313.6 ±240.7 µm for 0.3-mg patients and -347.4 ±253.8 µm for 0.5-mg patients. At one year, the 0.3-mg patients gained an average of 16.4 letters and the 0.5-mg group gained 18.3 letters compared to baseline. Sham patients gained 12.1.

The visual results for CRUISE and BRAVO appear in Table 1 on p. 35. 6452

Researchers from the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) say they’ve identified the factors predictive of acuity and central retinal thickness outcomes in patients treated with intravitreal triamcinolone injections for macular edema secondary to retinal vein occlusion.

The SCORE Study is a multicenter, randomized, Phase III trial designed to compare standard care versus triamcinolone injection(s) for the treatment of macular edema associated with CRVO and BRVO. In each of the two disease areas, 630 participants were randomized in a 1:1:1 ratio to one of three groups: standard care; intravitreal triamcinolone 4 mg or intravitreal triamcinolone 1 mg. Outcome measures of center point thickness include absolute change from baseline and a measurement of 250 µm or less. Outcomes were assessed at one and two years.

For CRVO and BRVO, younger age was significantly associated with improved acuity and central retinal thickness outcomes. For CRVO, treatment with triamcinolone and less severe anatomical abnormalities of the retina (center-point thickness and areas of retinal hemorrhage, thickening and fluorescein leakage) were predictive of better acuity outcomes.

For BRVO, lack of coronary artery disease history was predictive of improved acuity outcomes. For OCT outcomes, shorter duration of macular edema and anatomical features of the retina were significantly associated with improvement in both disease entities. For CRVO, higher baseline acuity letter score, and for BRVO, lower baseline letter score, dense macular hemorrhage and absence of prior grid photocoagulation were predictive of favorable OCT outcomes.3558

Researchers for Allergan say that a randomized trial of the company’s intravitreal dexamethasone implant Ozurdex found it to be effective in the treatment of macular edema due to central retinal vein occlusion.

In two identical trials, patients with ME due to CRVO were randomized to receive a 700-µg implant, a 350-µg implant or sham treatment. Patients could receive open-label treatment with a 700-µg Ozurdex implant at day 180 if their BCVA was worse than 84 letters or retinal thickness was greater than 250 µm.

At baseline, 136 patients received the 700-µg implant and 147 received sham (the study focuses on the 700-µg results). At day 180, 114 patients from the 700-µg group and 117 from the sham group received open-label treatment with the 700-µg implant. Thirty-one percent of the patients gained at least 15 letters of BCVA 60 days after receiving the first 700-µg implant (peak effect) and 27 percent gained at least 15 letters 60 days after the second implant (day 240). Twenty-one percent of patients from the sham group who received their first implant at day 180 gained at least 15 letters by day 240. Among patients who received a single, baseline 700-µg implant (n: 19), 53 percent completed the study, 21 percent gained at least 15 letters at day 60, 42 percent gained this much at day 180, and 26 percent at day 360. Increases in IOP were generally transient and similar following each implant treatment.6397

Radiation Treatment

In a small study, a group of investigators from the United States and Mexico says the investigational radiation treatment IRay (Oraya Therapeutics, Newark, Calif.) was able to stabilize choroidal neovascularization in patients with age-related macular degeneration. Some of the investigators are consultants to Oraya.

In the study, the researchers used the IRay system to give a 16-Gy dose of external radiation to 12 patients with exudative AMD. The dose was divided into three external beams that penetrated through the pars plana and converged on the macula. The investigators also injected ranibizumab intravitreally if there was a subsequent loss of 10 or more ETDRS letters, new subretinal blood or fluid recurrence on spectral domain OCT of greater than 100 µm.

At a mean follow-up of 5.7 months (r: two to 11 months), the average letter change from baseline was zero (r: -17 to +16 letters). All but two of the patients needed intravitreal ranibizumab. The average injection rate was 1 ±0.6 (r: one to two injections). Leakage on fluorescein angiography improved in six cases, was stable in five and worse in one.

The researchers concluded that the radiation produced clinical stabilization of the CNV that isn’t consistent with either the natural history of the disease or anti-VEGF treatments at the five-month follow-up interval used in the study. The changes in best-corrected acuity weren’t significant.85

Interim results from the MERITAGE study sponsored by NeoVista found that the company’s epimacular brachytherapy treatment for wet AMD may reduce the need for treatment with an anti-VEGF drug in cases of previously treated AMD.

In the study, 50 subjects with classic, minimally classic and occult CNV lesions were enrolled. Each group received a minimum of three intravitreal anti-VEGF injections in the six months preceding enrollment or five injections in the year preceding enrollment. The patients underwent a pars plana vitrectomy and 24-Gy beta irradiation for four to five minutes from NeoVista’s retractable Strontium-90 source via an endoscopic probe. The investigators would administer anti-VEGF injections if there was a five-letter loss, greater than 50-µm increase of central retinal thickness on OCT, new macular hemorrhage or new activity visible with fluorescein angiography. The patients received the same anti-VEGF agent they were receiving prior to enrollment (bevacizumab 1.25 mg or ranibizumab 0.5 mg).

To date, 16 subjects have reached the six-month milestone. Subjects received a mean of two retreatment injections with 88 percent maintaining vision and 63 percent gaining vision. Mean visual gain was 1.2 letters (3.0 in pseudophakes). The researchers say there were no retinal breaks, detachments or radiation retinopathy. A large-scale (n: 363), multicenter study called MERLOT is now under way.1254

A pilot study supported by Genentech found that a combination of ranibizumab and proton beam radiation appears to be well-tolerated by patients with wet AMD.

In the small study, six eyes of six patients were treated with four monthly injections of ranibizumab and 24 Gy PBR (two fractions, 24 hours apart). Subjects were seen monthly and retreated with ranibizumab for a decrease in best-corrected vision of two or more lines, new macular hemorrhage or fluid on OCT.

Best-corrected vision at enrollment ranged from 20/40 to 20/250. At month 12, vision was 20/40 or better with an improvement of at least three lines in four of the five eyes that remained enrolled. One eye exited the study at four months but returned with a stable Snellen acuity without further treatment at month 12. Among four eyes with newly diagnosed wet AMD, three eyes had no fluid on OCT at month 12 with no further treatment, and one eye required two additional ranibizumab injections for mild recurrent macular edema. Among two eyes previously treated with ranibizumab, both continued to require frequent retreatment with the drug for recurrent or increasing fluid on OCT. One of these eyes, which had persistent subretinal fluid at enrollment after 23 prior ranibizumab injections, had progressive vision loss with enlargement of its choroidal neovascular membrane and increasing subretinal fluid despite almost monthly ranibizumab treatments. No radiation retinopathy or other adverse effect was seen in any eye. The investigators say the study is ongoing to evaluate the treatment’s long-term effects.912

Anti-VEGF
Researchers from London say a study of their “three-strikes” method of administering anti-VEGF injections in wet AMD patients shows that it’s cost-effective and practical.

The three-strikes method consists of an initial loading dose of three anti-VEGF injections.
Then, any reaccumulation of intraretinal fluid is met with three more injections, each spaced a month apart. In the study, the researchers reviewed the charts of 403 patients who received either intravitreal ranibizumab (n: 261) or bevacizumab (n: 142) and completed a three-year follow-up.

The researchers say that the three-injection retreatment approach produced gains in visual acuity comparable to those in the ANCHOR and MARINA trials, with ranibizumab patients gaining 13 letters and bevacizumab patients gaining 11. These gains were maintained over the three-year follow-up. There was a mean number of injections of six in the first year for each group, six in the second year and five in the third. There were no injection-related ocular complications.

The physicians say that it appears the three-strike approach produces efficacy equivalent to the trial gold standard of monthly injections, with fewer injections than either monthly or treat-and-extend regimens.2059

Researchers from Philadelphia’s Wills Eye Institute and Temple University Hospital say that a treat-and-extend regimen of intraocular VEGF injections for wet AMD is economical and yields good results.

In the study, the treat-and-extend approach consists of treating a patient every four weeks with intravitreal bevacizumab until there’s no intraretinal or subretinal fluid on OCT. The follow-up interval is then extended continuously by two weeks until there are signs of recurrent exudation. Exclusion criteria in the study included a history of photodynamic therapy.

There were 74 patients in the study, with a mean follow-up of 1.3 years. At baseline, the mean visual acuity was 20/230, which improved significantly to 20/118 at six months (p<0.001), 20/109 at a year (p<0.001) and 20/106 at two years (p<0.001). The mean number of injections over the first year was 7.27. The OCT central retinal thickness decreased from 316 µm to 239 µm (p<0.05). Also, the treat-and-extend regimen’s direct medical cost per patient was $6,160.13.905

Researchers with the Pan-American Collaborative Retina Study Group say that 1.25- and 2.5-mg doses of intravitreal bevacizumab can stabilize or improve acuity and other parameters in eyes with exudative AMD, even after two years.

In a multicenter, retrospective case series, the researchers reviewed the records of 180 consecutive patients (207 eyes) with wet AMD. They were treated with at least one intravitreal injection of 1.25 mg (124 eyes) or 2.5 mg (83 eyes) of bevacizumab. The mean number of injections was 5.1 (r: one to 24).

In the 1.25-mg group, baseline best-corrected acuity improved from 20/235 to 20/172 at 24 months (p<0.0001). Similar acuity changes were observed in the 2.5-mg group. Central macular thickness by OCT at baseline in the 1.25-mg group had a mean of 308.4 ±127.52 µm which was reduced to 269.35 ±97.92 µm at one month, 262.1 ±94.81 µm at three months, 264.03 ±97.06 µm at six months, 245.91 ±89.52 µm at a year and 249.27 ±89.14 µm at two years (p<0.0001). Similar changes were observed in the 2.5-mg group. In that group, systemic complications included two cases (2.6 percent) of arterial hypertension, one stroke (1.3 percent) and one death. There was no significant difference in outcomes between the two dosage groups, say the investigators.1250

Researchers from Italy and Germany say a suprachoroidal drug delivery method they’ve tested may help patients with exudative AMD that has resisted other treatments.

The study was prospective and conducted at three centers. To be included, patients had to have AMD that had failed multiple conventional treatments and a lesion size of at least four disc areas, with an acuity of 20/400 to 20/40. The patients underwent a single combination treatment of 1.25-mg bevacizumab and 4-mg triamcinolone administered to the macular region of the suprachoroidal space through a microcatheter called the iTRACK 400 (iScience Interventional Corp., Menlo Park, Calif.). The microcatheter is introduced through a 2- to 3-mm dissection of the pars plana and advanced posteriorly while visualizing the illuminated tip beneath the retina through the operating microscope.

Twenty-one patients have undergone the treatment so far. Their baseline acuity was LogMAR 0.98 (Snellen: a little better than 20/200) and mean macular thickness was 407 µm. At six months, their mean LogMAR acuity is 0.97 and mean macular thickness is 408 µm. Twenty-nine percent of the eyes improved by more than two lines.

The investigators say that administering agents through the suprachoroidal space may be desirable to allow direct drug exposure to the choroid, which could potentially increase choroidal drug levels.1256

A randomized, multicenter, controlled study sponsored by Allergan found that the intravitreal dexamethasone implant Ozurdex was a helpful adjunct to intravitreal VEGF injections in patients with exudative AMD.

At screening, all patients (n: 243) received an intravitreal injection of ranibizumab 0.5 mg. Four weeks later at the baseline visit, patients who met OCT and clinical examination criteria for retreatment with ranibizumab were randomized to receive the Ozurdex implant (n: 123) or sham procedure (n: 120). Patients were given a second ranibizumab injection seven to 14 days after their baseline visit. For patients meeting certain retreatment criteria, up to five additional ranibizumab injections were given prior to their exit of the study (week 25). The primary efficacy outcome measure was injection-free interval.

The investigators say that adjunctive therapy with the implant statistically significantly delayed the first as-needed ranibizumab injection based on Kaplan-Meier product-limit method (p=0.016). The 75th percentile of injection-free interval was 12 weeks in the implant group vs. eight weeks in the control group over six months. Relative risk of not requiring additional as-needed ranibizumab injection was 3.28 (implant vs. sham, p=0.048). Treatment-related adverse events were similar between groups, except for increased intraocular pressure in the implant group (9.9 percent vs. 3.4 percent) and conjunctival hemorrhage (6.6 percent vs. 0.8 percent) in the implant group vs. control group (p≤0.044).1255

Researchers from Honolulu say that switching patients from p.r.n. anti-VEGF therapy to monthly ranibizumab injections can improve outcomes in exudative AMD.

One hundred patients (121 eyes) who had received anti-VEGF induction, maintenance and p.r.n. therapy in the preceding 42 months were prospectively enrolled into an open-label Phase II study of intravitreal bevacizumab (0.5 mg) administered monthly for the first six months and p.r.n. for the next six months.

During the initial four to 40 months of anti-VEGF therapy, the patients experienced a mean acuity improvement of 3.48 ±2.9 letters.

When these patients were switched from p.r.n. to monthly treatment, they demonstrated an additional acuity improvement of 3.4 ±0.7 letters at six months and 5.8 ±0.7 letters at one year. Central foveal thickness improved by a mean of 44.5 ±7 µm at a year. At study conclusion, compared with baseline, patients previously treated for less than 12 months (n: 26) improved by 4.9 letters, those treated for 12 to 18 months (n: 30) improved by 6.8 letters, and patients previously treated for 18 months (n: 65) improved by 5.3 additional letters. One patient experienced a transient ischemic attack and one had a retinal pigment epithelium tear prior to month six. The researchers conclude that regardless of disease duration, wet AMD patients with edema on OCT may improve acuity with monthly ranibizumab therapy.2057

A randomized study partially sponsored by Novartis has found that combination therapy with ranibizumab and PDT can decrease the number of treatments necessary for many sub-types of CNV due to AMD.

In the study, 40 patients were randomized to receive initial PDT (n: 19) or sham PDT (n: 21) followed by three consecutive monthly intravitreal injections of ranibizumab 0.3 mg. Thereafter, both groups received ranibizumab injections on a p.r.n. basis if disease activity was detectable based on a loss of greater than five ETDRS letters in best-corrected acuity or an increase of central retinal thickness by at least 100 µm on OCT compared to any prior visit.

The researchers found that 44 retreatments were necessary in the monotherapy group compared to 19 in the combination-treatment group, which was statistically significant (p<0.05). Seventy-four percent of the patients in the monotherapy and half in the combination arm needed retreatment during the maintenance phase.

Retreatment-inducing criteria were loss of BCVA (59 percent monotherapy/58 percent combination) and increase in CRT on OCT (27 percent monotherapy/26 percent combination) or both criteria together (14 percent monotherapy/16 percent combination).
But intraretinal cysts already present at OCT one month before the retreatment criteria were fulfilled in 84 percent of the monotherapy and 74 percent of the combination group.
One month before retreatment subretinal fluid was found in 70 percent of monotherapy patients and 63 percent of combination patients, and at least one of either condition, intraretinal cysts or fluid, occurred in 84 percent of monotherapy eyes and 89 percent of combo eyes. During the last month before retreatment was indicated, the mean loss of BCVA was 2.7 letters in the monotherapy group vs. 3.6 letters in the combination group, but one month before it was just 0.6 letters for monotherapy and 0.1 letters for combination. That means that before significant vision loss occurred, the intraretinal cysts, subretinal fluid, or both, were present on OCT in almost all eyes. The researchers say that qualitative OCT parameters may do better than the quantitative parameter of CRT when it comes to an early retreatment indication.2054

Diabetes

Researchers in the DA VINCI Phase II study of VEGF Trap-Eye say that the agent is well-tolerated and produces significant improvements from baseline in acuity and retinal thickness compared to laser photocoagulation for diabetic macular edema.

In the multicenter, randomized, controlled study, 221 patients were randomized to one of the following arms: 0.5 mg q4 weeks; 2 mg q4 weeks; 2 mg q8 weeks; 2 mg p.r.n. or laser (219 were treated).

At six months, the mean change in BCVA for each VTE arm ranged from +8.5 to +11.4 letters and was statistically significantly better than the mean change in BCVA in the laser arm (+2.5 letters; p<0.01). No significant difference was noted among the VTE arms. Anatomical effects (mean change in CRT) for each VTE arm ranged from -127 µm to -195 µm and were significantly greater than the mean change in CRT for the laser arm (-68 µm; p<0.01).

The researchers say that VTE was generally well-tolerated, and adverse events reported were those typically associated with intravitreal injections or underlying disease. There were two cases of endophthalmitis, one culture negative and one positive for Staphylococcus epidermidis. The most frequent AEs reported in the VTE arm included conjunctival hemorrhage, eye pain, floaters, ocular hyperemia and increased IOP.6426

Researchers from Singapore and Australia say that, at two years follow-up, intravitreal triamcinolone plus laser may be more effective than laser alone for DME.

Eighty-four eyes of 54 patients entered the study, with 42 eyes randomized to receive IVTA 4 mg and laser, and 42 to get a placebo six weeks prior to laser. Further laser treatment was applied according to prospectively defined criteria. Two years of data was available for 71 eyes (84.5 percent).

At two years, improvement of 10 LogMAR letters or greater was found in 15 eyes (36 percent) in the combination group compared with seven eyes (17 percent) treated with laser only (p=0.047). The mean central macular thickness was 346.8 ±114.9 µm for the combination group and 372.6 ±154.2 µm for laser only (p=0.349). Mean logMAR visual acuity was 56.1 ±15.7 letters for the combination patients and 54.5 ±16.1 for laser only (p=0.439). Six eyes (14 percent) in the combination group needed retreatment at two years, compared to three (7 percent) for laser (p=0.48). There were adverse events related to treatment in eight eyes from the combination group and one eye from the laser only group.6425

Investigators in the READ 2 study say that, at the two year follow-up point, intravitreal ranibizumab appears to be safe and effective for the treatment of DME.

Subjects were randomized 1:1:1 into one of three treatment groups: ranibizumab 0.5 mg (group 1); focal laser from baseline to month six with laser or ranibizumab 0.5 mg used after month six (group 2); or ranibizumab 0.5 mg combined with focal laser from baseline to month six with continued combination therapy or monotherapy with ranibizumab starting after month six (group 3). After the six-month follow-up point, the decision on the type of treatment was at the discretion of investigators.

At month six, the primary endpoint of the study, mean change in BCVA (in letters) was +7.2 in group 1, -0.4 in group 2 and +3.8 in group 3. Starting at month six, the majority of treatments given in all three of the groups from month six to 24 included monotherapy with ranibizumab.

At month 24, the mean change in BCVA (in letters) was +7.6 in group 1, +5 in group 2 and +6.4 in group 3. Excess retinal thickness on OCT at month 24 was +125.6 µm, +75.5 µm and +58.4 µm for groups 1, 2, and 3, respectively. There were no drug-related ocular or systemic adverse events. The re--searchers say that additional studies are necessary to determine the optimal dosing schedule of ranibizumab in diabetic macular edema.5842 

Dr. Regillo is professor of ophthalmology at Thomas Jefferson University and director of the Clinical Retina Research Unit at Wills Eye Institute.