Background

PBT2 is a metal protein-attenuating compound (MPAC) being developed for treatment of both Alzheimer's and Huntington's diseases. It is an 8-hydroxyquinoline derivative that disrupts the interaction between metals and the Aβ peptide in the brain. The rationale is that as an MPAC, PBT2 prevents Aβ accumulation while also restoring copper and zinc ion homoeostasis in cells. According to scientists at Alterity Therapeutics, formerly Prana Biotechnology Ltd., increasing bioactive metal levels in the aging brain accelerates formation of amyloid plaques as well as neurotoxic oxidative processes. PBT2 translocates copper and zinc ions into the cell, reducing their extracellular levels and thereby reducing metal-mediated Aβ aggregation. It does so by acting as a copper and zinc ionophore rather than a chelator. PBT2 was reported to improve indicators of synaptic health such as spine density and synaptic protein levels in APP transgenic mice (Bush and Tanzi, 2008; Crouch et al., 2011; Adlard et al., 2011). 

Two studies reported that copper drives aggregation of the mutant huntingtin protein and that PBT2 improved motor performance and extended the lifespan in a mouse model of HD (see Fox et al., 2007; Cherny et al., 2012). 

PBT2 is taken as an oral capsule and crosses the blood-brain barrier. PBT2 is the second-generation compound with improved brain penetrance and pharmacokinetics to PBT1, which was discontinued because of formulation and safety issues.

Findings

In 2007, Prana conducted a Phase 2 trial at sites in Australia and Sweden. The 12-week trial enrolled 78 people with early Alzheimer's disease and compared 50 mg and 250 mg of PBT2 taken once daily to placebo on safety, as well as some fluid biomarker and cognitive and global function scales. PTB2 was reported to have been safe and well-tolerated, without serious side effects or withdrawals related to adverse events. The higher dose reportedly reduced Aβ42 levels in CSF, though not in plasma. There was no statistically significant improvement on the ADAS-Cog battery; however, a treatment benefit was seen in individual executive function tests (see March 2008 news story, Lannfelt et al., 2008). A subsequent post hoc analysis ranking the treatment responses reported that the findings of benefit were more likely with the higher dose than the lower dose or placebo (Faux et al., 2010 ). These studies called for larger trials to test PBT efficacy.

In 2011, Prana conducted a second Phase 2 study of 250 mg PBT2 once daily in 42 people with prodromal or mild AD. This trial used amyloid imaging as its primary outcome. On March 31, 2014, Prana reported top-line results stating that there was no significant difference between the treatment and placebo groups (see news story and extensive expert commentary). Results of this trial were published (Villemagne et al., 2017). The treated group showed a 3 percent decline in amyloid over one year, but there was no change in the placebo group. Amyloid levels stabilized during a one-year, open label extension. For more details on this trial, see Australian New Zealand clinical trials registry.

In 2012/2013, the Huntington Study Group ran Reach2HD, a Phase 2 trial, at 20 research sites in the U.S. and Australia. This trial compared a six-month course of 100 or 250 mg of PBT2 once daily to placebo in 109 patients with mild to mid-stage Huntington's disease. Prana disclosed top-line results on February 18, 2014. On the primary endpoint of safety and tolerability, Prana reported that five people dropped out of the trial and that PBT2 met safety and efficacy criteria for the remaining participants. Ten serious adverse events occurred, nine of them in the PBT2 groups. Prana claims that all serious adverse events were unrelated to PBT2 except for one person who reported a worsening of Huntington's symptoms after the treatment period. Of seven secondary outcomes, cognition was prespecified as the main efficacy variable based on the previous Phase 2 results in AD. An executive-function composite score comprising Category Fluency and the Trail Making Test Part B showed a trend toward improvement in people taking the higher dose, and statistical significance in people with mild HD. This this was due to an improvement compared with placebo for the high dose in the Trail Making Test, which was also the basis for the positive effect seen in the AD trial. No treatment effect was seen on any other outcome (for detail and expert commentary, see Feb 2014 news story). Results were published after peer review (Huntington Study Group Reach2HD Investigators, 2015).

In 2014, Phase 1 trials evaluating the relationship of food and caffeine to the pharmacokinetics of PBT2, and a bioavailability study, recruited a total of 44 healthy volunteers. Results are posted on clinicaltrials.gov.

In 2014 and 2015, PBT2 received Orphan Drug Designation for Huntington's disease from regulators in the U.S. and Europe. In February 2015, Prana announced that the U.S. FDA had placed a partial clinical hold, which limited the allowed dose to below the level the company considered to be clinically useful. In December 2016, the company disclosed that European regulators had recommended further animal work to establish whether neurotoxicity detected in dog studies was reversible (press release). At that time, Prana said they were looking for a collaborator on this project. No further development activity of PBT2 for neurodegeneration has been announced.

In 2019, Prana changed its name to Alterity Therapeutics.

For clinical trials of PBT2, see clinicaltrials.gov.