On March 31, the Australian company Prana Biotechnology announced negative top-line results of its only Phase 2 study of the anti-amyloid drug PBT2. Called IMAGINE, the trial had enrolled 42 people with prodromal or mild Alzheimer’s disease who had a positive brain amyloid scan.
This trial evaluated how a one-year course of a once-daily, 250 mg PTB2 capsule would affect brain amyloid deposition as measured by positron emission tomography with the amyloid imaging tracer Pittsburgh compound B (PiB). Based on draft results, the trial missed its primary endpoint, which was defined as a statistically significant reduction in plaque levels. Overall PiB retention in PBT2-treated patients did go down, but it went down in the placebo group as well. Of the 42 enrolled patients, 27 received the drug, 15 the placebo.
The market’s response was swift. Within hours, the company’s stock plummeted after it had risen temporarily in response to a February 18 announcement of top-line results of a separate Phase 2 trial in Huntington’s disease (see Feb 2014 news story).
In addition to amyloid load, the IMAGINE AD trial had five secondary outcomes. The first confirmed the results of the recent Huntington’s trial in that PBT2 was both safe and tolerable, with equivalent adverse event profiles between groups, according to Prana’s announcement. The second secondary outcome was neuronal function as measured by fluorodeoxyglucose (FDG) PET. On that measure, the company reported no benefit.
The third secondary outcome was PBT2’s effect on brain volume as measured by magnetic resonance imaging of cortical gray matter, hippocampus, and ventricles. On that, the company reported no statistical significance but a trend toward less hippocampal atrophy in the treated group. The fourth secondary outcome was cognition as measured by the neuropsychological test battery (NTB) and the mini-mental state examination (MMSE); PBT2 was negative on both. The final secondary outcome sought to quantify how patients function by way of the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL); PBT2 had no effect on this measure.
Prana scientists offered their interpretation of the results in the company press release. The company posted an audio recording of a March 31 investor call, in which company and associated scientists discussed the results and took questions.
PBT2 is a second-generation drug growing out of prior research on clioquinol. Both are so-called metal-protein interaction-attenuating compounds. MPACs are thought to reduce amyloid aggregation by interfering with the interaction of copper and zinc with beta amyloid.
For details of the IMAGINE trial design, see Australian New Zealand Clinical Trials Register. An extension study is still ongoing. The trial was partially funded by the Alzheimer’s Drug Discovery Foundation in New York City.—Gabrielle Strobel