18 June 2008. With mounting evidence that Alzheimer disease can silently ravage the brain years before symptoms emerge, the race is on to develop compounds that can detect preclinical changes—much like a mammogram would pick up signs of probable cancer. One such compound, developed by Avid Radiopharmaceuticals, Inc. in Philadelphia, Pennsylvania, entered a first Phase 2 clinical trial earlier this month. This molecular imaging agent, AV-45, is one of several being developed at Avid and elsewhere for broad use with positron electron tomography (PET) to detect the buildup of amyloid plaques in the brain.
Dean Wong of Johns Hopkins University, Baltimore, Maryland, presented data from Phase 1 trials of the Avid compound on June 16 at the Society of Nuclear Medicine conference in New Orleans. In this study of 30 people, AV-45 correctly diagnosed 14 of 15 participants who entered the trial with “possible or probable AD” (the fifteenth person was found later to have a non-AD-related dementia). The PET tracer also detected amyloid plaque in the brains of two of 15 healthy controls, who were both in their mid-eighties. Researchers are keenly interested in whether amyloid accumulation in cognitively normal people predicts AD later in life (see ARF related news story and ARF related news story), and the availability of reliable amyloid tracers for longitudinal studies will be key to answering this question.
Enrollment for the Phase 2 trial of AV-45 began several weeks ago at 30 centers across the U.S., according to Alan Carpenter, a vice president at Avid. The trial—involving about 200 patients, each undergoing a single 10-minute PET scan performed within an hour of AV-45 injection—is designed to show how AV-45 brain imaging can distinguish healthy volunteers from patients with mild cognitive impairment (MCI) or AD. The trial is due to appear on ClinicalTrials.gov by the end of this week, said Carpenter. Later this year, supplemental studies will test AV-45’s mettle as a biomarker to detect amyloid changes induced by experimental AD drugs, Carpenter told Alzforum. He did not disclose specifics but said one study would involve secretase inhibitors. These drugs target enzymes that promote the generation of Aβ peptides, which make up the harmful plaques found in the brains of AD patients.
Most PET imaging studies to probe amyloid content in the brain thus far have used the 11C-labeled Pittsburgh Compound B (PIB), which is highly specific for Aβ plaques but limited by its short (20-minute) radioactive half-life. Many newer compounds, such as AV-45, are instead conjugated with 18F, a radioisotope with a longer (two-hour) half-life that would enable wider availability of these reagents in the future.
Clinical tests of another non-PIB-based 18F amyloid tracer, BAY94-9172 (also known as AV-1/ZK)—which was invented by Avid and sublicensed to Bayer Schering Pharma —are led by Chris Rowe of Austin Health in Melbourne, Australia. Phase 2 trials of BAY94-9172 are set to begin in August at sites in the U.S., Europe, and Australia, Rowe told ARF via e-mail.
GE Healthcare plans to begin Phase 2 studies of an 18F-labeled PIB derivative, AH110690, this fall in Europe, according to Gill Farrar, who heads development of this compound at GE Healthcare. Initial data from Phase 1 tests of AH110690 were presented in March at the Human Amyloid Imaging conference in Chicago (see ARF related news story). Rik Vandenberghe of K.U. Leuven, Belgium, will report the full set of Phase 1 data next month at the ICAD meeting.—Esther Landhuis.