Results from the first year of a two-year clinical trial suggest that Avastin, a drug approved to treat some cancers and that is commonly used off-label to treat age-related macular degen-eration, is as effective as the Food and Drug Administration-approved drug Lucentis for the treatment of AMD.

The report, from the Comparison of AMD Treatments Trials (CATT), was published online in the New England Journal of Medicine on May 1, 2011. CATT is funded by the National Eye Institute.

“Over 250,000 patients are treated each year for AMD, and a substantial number of them receive Avastin. Given the lack of efficacy data regarding Avastin for AMD treatment, the NEI had an obligation to patients and clinicians to conduct this study,” said Paul A. Sieving, MD, PhD, NEI director.

Genentech, maker of both drugs, developed Avastin to prevent blood vessel growth that enables cancerous tumors to develop and spread. In 2004, the FDA approved Avastin for the systemic treatment of metastatic colon cancer. Genentech later developed Lucentis, derived from a protein similar to Avastin, specifically for injection in the eye to block blood vessel growth in AMD. In 2005, two Genentech-sponsored clinical trials established Lucentis as highly effective for the treatment of wet AMD. During the year between the announcement of the trial results and the release of Lucentis, physicians began injecting AMD patients with low doses of Avastin, due to its similarity to Lucentis and its availability. The FDA has not licensed Avastin for AMD treatment.

Numerous physicians noted a beneficial treatment effect and Avastin’s use grew rapidly despite the lack of data on safety, efficacy and dosing from randomized clinical trials to support its use. Ophthalmologists used Avastin primarily as needed when there was evidence of active disease. The FDA approved Lucentis in 2006. However, most clinicians adopted PRN dosing for Lucentis, which was a departure from FDA-approved labeling and the monthly dosing schedule evaluated in the Genentech-sponsored clinical trials. It was not known if PRN dosing would produce the same long-term vision benefits that were achieved with monthly administration. 
NEI launched CATT in 2008 to compare Lucentis and Avastin for treatment of wet AMD. The study has now reported results for 1,185 patients treated at 43 clinical centers in the United States. Patients were randomly assigned and treated with one of four regimens for a year. They received Lucentis monthly or PRN, or Avastin monthly or PRN. Enrollment criteria required that study participants had active disease.

Patients in the monthly dosing groups received an initial treatment and then had an injection every 28 days. Patients in the PRN groups received an initial treatment and were then examined every 28 days to determine medical need for additional treatment. PRN groups received subsequent treatment when there were signs of disease activity, such as fluid in the retina. Ophthalmologists involved in patient care were masked to treatment to assure that the data was not affected by how anyone felt about the treatment.

Change in visual acuity served as the primary outcome measure for CATT. Thus far, VA improvement was virtually identical (within one letter difference on an eye chart) for either drug when given monthly. In addition, no difference was found in the percentage of patients who had an important gain or loss in visual function. Also, when each drug was given on a PRN schedule, there also was no difference (within one letter) between drugs. PRN dosing required four to five fewer injections per year than monthly treatment. Visual gains were about two letters less with PRN than with monthly treatment but overall visual results were still excellent.

“In addition to the primary finding of equivalence between Lucentis and Avastin for visual acuity, CATT also demonstrates that PRN dosing is a viable treatment option for either of these drugs,” said Daniel F. Martin MD, study chair for CATT and chairman of the Cole Eye Institute at the Cleveland Clinic. “Substantial visual acuity gains may be accomplished with a lower treatment burden.”

Adverse events may or may not be causally associated with the clinical trial treatment. The median age of patients in CATT was over 80 years, and a high rate of hospitalizations might be anticipated as a result of chronic or acute medical conditions more common to older populations.

Serious AEs (primarily hospitalizations) occurred at a 24-percent rate for patients receiving Avastin and a 19-percent rate for patients receiving Lucentis. These events were distributed across many different conditions, most of which were not associated with Avastin in cancer clinical trials where the drug was administered at 500 times the dose used for AMD. The number of deaths, heart attacks and strokes were low and similar for both drugs during the study. CATT was not capable of determining whether there is an association between a particular adverse event and treatment. Differences in serious adverse event rates require further study.

Investigators in the CATT study will continue to follow patients through a second year of treatment. These additional data will provide information on longer-term effects of the drugs on vision and safety. The FDA has not evaluated data from the CATT trial.

SARcode T-Cell Inhibitor Shows Positive Results
SARcode, a Brisbane, Calif. biopharmaceutical company, reported data from a Phase II dry-eye trial of its lead investigational molecule, SAR 1118. Subjects receiving SAR 1118 demonstrated a reduction in corneal staining, increased tear production, and improved visual-related function as compared to placebo. SAR 1118 is a first-in-class topically administered small molecule integrin antagonist that inhibits T-cell-mediated inflammation, a key component of dry-eye disease.

In the randomized, placebo-controlled, multicenter trial, which included 230 subjects with dry-eye disease, SAR 1118 demonstrated dose-dependent significant improvements (p<0.05) in inferior corneal staining over 12 weeks. As early as two weeks, a statistically significant (p<0.05) increase in tear production and improvement in visual-related functions (ability to read, drive at night, use a computer and watch television) were observed, demonstrating early onset of action. Visual-related function was assessed using the Ocular Surface Disease Index. SAR 1118 was safe and well-tolerated with no serious ocular adverse events reported. Most ocular adverse events were transient and related to initial instillation.

Merck Releases Phase III Data on New Prostaglandin
Merck announced that new Phase III data showed that patients with open-angle glaucoma or ocular hypertension who were dosed once-daily with tafluprost, Merck’s investigational, preservative-free prostaglandin analogue ophthalmic solution, experienced a reduction in intraocular pressure comparable to patients taking twice-daily preservative-free timolol maleate. The New Drug Application for tafluprost is under review by the FDA for the proposed use in the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension.

The multicenter, double-masked, randomized, active-controlled non-inferiority study of 643 patients with open-angle glaucoma or ocular hypertension was designed to evaluate the safety and efficacy of tafluprost once-daily (n=320) and preservative-free timolol twice-daily (n=323) over a 12-week treatment period.

At the beginning of the study, baseline IOPs ranged from 23.8 to 26.1 mmHg in patients treated with tafluprost and 23.5 to 26.0 mmHg in those treated with timolol. At the 12-week end of the study visit, IOPs ranged from 17.4 to 18.6 mmHg in patients treated with tafluprost and 17.9 to 18.5 mmHg in those treated with timolol. The IOP-lowering effect of treatment in patients receiving tafluprost and timolol was achieved by week two and sustained through week 12.

For the primary endpoint, at all nine time points, the difference between treatments in lowering IOP was less than the prespecified 1.5 mmHg non-inferiority margin, demonstrating a comparable IOP-lowering effect in patients treated with tafluprost and timolol. In four of nine time points the difference between treatments in lowering IOP favored PF tafluprost, based on an upper 95 percent confidence interval limit.

In addition, for a secondary endpoint the proportion of patients treated with tafluprost and timolol with ≥25-percent reduction in diurnal IOP from baseline was 56.7 percent vs. 50.5 percent at week two, 58.7 percent vs. 52.6 percent at week six, and 59.7 percent vs. 55.4 percent at week 12, respectively.

Drug-related adverse events were experienced by 12.2 percent of patients treated with tafluprost and 11.1 percent of patients treated with timolol. Ocular AEs of special interest assessed for tafluprost and timolol, respectively, were conjunctival hyperemia (4.4 percent vs. 1.2 percent); ocular pain, stinging, and/or irritation (4.4 percent vs. 4.6 percent); and ocular pruritus (2.5 percent vs. 1.5 percent). The incidence of conjunctival hyperemia, a known prostaglandin-associated adverse event, was higher (p=0.016) in the group receiving tafluprost. Serious AEs were reported in 0.6 percent of patients in the tafluprost group and 2.2 percent in the timolol group, but none of the AEs reported in either treatment group were assessed by the investigators as drug-related. In the tafluprost group, 1.3 percent of patients discontinued because of drug-related AEs, compared with 0.9 percent in the timolol group.

Oraya Completes
Enrollment of 
Radiotherapy Trial
Oraya Therapeutics has completed enrollment of its INTREPID clinical trial in Europe. The study is the first sham-controlled, double-masked trial to evaluate the effectiveness and safety of radiation therapy in conjunction with standard of care anti-VEGF injections for the treatment of wet AMD.

Oraya’s proprietary IRay stereotactic radiotherapy system employs externally delivered robotically controlled low-energy X-rays. The IRay treatment is a one-time, non-surgical procedure which may significantly reduce or eliminate the need for subsequent anti-VEGF injections, while maintaining or improving vision outcomes in treated patients. One year efficacy results of INTREPID will be available in the second quarter of 2012.

Enrollment in the INTREPID trial was completed on April 15 with 226 subjects. One third of those subjects received a sham exposure, with the remainder receiving a radiation dose of either 16 or 24 Gray (Gy).