This was a placebo-controlled, randomized, double-blind study in 78 patients with mild to moderate Alzheimer disease who were still functioning at home. Its primary outcome measures were safety and tolerability; secondary outcomes were assessment of amyloid-specific biomarkers in cerebrospinal fluid (CSF) and plasma, plus cognitive measures such as the ADAS-cog and NTB batteries of tests. Prana tested both 50 mg and 250 mg once-daily doses of PBT2 in this study, which lasted three months.

The researchers reported that the safety and tolerability of PBT2 at both doses were indistinguishable from placebo. There were no study withdrawals related to adverse events and no serious adverse event.

No statistically significant impact was seen on the ADAS-cog battery after three months of treatment. The researchers did report seeing signs of cognitive improvement as measured by the Neuropsychological Test Battery (NTB). They saw improvement above baseline, which indicated that the patients may have recovered some function, in two of the four executive function tests on the NTB, that is, the Category Fluency Test and the Trail Making Test part B. Both changes were seen after 12 weeks of treatment at the higher dose compared to placebo. Trial participants were also receiving standard AD therapy, either acetylcholinesterase inhibitors or memantine.

On the biomarker front, PBT2 showed statistically significant reduction of Aβ42 in the cerebrospinal fluid (CSF) in a dose-dependent manner. The researchers observed a 12.8 percent decrease, at the higher 250 mg dose, according to Prana cofounder Ashley Bush at the Mental Health Research Institute of Victoria, Australia. The CSF tau concentration was unchanged in this trial.

PBT2 is a second-generation drug derived from clioquinol, a known antibiotic and weak metal chelator. After clioquinol looked promising in the clinic (Ritchie et al., 2003), scientists headed back to the lab to design a safer, better drug based on the same scaffold. “PBT2 is not a chelator and doesn’t deplete metal ions in the brain. We believe PBT2 binds to the metal/Aβ complex causing amyloid aggregates to disassociate, releasing metal ions and allowing the brain to clear the toxic Aβ,” Bush said.

“Our approach is unique in that we are trying to inhibit the metal binding of Aβ, which is involved in forming plaque in the brain. There is no evidence that PBT2 is working in a non-specific manner,” said Colin Masters, who directs the Mental Health Research Institute of Victoria and is on the Research and Development Advisory Board of Prana. In particular, Prana researchers think PBT2 is targeting Aβ dimers and trimers. This approach would have the advantage of specifically targeting an abnormal process, i.e., oligomer formation, whereas other approaches to stop the formation of amyloid have to avoid interfering with the normal physiological function of necessary enzymes, such as γ-secretase, Masters added.

This trial was conducted in Sweden and Australia, largely because of the CSF biomarker component. “In Sweden we had the advantage that doctors routinely do lumbar punctures [spinal taps], so the researchers are experts in this technique and it is easier to enroll patients,” says Craig Ritchie, at Imperial College, London, who is on Prana’s scientific advisory board. Researchers doing clinical trials with patients in early stages of disease are realizing that they need to use biomarkers, though none have been formally validated. In early disease especially, biomarkers may prove an effective tool to measure a drug effect, even if the bridge from a biomarker change to clinical improvement has not been made yet in AD. In this short study, using CSF biochemistry made sense, since brain imaging probably would not have shown changes this quickly, said Ritchie. Prana used no brain imaging in this study. The company plans to do so in further trials, but has yet to decide which type of imaging, and whether all participants or a subgroup will receive it, he added.

The researchers chose to use the NTB battery in addition to the ADAS-cog test, which some researchers feel is not sensitive enough to quantify changes in cognitive performance among patients with the mildest forms of AD. The NTB battery comprises 10 cognitive tests to measure early changes in AD, and the Prana researchers added the Trail Making Test to further quantify executive function. Ritchie acknowledged that there has been some criticism of Prana “going on a fishing trip” with the use of both sets of tests, essentially searching for a set that allows them to see drug effects, but he said that it was necessary to document results of these tests as a baseline reading for future trials. The NTB has come into the spotlight recently after Elan/Wyeth announced their intent to use it as the primary outcome measure in their ongoing Phase 3 trials for their anti-amyloid monoclonal antibody AAB-001 (see ARF related drug story). The firms believe that they can persuade the FDA to accept the NTB as an alternative to the ADAS-cog.

The researchers hope that these results will generate the funding for additional trials. “We know that we hit the key biomarker Aβ42, which appears to have impact on executive function. While this study answered some questions, it has raised questions, also. There is sufficient interest and excitement for larger, longer studies to test for efficacy and determine best dosage,” says Ritchie.

Several other researchers contacted for this story shared a general excitement that this trial supports the MPAC route to AD treatment, but cautioned against overenthusiasm. “The drug was designed to lower Aβ and we are told in this news release that the higher dose is doing that, although to a modest extent. We don't know what impact this will have on disease progression or symptoms. CSF Aβ is being used as a biomarker for the drug's potential clinical actions, but the correlation between Aβ concentration and cognitive function is not proven. It will be necessary to have larger, longer trials to test the direct relationship between the marker and cognitive improvement," said Lon Schneider of the Keck School of Medicine of the University of Southern California. Other sources spoke off the record, but took the same stance.—Nadia Halim.

Nadia Halim is a freelance writer in Bridgewater, New Jersey.