KEY PAPERS PRESENTED DURING SUBSPECIALTY DAY AND THE ANNUAL MEETING OF THE AMERICAN ACADEMY OF OPHTHALMOLOGY IN CHICAGO, ILL.

Investigators Report Results from ISIS-DME Pilot Study
Results of the six-month ISIS-DME (Intravitreal Steroid Injection Studies--Diabetic Macular Edema) pilot study indicated that the treatment may result in significant visual improvement in patients with persistent DME after maximal laser treatment. In the prospective, randomized, dose-escalation trial, 33 patients were given either a 2-mg or 4-mg dose of intravitreal triamcinolone acetonide. Thirty-eight percent of patients from the combined 2-mg and 4-mg dose groups experienced three lines or more of visual improvement at some point during the six-month follow-up period. Twenty-nine percent of patients gained three or more lines of vision at three months; that number dropped to 12 percent at six months.

Investigators reported a trend toward greater efficacy and longer duration in the 4-mg dose group. An intraocular pressure increase of 10 mmHg or more occurred in 31 percent of patients, with a trend favoring the 4-mg dose. IOP of 30 mmHg or higher occurred in 25 percent of patients. No patient required surgery for glaucoma. One case of mild vitreous hemorrhage occurred in a patient with proliferative diabetic retinopathy.

A subgroup analysis suggested that intravitreal triamcinolone is more effective for cystoid macular edema than for non-cystoid macular edema. Among patients with a cystoid pattern of angiographic leakage, 62 percent experienced vision improvement of three lines or more compared with 9 percent among patients with non-cystoid leakage.

Source: Steroid for diabetic macular edema: the ISIS trial, Pollack JS for the ISIS Trial Group, 2005 American Academy of Ophthalmology Subspecialty Day paper presentation, Chicago, Ill.

Preliminary Phase II Results of Combined Squalamine and PDT Announced
Preliminary data from a Phase II clinical trial of squalamine lactate (Evizon) administered with verteporfin (Visudyne) photodynamic therapy (PDT) compared with PDT alone in 45 wet age-related macular degeneration (AMD) patients showed the combination to be well-tolerated, and visual acuity outcomes suggested a clinical benefit. This multi-center, randomized, controlled, masked trial was designed to evaluate three different doses of squalamine (10 mg, 20 mg or 40 mg) along with initial concomitant PDT in 10 subjects per group, or PDT alone in 15 control subjects. It includes monthly squalamine maintenance therapy through six months with an additional 12 months of open-label treatment and follow-up for all patients.

Results were presented for 40-mg and 20-mg doses squalamine lactate. At 29 weeks, the combined therapy met the study’s primary endpoint of safety. No drug-related serious adverse events were reported. The most common adverse events involved infusion site reactions, which were generally mild and distributed evenly across the squalamine-plus-PDT treatment groups.

In addition, at 29 weeks, there was a 5.2-letter difference in mean change in visual acuity from study entry between patients treated with 40 mg of squalamine plus PDT and those treated with PDT alone. Patients treated with the 40-mg dose plus PDT gained an average of 0.4 letters in visual acuity, while those treated with PDT alone lost an average of 4.8 letters. Ten percent of patients in the combination 40-mg therapy group required a second PDT treatment, while 47 percent of the PDT-alone patients did. Among combination-treated patients, 90 percent had stable vision compared with 71 percent of patients treated with PDT only. Ten percent treated with 40 mg of squalamine and PDT lost more than 15 letters from study entry compared with 18 percent treated with PDT alone, of which 12 percent lost 30 letters or more. Patients treated with 20 mg of squalamine plus PDT achieved results similar to those treated with PDT alone; 78 percent maintained stable vision.

Source: Safety and efficacy results from a phase 2, multicenter, randomized, controlled, masked study (MSI-1256F-208) of the effects of Evizon (squalamine lacate for injection) with concomitant verteporfin in patients with wet AMD, Ciulla TA, Rosberger DF, Katz RS, et al., 2005 American Academy of Ophthalmology paper presentation, Chicago, Ill.

Phase I Trial Shows siRNA Therapy for AMD to be Safe
A Phase I clinical trial evaluating a small interfering RNA therapy (Cand5) for the treatment of wet AMD showed it to be safe and well-tolerated after repeat intravitreal injection of escalating dose levels, up to 3 mg per eye. The trial, which involved 15 patients, tested five dose levels administered at six-week intervals. The most common ocular adverse events were related to the injection, mild to moderate in severity, and transient. Study drug was not present in the plasma of any of the patients at any of the doses tested. The Phase ll clinical trial program for Cand5 is under way.

Source: An open label study for the evaluation of tolerability of five dose levels of intravitreous VEGF siRNA (Cand5) in patients with wet age-related macular degeneration, Prenner JL, Thompson JT, Miller DG, et al., 2005 American Academy of Ophthalmology poster presentation, Chicago, Ill.

Two-Year Data Confirm Anecortave Acetate Safety and Efficacy vs. PDT
Two-year data from the clinical trial comparing anecortave acetate suspension (Retaane) with verteporfin PDT for the treatment of wet AMD continued to show the two treatments are clinically equivalent. Mean visual acuity in both treatment groups remained stable from month 12 to month 24. No clinically relevant safety issues due to the drug or its posterior juxtascleral depot delivery were observed during entire course of the study. Ocular and non-ocular adverse events were reported at similar rates in both arms of the study. However, there was no mention of whether a positive endpoint was achieved in this non-inferiority study.

Source: Evaluation of anecortave acetate 15 mg suspension vs. photodynamic therapy for inhibition of choroidal neovascularization in patients with exudative AMD: 24-month clinical outcomes, Slakter JS, Bochow TW, Harper CA, et al., 2005 American Academy of Ophthalmology paper presentation, Chicago, Ill.

Study Evaluates Safety and Feasibility of AdPEDF for CNV
An open-label, multi-center, dose-escalating study of a single intravitreal injection of a modified adenovirus designed to carry pigment epithelial-derived factor (AdPEDF) in patients with subfoveal choroidal neovascularization due to AMD and visual acuity of 20/200 or worse showed the treatment to be safe and feasible. It was well-tolerated at all dose levels with no occurrences of dose-limiting toxicities, endophthalmitis, retinal or vitreous detachments, cataracts, or glaucoma. At three months, lesion size progressed in six of 11 patients receiving the four lowest doses compared with one in 16 receiving the four highest doses (p=.0087). At six months, lesion size progressed in six of 10 patients receiving the four lowest doses compared with three of 12 patients receiving the four highest doses (p=.192). Evaluation in patients with less advanced AMD is ongoing.

Source: AdPEDF therapy for subfoveal choroidal neovascularization due to AMD, Campochiaro PA, Klein ML, Holz ER, et al., 2005 American Academy of Ophthalmology paper presentation, Chicago, Ill.

Randomized Trials Show Benefit to Triamcinolone-Assisted Vitrectomy
Because of improved intraoperative visualization of the vitreous body, fewer complications occur during triamcinolone-assisted vitrectomy than during conventional vitrectomy, according to the results of nine multicenter, prospective, randomized clinical trials conducted in Japan. In the trials, 642 eyes were block randomized to one of the two techniques. Retinal break formation occurred in 9.3 percent of the triamcinolone-assisted cases compared with 14.6 percent of the conventional cases (p<.05). Retinal detachment occurred in 0.7 percent of the triamcinolone-assisted cases compared with 4.3 percent of the conventional cases (p<.01).

Triamcinolone makes grasping the posterior hyaloid and creating a posterior vitreous detachment easier. (Images courtesy of Taiji Sakamoto, MD, PhD.)		Triamcinolone improves visibility for the removal of residual vitreous cortex, either with a cutter (A and B) or forceps (C and D). (Images courtesy of Taiji Sakamoto, MD, PhD.)

Source: Triamcinolone-assisted vitrectomy multicenter randomized controlled trial: results of intraoperative complications, Sakamoto T, Yamakiri K, Doi N, et al., 2005 American Academy of Ophthalmology paper presentation, Chicago, Ill.

Infection Rate of Intravitreal Steroids vs. Other Drugs
There is emerging clinical evidence that intravitreal steroids are associated with a higher incidence of infectious endophthalmitis than intravitreal injection of other drugs, according to Mark W. Johnson, MD. A recent study of experimental endophthalmitis indicated that triamcinolone acetonide greatly increases ocular susceptibility to infection, presumably because of a high level of local immune suppression. In this experimental model, as in clinical cases, triamcinolone appears to delay the onset of vitreous inflammation and increase the severity of vitritis in untreated eyes.

A study of experimental endophthalmitis indicated that triamcinolone acetonide greatly increases ocular susceptibility to infection. (Image courtesy of Mark W. Johnson, MD.)

Dr. Johnson said that information presented in the literature to date underlines the importance of adhering to a strict aseptic technique when utilizing intravitreal triamcinolone, i.e., avoiding eyes with untreated eyelid or adnexal infections, avoiding paracentesis, prepping the ocular surface with povidone iodine, and using a lid speculum and single-use medication bottles. Also, while they are not part of established consensus guidelines, he recommended using topical antibiotics before and after injections, sterile gloves and an adhesive eye drape. Injecting intravitreal triamcinolone prior to or at the time of intraocular surgery adds to the potential risk of postoperative endophthalmitis, given the frequency with which organisms are introduced into the eye during surgery.

Regarding the fluocinolone acetonide implant (Retisert), Dr. Johnson recommended that surgeons ensure a small distance (0.5 mm) between the implant suture hole and the end of the strut to reduce the extrusion rate, avoid exposed sutures, and pay special attention to proper wound closure and late wound problems.

Source: Infectious complications of intravitreal steroids, Johnson MW, 2005 American Academy of Ophthalmology Subspecialty Day paper presentation, Chicago, Ill.