Chemical Name: Hydroxyquinoline
Therapy Type: Small Molecule
Target Type: Amyloid-Related (timeline), Metals
Condition(s): Alzheimer's Disease, Huntington's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Huntington's Disease (Phase 2)
Company: Prana Biotechnology Limited
PBT 2 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 Prana, 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.
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 averse 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). For more details on this trial, see the 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 United States 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 pre-specified 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 doese, 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).
Two Phase 1 trials evaluating the relationship of food and caffeine, respectively, and the pharmacokinetics of PBT2, are getting ready to recruit healthy volunteers.
For clinical trials of PBT2, see clinicaltrials.gov.
- Anti-Amyloid Drug Clears Phase 2a Hurdle
- PBT2 Takes a Dive in Phase 2 Alzheimer’s Trial
- Drug Appears Safe in Huntington’s; Experts Split on Functional Benefit
- Lannfelt L, Blennow K, Zetterberg H, Batsman S, Ames D, Harrison J, Masters CL, Targum S, Bush AI, Murdoch R, Wilson J, Ritchie CW, . Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008 Sep;7(9):779-86. PubMed.
- Faux NG, Ritchie CW, Gunn A, Rembach A, Tsatsanis A, Bedo J, Harrison J, Lannfelt L, Blennow K, Zetterberg H, Ingelsson M, Masters CL, Tanzi RE, Cummings JL, Herd CM, Bush AI. PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. J Alzheimers Dis. 2010;20(2):509-16. PubMed.
- Bush AI, Tanzi RE. Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics. 2008 Jul;5(3):421-32. PubMed.
- Crouch PJ, Savva MS, Hung LW, Donnelly PS, Mot AI, Parker SJ, Greenough MA, Volitakis I, Adlard PA, Cherny RA, Masters CL, Bush AI, Barnham KJ, White AR. The Alzheimer's therapeutic PBT2 promotes amyloid-β degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem. 2011 Oct;119(1):220-30. PubMed.
- Adlard PA, Bica L, White AR, Nurjono M, Filiz G, Crouch PJ, Donnelly PS, Cappai R, Finkelstein DI, Bush AI. Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer's disease. PLoS One. 2011;6(3):e17669. PubMed.
- Fox JH, Kama JA, Lieberman G, Chopra R, Dorsey K, Chopra V, Volitakis I, Cherny RA, Bush AI, Hersch S. Mechanisms of copper ion mediated Huntington's disease progression. PLoS One. 2007;2(3):e334. PubMed.
- Sampson EL, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer's dementia. Cochrane Database Syst Rev. 2014 Feb 21;2:CD005380. PubMed.