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In clinical trials as an Alzheimer therapy.
Small molecule metal-protein attenuating compound, of the 8-hydroxyquinoline class. Brain penetrable, designed to be safer and more efficacious than parent compound clioquinol.
Inhibits oligomer formation, disaggregates plaques, neutralizes Aβ toxicity.
investigational in U.S.
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 &
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
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.,
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
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.
Prana Biotechnology Ltd.
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.
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,
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