FROM THE 2005 ARVO MEETING

Preclinical vs. Clinical Systemic Exposure of VEGFR Inhibitor AG-013958
Sub-Tenon administration of the VEGFR inhibitor AG-013958 (Pfizer, Inc.) in 21 patients with subfoveal CNV associated with AMD resulted in minimal levels of systemic exposure, which was similar to levels found in 13 cynomolgus monkeys dosed with the same compound. Researchers in the Netherlands collected plasma samples from the 21 patients at one day, two to four days, and four, eight, and 13 weeks after administration. In 16 patients, 9 percent of plasma samples contained measurable concentrations of AG-013958 on an LC-MS-MS assay with a sensitivity of 10 pg/mL. Similarly, minimal systemic exposure had been found in cynomolgus monkeys. In addition, at 13 weeks, dose site tissue contained approximately 2 percent of the dose, while the choroid contained concentrations approximately 25 times greater than the target IC90.
Among the human patients, 76 percent reported adverse events: four reported events related to administration (eye pain, increased tearing, sandy feeling, conjunctival hyperemia); three reported events related to the drug (dizziness, feeling abnormal, eye pain); and nine reported events related to "other." All reported adverse events related to the drug or its administration were classified as Grade 1.

Source: AG-013958 (VEGFR inhibitor) achieves effective choroidal concentrations with minimal systemic effects in cynomolgus monkeys and humans with age-related macular disease, Hoyng CB, Vingerling JR, Hooymans JMM, et al., ARVO 2005 paper presentation 2365.

SANA Study Investigates Systemic Bevacizumab for CNV in AMD
Researchers at the Bascom Palmer Eye Institute (Miami, Fla.) presented results from their study of systemic bevacizumab (Avastin, Genentech Inc.) for treating CNV in patients with AMD. The study is known as Systemic Avastin for Neovascular Age-Related Macular Degeneration, or SANA. The FDA recently approved bevacizumab as part of treatment for metastatic colorectal cancer.

The prospective, open-label, uncontrolled SANA study enrolled AMD patients with subfoveal CNV, central retinal thickness of at least 300 µm, and visual acuity between 20/40 and 20/400. Of the 15 patients in the study, nine have been followed for at least three months and four have been followed for at least 6 months. Patients were treated initially with either two or three infusions (5mg/kg) of bevacizumab at two-week intervals and then examined every week for the first six weeks, every two weeks for the next six weeks, and every four weeks thereafter. No patient required retreatment by three months, and only one of the four patients followed for at least six months received retreatment.

Improvement in the visual acuity of study eyes was evident one week after the first dose. By three months, the median visual acuity increased by eight letters (p=0.011), and the mean visual acuity increased by 12 letters (p=0.008). Only one of the first nine eyes treated showed continued evidence of leakage on fluorescein angiography, but it resolved by four months. No lesion growth was detected. On indocyanine green angiography, all hot spots identified at baseline were absent, the borders of all plaques were better delineated, there was no evidence of lesion growth and no change in areas of hypofluorescence. As assessed by optical coherence tomography, the median central retinal thickness of the first nine study eyes decreased by 157 microns (p=0.008) and the mean central retinal thickness decreased by 177 µm (p=0.001).

By six weeks, the median and mean systolic blood pressure of patients showed mild elevation, which was controlled by changing or initiating antihypertensive medication. While systemic bevacizumab has shown the potential to improve vision within one week of treatment and its effects may last longer than the effects of similar drugs administered intravitreally, the researchers said further study is needed to determine its safety in AMD patients. In January, the FDA issued an updated warning for Avastin in cancer patients receiving chemotherapy and Avastin. These patients were found to be at increased risk for arterial thromboembolic events, including cerebral infarction, transient ischemic attacks, myocardial infarctions and angina, compared with patients treated with only chemotherapy. Some of the events were fatal. The warning letter is available at www.fda.gov/medwatch/SAFETY/2005/Avastin_dearhcp.pdf.

The SANA study is supported by the National Institutes of Health, Research to Prevent Blindness, and the German Research Foundation.

Sources: Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration (SANA) study: visual acuity outcomes, Rosenfeld, PJ, Puliafito CA, Michels S, et al., ARVO 2005 paper presentation 2310. Rosenfeld PJ, Puliafito CA, Michels S, et al., ARVO 2005 poster presentations 1378-B147, 1382-B151, 1381-B150, 1377-B146, 1376-B145.

Combined Squalamine and Photodynamic Therapy
Interim data from a Phase II clinical trial evaluating systemic squalamine lactate (Envizon, Genaera Corp.) with verteporfin (Visudyne, Novartis Ophthalmics) photodynamic therapy for subfoveal CNV in wet AMD suggest that concomitant use of the drugs is well-tolerated. Forty-six patients were enrolled in this double-masked study, MSI-1256F-208; safety results and visual acuity data from up to nine weeks of treatment were reported.

Subjects in the primary treatment groups received intravenous infusions of 10, 20 or 40 mg of squalamine lactate in weeks one, two, four and five of the trial and were treated with PDT in week three. Control subjects were treated with PDT at week three but received vehicle-only infusions.

No drug-related serious adverse events occurred. The most common adverse events were infusion-site reactions, which were generally mild and distributed evenly across the squalamine treatment groups. No drug-related ocular adverse events have occurred.

Study eyes receiving both therapies (n=28) experienced a mean visual acuity gain of 1.5 ETDRS letters at week three (prior to PDT) compared with baseline. Similarly, at week thee, the study eyes of subjects in the PDT control group (n=17) gained an average of 1.5 ETDRS letters. At week nine, eyes treated with squalamine (n=24) gained an average of 1.3 ETDRS letters, while eyes treated with PDT only (n=15) lost an average of 0.9 ETDRS letters.

Monthly squalamine or control infusions will continue through week 25, with optional PDT at weeks 15 and 27 if investigators consider it medically necessary.

Source: A phase II, multicenter, randomized controlled, masked study of the effects of squalamine lactate in combination with Visudyne in patients with subfoveal choroidal neovascularization associated with age-related macular degeneration, Ciulla TA, Regillo C, Desai A, et al., ARVO 2005 paper presentation 2363.

Final Results of TTT4CNV Clinical Trial
Final analysis of the data from the two-year TTT4CNV multicenter, double-masked clinical trial mirrored preliminary results, showing that transpupillary thermotherapy for subfoveal occult CNV caused by AMD did not provide a benefit compared with sham treatment. However, TTT provided a statistically significant treatment benefit in the subgroup of patients (n=124) whose baseline visual acuities were 20/100 or worse.

Patients in the trial were examined at one, three, six, 12, 18 and 24 months. Retreatment was permitted only at three months. At months 12, 18 and 24, the mean loss of visual acuity in the subgroup was less by five to nine letters. Improvement in visual acuity of two or more lines was significantly greater (p=0.03) at 12 months (19 percent of TTT-treated eyes vs. 0 percent of sham-treated eyes) and 18 months (17 percent of TTT-treated eyes vs. 0 percent of sham-treated eyes). The best results were seen in TTT-treated eyes that were not retreated.

Source: Results from the TTT4CNV clinical trial, Reichel E, Musch DC, Blodi BA, Mainster MA, 2005 ARVO paper presentation 2311.

An illustration of retinal angiomatous proliferation (RAP) at Stage III showing CNV with a vascularized pigment epithelial detachment and a retinal-retinal anastomosis.

OCT of diabetic macular edema due to posterior hyaloidal traction.