BY REBECCA HISCOTT
WASHINGTON—An 18-month phase 2 study of TTP488, known as azeliragon, an oral antagonist of the receptor for advanced glycation endproducts (RAGE), found that the compound may slow decline in cognition in patients with mild to moderate Alzheimer’s disease (AD), researchers reported here in July at the Alzheimer’s Association International Conference (AAIC). While the phase 2b trial was discontinued in 2010 due to a futility analysis, the trial met its pre-specified endpoints and azeliragon has moved on to phase 3 testing in patients with mild AD.
Azeliragon, a RAGE inhibitor, may have “multiple mechanisms of action, including reduction or prevention of the aggregation of amyloid, anti-inflammatory pathways, et cetera, and that’s what makes it appealing,” said Marwan Sabbagh, MD, FAAN, director of the Banner Sun Health Research Institute and research professor of neurology at the University of Arizona College of Medicine in Phoenix, who presented the findings at the AAIC.
“The pre-specified futility analysis was that if there was less than a 10 percent conditional probability of meeting the trial’s endpoint, they would stop treatment. The conditional probability came out to 9.3 percent, and was done with preliminary and incomplete data,” he told the Neurology Today Conference Reporter. “But when you followed these patients to 18 months, and evaluate all available data, there was a statistically significant difference between azeliragon and placebo favoring azeliragon.”
The researchers found that mild to moderate AD patients on azeliragon showed a decrease in decline in cognition on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) at 18 months compared with those on placebo (p=0.008). While gastrointestinal disorders were more frequent, psychiatric disorders were less frequent in the group treated with azeliragon (p=0.04), they reported.
“While the study met its primary endpoint in the mild to moderate patient population, we found an even greater impact in the mild-only population, and that is the focus of the phase 3 trial,” Dr. Sabbagh said. Based on these findings, azeliragon has begun a phase 3 trial under a Special Protocol Agreement with the US Food and Drug Administration (FDA). Dr. Sabbagh will serve as the national principal investigator for the trial.
Commenting on the study, John C. Morris, MD, FAAN, the Friedman distinguished professor of neurology and director of the Knight Alzheimer Disease Research Center at Washington University School of Medicine, said: “If interim analyses do not provide much hope that a beneficial result will be found at study’s end, a trial is often terminated. This is in part to spare participants from being exposed to a therapy that is unlikely to benefit them (but potentially could harm them through adverse events), and in part to save effort, time, and money on a drug for which chances of benefit are predicted to be futile.”
But, he said, “criteria for futility in drug trials necessarily are arbitrary and may yield imperfect results.” Based on the data presented at the AAIC, he said, TTP488 appears to warrant a phase 3 trial.
David S. Knopman, MD, FAAN, a professor of neurology at the Mayo Clinic in Rochester, MN, agreed with Dr. Morris that including futility analyses in clinical trials of AD therapies remains important to protect human subjects from exposure to something that’s of no benefit to them.”
He also felt that TTP488 merited further investigation. “Contrary to the expectation of the futility analysis, the authors had a little bit of a signal in their primary outcome measure, the ADAS-cog,” he said. “In this case, the futility criteria they decided on didn’t work.”
LINK UP FOR MORE INFORMATION:
· Galasko D, Bell J, Mancuso JY, et al. Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease. Neurology 2014; 82 (17): 1536-1542: http://bit.ly/1CdxXDI
· Burstein AH, Grimes I, Galasko D, et al. Effect of TTP488 in patients with mild to moderate Alzheimer’s disease. BMC Neurol 2014; 14:12: http://bit.ly/1CNfKri
· ClinicalTrials.gov: A Phase 2 Study Evaluating The Efficacy And Safety Of PF 04494700 In Mild To Moderate Alzheimer's Disease: http://1.usa.gov/1gbKE89