CLINICAL TRIAL SPOTLIGHT

DENALI Trial Seeks to Reduce Number of Treatments for Wet AMD

Trial will combine verteporfin and ranibizumab in 2-year trial.

ANDREW E. MATHIS, PHD, MEDICAL EDITOR

Novartis (East Hanover, NJ) announced Nov. 10 that it will be carrying out the DENALI clinical trial, a trial designed to measure the efficacy and safety of verteporfin (Visudyne, Novartis) in combination with photodynamic therapy (PDT) and the anti-vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis, Genentech). This will be the first large-scale (300 patients in the United States and Canada) study to examine the use of verteporfin with ranibizumab for the treatment of exudative age-related macular degeneration (AMD).

This study will be looking at the oldest FDA-approved treatment for wet AMD (verteporfin, approved April 2000) and the most recently approved wet AMD injection approved by the FDA (ranibizumab, approved June 2006). Together with a European-based trial, called MONT BLANC, the DENALI trial is party of the SUMMIT Trial Program. Both trials take their names from the highest mountains on the continents on which they will be taking place — thus the SUMMIT name for the program of trials.

Peter K. Kaiser, MD, director of the Retinal Clinical Research Center at the Cole Eye Institute of the Cleveland Clinic and the study chairman of the DENALI trial, says the key issue being examined is whether the number of treatments for wet AMD patients can be reduced while maintaining efficacy. "Treatments are a big inconvenience for our patients," Dr. Kaiser says. "If, by combining treatments we know will work and we know are safe, we can reduce the number of treatments, we will reduce that inconvenience."

The study will be designed such that two-thirds of the patients enrolled will receive combination therapy and the remaining third will receive ranibizumab alone. Of the two-thirds of enrollees who receive verteporfin with PDT and ranibizumab, the investigators also intend to vary the fluence rate of the PDT in about half of these eyes. "We want to see whether changing the fluence rate has any effect on the efficacy of combination treatment," Dr. Kaiser says.

Asked whether the vision improvement that has been documented with ranibizumab may be further improved, Dr. Kaiser responds, "I don't think so." However, he notes, "We know that combination therapy improves vision." The question under examination, rather, will be whether this vision improvement can be attained with fewer treatments.

The duration of the study is expected to be 2 years. During the first year, participants will receive 12 monthly injections in the ranibizumab alone arm and as needed dosing after 3 monthly injections in the combination arms. Then they will be followed for another year. Earlier trials, such as the FOCUS, VERITAS, and PROTECH studies, were as short as 6 months. "So far," Dr. Kaiser says, "results have been excellent when combining PDT and an anti-VEGF treatment."

Because the DENALI trial will also be assessing the safety of the verteporfin with PDT and ranibizumab combination, Retinal Physician asked Dr. Kaiser whether there were any specific safety issues for which the investigation team would be on the lookout. "There have been excellent results combining these drugs in previous trials," Dr. Kaiser says. "There has been little or no uveitis or endophthalmitis seen with the marketed formulation of Lucentis, so we do not foresee any safety problems."

The primary endpoint of the study will come after
1 year of treatment, at which point best corrected protocol visual acuity will be measured. A key second endpoint will be the first time retreatment for wet AMD is necessary after 1 year. Novartis has stressed that the DENALI trial is not devised to produce additional indications for verteporfin. However, the company will be analyzing data generated by the study before the endpoint. The DENALI trial will begin enrolling patients in early 2007. RP