RESEARCH HIGHLIGHTS FROM THE ANNUAL MEETING OF THE AMERICAN SOCIETY OF RETINA SPECIALISTS

Investigators Report One-Year Data from Trials of Ranibizumab
One-year results from the Phase III, 716-patient MARINA trial of ranibizumab (Lucentis, Genentech Inc.) in minimally classic or occult subfoveal neovascular age-related macular degeneration (AMD) showed a 17-letter difference in mean visual acuity change between treated and control-group patients. Treated patients gained an average of seven letters from study entry, and control-group patients lost an average of 10.5 letters.

In addition, 95 percent (452/478) of treated patients lost fewer than 15 letters from baseline, the primary endpoint of the study, compared with 62 percent (148/238) of the control group. Twenty-five percent (59/238) of patients treated with a 0.3-mg dose and 34 percent (81/240) treated with a 0.5-mg dose gained 15 letters or more compared with approximately 5 percent (11/238) of patients in the control group. Nearly 40 percent (188/478) of treated patients had visual acuity of 20/40 or better at one year compared with 11 percent (26/238) of the control group.

MARINA is a multicenter, randomized, double-masked, sham-injection-controlled trial. Approximately one-third of participants’ lesions are minimally classic, and two-thirds are occult. Patients are randomized 2:1 to receive intravitreal ranibizumab or sham injections once a month for two years. Ranibizumab patients are further randomized to receive either a 0.3-mg or 0.5-mg dose once a month for two years. Twenty five of 238 patients in the control group also received photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis Ophthalmics) during the first year of the trial, as did 1 of 238 in the 0.3-mg dose group. No patients in the 0.5-mg dose group received PDT.

Mild to moderate side effects that occurred more frequently in the treatment arms of the trial included conjunctival hemorrhage, eye pain and vitreous floaters. Serious ocular adverse events occurring more frequently in treated patients (<1 percent) included uveitis and endophthalmitis. Investigators reported that no imbalance in serious non-ocular adverse events was observed.

One-year results from the 162-patient Phase I/II FOCUS trial of ranibizumab plus PDT vs. PDT alone in predominantly classic subfoveal wet AMD showed a 13-letter difference in mean visual acuity change between the two treatment groups. At one year, patients treated with the combination gained an average of five letters from baseline, and patients treated with PDT alone lost an average of eight letters. Twenty-four percent (25/105) of patients treated with the combination had vision improvement of 15 letters or more compared with 5 percent (3/56) of patients treated with PDT alone. Investigators had previously reported that the study met its primary endpoint of maintaining vision.

FOCUS is a randomized, single-masked, 25-center study. Patients are randomized 2:1 to receive either a 0.5-mg dose of ranibizumab or a sham injection monthly for one year in combination with PDT. All patients received PDT seven days before the first administration of drug or sham and then every three months thereafter if deemed necessary by the investigator and based on the verteporfin product labeling.

At one year, the data showed a higher risk of uveitis in the combination treatment group. The study protocol was amended when this became known. Endophthalmitis was the second most common serious ocular adverse event in the combination treatment group. The frequency of cerebral vascular events was higher in those treated with ranibizumab; the frequency of myocardial infarctions was higher in the group treated with PDT alone. In both cases, the difference between groups was not statistically significant. One of 105 patients treated with the combination experienced vision loss of 30 letters or more compared with five of 56 (9 percent) treated with PDT alone.

In a third ranibizumab-related study, PrONTO, central retinal thickness (CRT) as measured by optical coherence tomography (OCT) improved at one day after an injection, and visual acuity improved by day 14. Investigators reported continued, statistically significant improvement in CRT and acuity compared with baseline at post-injection day 90. PrONTO is a single-site, uncontrolled, open-label, FDA-reviewed study. To date, a total of 40 patients with subfoveal choroidal neovascularization (CNV) from AMD and CRT of at least 300 µm have been enrolled and 30 of the 40 patients have reached their three-month follow-up visits. No adverse events, including inflammation, have been observed. Each patient receives three consecutive monthly injections of ranibizumab (500 µg) in the study eye with subsequent injections only if CRT increases. Two-year follow-up is planned.

Genentech has applied to the FDA for fast-track designation of the ranibizumab development program.

Sources: Randomized, controlled phase III study of ranibizumab (Lucentis) for minimally classic or occult neovascular age-related macular degeneration, Miller JW for the MARINA Study Group, 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada. Intravitreal ranibizumab (Lucentis) with verteporfin photodynamic therapy for neovascular age-related macular degeneration: year one results, Heier JS for the FOCUS Study Group, 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada. OCT imaging of neovascular AMD patients treated with ranibizumab (Lucentis): the PrONTO study, Fung AE, Rosenfeld PJ, Puliafito CA, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada..

Investigators Report Six-Month Outcomes from the Systemic Avastin for Neovascular AMD (SANA) Study
The six-month outcomes were reported from the 18-patient, open-label, prospective clinical study of systemic bevacizumab (Avastin, Genentech) for the treatment of neovascular AMD. The major inclusion criteria for the study eye included any angiographic subtype of subfoveal macular neovascularization as long as the OCT central retinal thickness was at least 300 µm. At baseline for each patient, one eye was designated the study eye and the non-study eye was designated the fellow eye. Of the 18 fellow eyes, 16 had a history of neovascular AMD. The oncologic dose of 5mg/kg was administered intravenously at baseline and at two-week intervals for two or three doses over four weeks and then the patients were observed. Notable improvements in visual acuity were observed after one week following the first infusion and these improvements were associated with decreases in the OCT central retinal thickness measurements. By six months, the study eyes had an average improvement in vision of two to three lines and the fellow eyes improved between three to four lines. This improvement in visual acuity was associated with a decrease in OCT central retinal thickness of about 110 µm in the study eye and 70 µm in the fellow. The only drug-related adverse event observed was mild hypertension that was easily controlled with medication. During the first six months of the study, only six of the 18 patients required retreatment at either five or six months and the retreatment was based on increasing OCT central retinal thickness measurements. All patients responded predictably and reproducibly to the retreatment, including two patients who were retreated with intravitreal bevacizumab (see noteworthy developments below). This study provided the first unambiguous demonstration that a systemic drug can have a profound impact on macular neovascularization in AMD. While this study is ongoing, patients are no longer receiving intravenous bevacizumab but are being offered retreatment with either intravitreal bevacizumab or pegaptanib sodium (Macugen, Eyetech Pharmaceuticals) to avoid the potential systemic adverse events that may be associated with high-dose bevacizumab, which include hypertension and thromboembolic events.

Source: Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration (SANA) study: 12-week outcomes, Rosenfeld PJ, Moshfeghi AA, Puliafito CA, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada. Durability of treatment benefits in the systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration (SANA) study, Moshfeghi AA, Rosenfeld PJ, Puliafito CA, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.

Squalamine for AMD Trials Progress
The most recent visual acuity data from the 18-patient, multi-dose Phase II trial of squalamine lactate (Evizon, Genaera Corp.) in exudative AMD show that 17 percent of eyes infused with 20-mg doses of the drug once a week for four weeks had improvement in vision of three or more lines at four months. Also at the four-month time point, 83 percent of patients in this group had either stable or improved vision, as did 100 percent of patients diagnosed with wet AMD in the fellow eye. As previously reported, 17 percent of study eyes and fellow eyes of patients who received 40-mg doses of squalamine had vision improvement of three or more lines at month four, and 100 percent of these patients had either stable or improved vision in both eyes.

The study is also designed to evaluate the pharmacokinetics and safety of the treatment. At the end of both the one-week and four-week infusions, mean plasma concentration of the drug was 3 µg/mL in the lowest dose tested (10 mg) and 8 µg/mL in the highest dose tested (40 mg). This decreased to below 0.1 µg/mL six to eight hours after the doses. At all three dose levels, results to date suggest a rapid clearance of squalamine from blood and a biphasic plasma concentration-time profile that is not affected by repeated dosing. No adverse events related to the drug occurred. A small number of patients reported pain at the injection site, but none withdrew from the study because of adverse events.

Twenty-nine-week interim results from another Phase II squalamine trial, which is evaluating the safety and efficacy of three different doses with concomitant PDT, are expected to be reported in the fourth quarter of this year. Squalamine has been accepted into the FDA’s Continuous Marketing Application Pilot 2 program, and had been granted Fast Track status in 2004.

Source: An analysis of Evison (squalamine lactate) for exudative ARMD: preliminary safety and pharmacokinetic results from a phase 2 multi-dose trial, Connolly BP, Garcia CA, Thomas EL, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.

Two Recent Studies of Steroid Plus PDT in AMD
A retrospective review of charts for 31 patients (35 eyes) treated with verteporfin PDT and 4 mg of intravitreal triamcinolone acetonide for minimally classic subfoveal CNV with and without retinal angiomatous proliferation (RAP) lesions revealed that 16 of 35 eyes (46 percent) had improved final corrected visual acuity (CVA).

All patients were newly diagnosed. All eyes were followed for at least 12 months, and median follow-up was 16 months (range 12 to 24 months). Triamcinolone was administered either within 30 minutes after PDT or within one week prior to PDT. Retreatments were performed with the same combined treatment if leakage appeared on fluorescein angiography.

Overall, median CVA changed from 20/100 at study entry to 20/80 at the end of follow-up. In five of 35 eyes (14 percent), final CVA was the same; eight of 35 eyes (23 percent) lost three or more lines. Fifteen eyes (43 percent) required treatment only once; nine eyes (26 percent) required from two to five additional treatments. The overall median interval between treatments was five months.

RAP lesions were present in 16 eyes, all of which were followed for 12 or more months. Median follow-up in this group was 16 months (range 12 to 24 months). Median CVA changed from 20/70 at study entry to 20/63 at final follow-up. Eight of 16 eyes (50 percent) gained visual acuity; three of 16 (19 percent) had the same final visual; two (13 percent) lost three or more lines. Among the eyes with RAP lesions, six (38 percent) required only one treatment; four (25 percent) required one additional treatment; and six required two additional treatments. The median interval between treatments was five months.

Overall, five eyes required topical medication for steroid-responder glaucoma, and two eyes developed large submacular hemorrhages and underwent pars plana vitrectomy, submacular TPA and gas exchange.

Another retrospective analysis evaluated PDT plus triamcinolone in 78 eyes of 78 patients with subfoveal CNV secondary to AMD. Lesions were predominantly classic in 32.1 percent of eyes, minimally classic in 26.9 percent, and occult in 41 percent. Forty eyes had previously undergone PDT. Most of the patients received triamcinolone injection (4 mg) within 24 hours of PDT. Mean follow-up was 8.2 +/-4.8 months.

Mean Snellen visual acuity before and after treatment was not clinically different, but mean LogMar acuity changed from 0.91 +/-0.39 to 0.99 +/-0.41 (p=0.03). Mean intraocular pressure did not change in the postoperative period. Cataract progression was noted in 10 percent of the phakic eyes; intraocular pressure rose in 5 percent of eyes; and 5 percent of patients experienced back pain. At the end of follow-up, 61 patients (78 percent) had no leakage on fluorescein angiography and no subretinal fluid on OCT. The remaining 17 eyes had indication for retreatment.

Sources: Combined intravitreal triamcinolone and PDT in the treatment of minimally classic subfoveal CNV with or without RAP lesions, Bhavsar AR, 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for subfoveal choroidal neovascularization in AMD, Avila MP, Farah ME, Aggio FB, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.

The 4-mm-long IMT contains two wide-angle, glass microlenses.

One-Year Results with the Implantable Miniature Telescope
In a Phase II/III prospective, multicenter trial, the Implantable Miniature Telescope (IMT) improved mean distance and near visual acuity at one year and appeared to be well-tolerated in patients with bilateral, end-stage AMD. The prosthetic telescope works with the cornea to enlarge images, focusing them on healthy areas of the central and peripheral retina rather than only on the damaged macula. Surgeons implant the device monocularly; the fellow eye remains unimplanted for peripheral vision for orientation and mobility.

The trial involved 206 patients at least 55 years old with bilateral, moderate to profound vision impairment (20/80 to 20/800). At one year after implantation, mean distance best-corrected visual acuity (BCVA) improved from 20/316 to 20/141, or 3.5 lines. Mean near BCVA improved from 20/156 to 20/89 at 8 inches and from 20/240 to 20/146 at 16 inches, or approximately 2.5 lines. Improvements at all three test distances were statistically significant (p<0.0001). Overall, 96.3 percent (185/192) of patients experienced no change or improved distance BCVA, and 89.6 percent (172/192) achieved the primary efficacy endpoint of greater than or equal to two lines of improvement in near or distance BCVA. Corneal endothelial cell loss was 25.3 percent. Intraoperatively, two choroidal hemorrhages occurred and one device dropped into the vitreous. Postoperatively, one patient developed a wet membrane, which was successfully treated by photocoagulation. No retinal detachments occurred.

Quality of life outcomes were a secondary efficacy endpoint of the trial. The National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and Activities of Daily Life (ADL) scale were administered before and after implantation. The mean preoperative composite VFQ score was 43.9 out of a 100-point maximum. At one year, it improved to 50.3 (p<.0001). Also at one year, investigators found statistically significant improvement in total composite ADL score and all subcategories of activities of daily life.

Sources: Treatment of central vision loss due to macular degeneration: one-year phase II/III visual acuity and safety results of a visual prosthesis (IMT002), Hudson HL, Martin DF, Berinstein DM, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada. Quality of life after treatment of moderate to profound visual impairment due to end-stage AMD: NEI-VFQ and ADL results from the IMT002 trial, Chang TS, Hudson HL, Singerman LJ, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.

Combining 25-ga. and 20-ga. Vitrectomy
Prospective, single-surgeon data from 49 consecutive cases indicate that a combined 25-ga./20-ga. approach to vitrectomy is safe and effective. In these cases, one of three 25-ga. sclerotomies was enlarged to facilitate certain tasks, such as silicone infusion in reoperations, air-silicone exchange in initial silicone placement, phacofragmentation for lensectomy or removal of dislocated lens material, or use of forceps for foreign body removal. In general, an 8-0 nylon sclerotomy suture cut on the knot and a 6-0 plain gut conjunctival suture was used for the 20-ga. sclerotomy.

Using one 20-ga. sclerotomy with two 25-ga. sclerotomies reportedly mitigated the issues of silicone oil viscosity, instrument flexion, the mechanical properties of dense lens material, and the size of intraocular foreign bodies, but the advantages of 25-ga. surgery were maintained.

Source: 20/25 vitrectomy; combined 25 and 20-gauge vitrectomy, Charles ST, 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.

Delivered Doses of Triamcinolone Acetonide Prone to Wide Variability
A comparison of four different preparation methods confirmed that achieving a reproducible 4.0-mg per 0.1-mL dose of triamcinolone acetonide (TA) for injection is variable and inconsistent. For Method One, TA (Kenalog-40, Bristol-Myers-Squibb) was drawn into a 1-mL syringe, either after shaking the vial 10 or 30 times. Serial 0.1-mL aliquots of TA suspension were then dispensed with a 30-ga. needle and weighed after drying. Method Two employed a 27-ga. needle to allot 0.1 mL. Method Three concentrated TA by allowing a 1-mL vial to settle for 24 hours upside down. After removal of the clear supernatant, the crystals were withdrawn into a 1-mL syringe. After drying, the mass was determined. Method Four produced concentrated TA by washing the crystals with a saline solution. The contents of a TA vial were drawn into a 1-mL syringe and capped with a 0.2-µm micropore filter, which was placed on a three-way stopcock with a normal saline-filled syringe. The TA suspension was then pushed through the filter. One mL of saline then forced the crystals back into the syringe via the stopcock and filter. The new suspension was pressed through the filter again, and the process was repeated three times. Finally, 0.2 mL of saline was forced through the stopcock and filter, yielding the mixture that was dispensed with a 30-ga. needle, dried, and weighed.

The initial 70 percent of 0.1-mL doses from a 1-mL syringe differed significantly from the final 30 percent (p<0.0001). A mean dose of 3.79 +/- 1.5 mg was delivered from the first 70 percent, and the final 30 percent produced an average dose of 13.15 +/- 4.8 mg in methods One and Two. TA dispensed from a 30-ga. needle in Method One resulted in a mean dose of 3.38 +/- 1.9 mg, not significantly different from the 27-ga. needle used in Method Two. There was no statistical difference between shaking the TA vial 30 times or 10 times. The Method Three concentrated suspension produced a mean dose of 32.08 +/- 7.0 mg. The washing in Method Four produced an average dose of 25.23 +/- 1.7 mg.

Based on these findings, the investigators recommended avoiding injection of TA from the final 30 percent of solution drawn from a 1-mL vial into a 1-mL syringe. They also emphasized that concentrating and/or washing TA crystals results in increased dosages of TA.

Source: Intravitreal triamcinolone: what dose are we delivering?, Barile GR, Ober MD, Schiff WM, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.

Results of Phase II Trial of Pegaptanib for DME
In the 172-patient Phase II trial of pegaptanib sodium (Macugen, Eyetech Pharmaceuticals) for the treatment of diabetic macular edema (DME), patients who received a 0.3-mg dose had better visual acuity, greater reduction in CRT, and less need for photocoagulation than patients who received sham.

Intravitreous pegaptanib (0.3 mg, 1 mg, or 3 mg) or sham injection was administered every six weeks for 12 weeks with the option of subsequent doses and/or focal photocoagulation thereafter. At week 36, a larger percentage of patients treated with 0.3 mg of pegaptanib had stable or improved vision compared with the sham group. Seventy-three percent of those treated gained greater than or equal to 0 lines of vision compared with 51 percent of the sham group (p=.02). Eighteen percent of treated patients gained greater than or equal to 3 lines of vision compared with 7 percent of the sham group (p=.12). CRT decreased by 68.0 µm in the 0.3-mg group compared with 3.7 µm in the sham group (p=.021). Also, more patients in the 0.3-mg group had absolute decreases in CRT. For example, 42 percent of patients in that dosage group had decreases of greater than or equal to 100 µm vs. 16 percent in the sham group (p=.02).

Twenty-five percent of patients in the 0.3-mg group required photocoagulation compared with 48 percent in the sham group. Pegaptanib was well-tolerated at all tested doses. One case of endophthalmitis, which was not associated with severe vision loss, occurred.

Source: Macugen in the treatment of diabetic macular edema: results of the phase 2 trial, Gonzales CR for the VEGF Inhibition Study in Ocular Neovascularization (VISION) Clinical Trial Group, 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.

Majority of Patients Experience Complications in Study of RON for CRVO
Based on the results of their five-center, multi-country, retrospective, interventional study of radial optic neurotomy (RON) for central retinal vein occlusion (CRVO), a group of investigators concluded that the procedure alone does not seem to enhance the evolution of the condition compared with its natural history, and sometimes seems to be harmful; therefore, further studies are needed to determine its role in the management of CRVO.

The 37 study patients had CRVO and visual acuity below 20/80. Twenty-seven eyes were classified as ischemic, and 10 were classified as non-ischemic. In the ischemic group, 18.6 percent of eyes had an improvement in visual acuity, 40.7 percent had a decrease, and 40.7 percent remained the same after the procedure. In the non-ischemic group, 50 of eyes had an improvement in acuity, 30 percent had a decrease and 20 percent remained the same.

Complications occurred in 67.6 percent of cases and included macular edema (24.3 percent), vitreous hemorrhage (18.9 percent), neovascular glaucoma (16.2 percent), cataract (13.5 percent), retinal detachment (5.4 percent), and phthisis bulbi, choroidovitreal neovascularization, rubeosis iridis, and central retinal artery perforation in one eye each.

Source: Complications after radial optic neurotomy for central retinal vein occlusion, Arevalo JF, Garcia RA, Wu L, et al., 2005 ASRS scientific paper presentation, Montreal, Quebec, Canada.