Name:	PBT2
Therapeutic Applications:	In clinical trials as an Alzheimer therapy.
Therapy Types:	Small molecule metal-protein attenuating compound, of the 8-hydroxyquinoline class. Brain penetrable, designed to be safer and more efficacious than parent compound clioquinol.
Mechanisms:	Inhibits oligomer formation, disaggregates plaques, neutralizes Aβ toxicity.
Development Status:	investigational in U.S.
FDA Phase:	Phase II/IIa/IIb
Primary Medical Role:	Inhibits catalytic redox activity via metal chelation.
Role in Alzheimer's Disease:	Designed to modify the course of AD by preventing metal- dependent aggregation, deposition, and toxicity of Aβ (Ritchie et al., 2003). Aβ is a high-affinity metal binding protein which adopts a toxic gain of function in the presence of copper and zinc. PBT2 acts at three levels of the “amyloid cascade”: it inhibits the redox-dependent formation of toxic soluble oligomers, prevents deposition of Aβ as amyloid plaques, and promotes clearance by mobilizing and “neutralizing” Aβ from existing deposits (Cherny et al., 2001). A 12 week Phase IIa study testing safety and efficacy of PBT2, with biomarker analysis, in a double-blind, randomized, placebo-controlled trial showed that treated patients had a dose-dependent and significant reduction of CSF Aβ, and demonstrated significant improvement in two tests of executive function: the category fluency test and trail making part B test (Lannfelt et al., 2008). The parent compound clioquinol (PBT1) was tested in clinical trials for AD. It was not clear from this trial that clioquinol showed any positive clinical result. The two statistically significant positive results were seen for the more severely affected subgroup of patients; however, this effect was not maintained at the 36-week end- point, and this group was small (eight treated subjects). The sample size was small. Details of randomization procedure or blinding were not reported (Jenagaratnam & McShane, 2006).
Pharmacological Role:	PBT2 is a small, orally bioavailable molecule which has been designed to inhibit catalytic redox activity of Aβ attending its abnormal binding to copper. As a consequence of its metal ionophore properties, PBT2 is believed to act secondarily by promoting normal copper and zinc homeostasis in the brain, redistributing these crucial metals to their correct anatomical compartments, and preventing further pathological interactions with Aβ.
Contraindications:	This molecule is both structurally and mechanistically related to clioquinol (PBT1), which was responsible for subacute myelo-optico-neuropathy (SMON) in Japan 30 years ago and resulted in the ban of this anti-parasitic drug. Clioquinol-Zn chelate is a potent mitochondrial toxin, causing mitochondrial damage and a decrease in mitochondrial membrane potential (Arbiser et al., 1998). Prana has undertaken considerable nonclinical and clinical testing with PBT2 (unpublished data). No evidence of SMON has been detected despite PBT2 being of the same chemical class as clioquinol. Therefore, co-administration of any vitamins to mitigate SMON risk is unnecessary (Prana disclosure).
Side Effects:	In the recent 12 week Phase IIa study testing safety and efficacy of PBT2, both doses of PBT2 tested (50 and 250 mg/day orally administered) were well tolerated (Lannfelt et al., 2008). The most common adverse events in the test groups included headache, dizziness, and somnolence, nasopharyngitis, and fatigue. Three patients (two with pre-existing hypertension, one with heart palpatation; all were treated with antihypertensives) developed hypertension during the study: two of the cases were deemed to be causally related to the treatment (one patient in each PBT2 dose). No opthalmological adverse effects were noted.
Evidence pro its efficacy:	Due to the structural and mechanistic relatedness with clioquinol, PBT2 may inhibit Aβ accumulation and may have positive effects on cognitive function.
Companies:	Prana Biotechnology Ltd.
Notes:	Phase IIb clinical trial testing of PBT2 in mild to moderate Alzheimer Disease is planned but not yet initiated (Prana Biotechnology). This record was last updated July 23, 2009.

References

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. Abstract

Jenagaratnam L, McShane R. Clioquinol for the treatment of Alzheimer's Disease. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005380. Abstract

Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003 Dec 1; 60(12):1685-91. Abstract

Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim YS, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL , Bush AI. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta- amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001 Jun 1; 30(3):665-76. Abstract

Arbiser JL, Kraeft SK, van Leeuwen R, Hurwitz SJ, Selig M, Dickersin GR, Flint A, Byers HR, Chen LB. Clioquinol-zinc chelate: a candidate causative agent of subacute myelo- optic neuropathy. Mol Med. 1998 Oct;4(10):665-70. Abstract