Elsevier

The Lancet Neurology

Volume 7, Issue 9, September 2008, Pages 779-786
The Lancet Neurology

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Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial

https://doi.org/10.1016/S1474-4422(08)70167-4Get rights and content

Summary

Background

PBT2 is a metal-protein attenuating compound (MPAC) that affects the Cu2+-mediated and Zn2+-mediated toxic oligomerisation of Aβ seen in Alzheimer's disease (AD). Strong preclinical efficacy data and the completion of early, clinical safety studies have preceded this phase IIa study, the aim of which was to assess the effects of PBT2 on safety, efficacy, and biomarkers of AD.

Methods

Between December 6, 2006, and September 21, 2007, community-dwelling patients over age 55 years were recruited to this 12-week, double-blind, randomised trial of PBT2. Patients were randomly allocated to receive 50 mg PBT2, 250 mg PBT2, or placebo. Inclusion criteria were early AD (mini-mental state examination [MMSE] score between 20 and 26 points or Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) score between 10 and 25 points), taking a stable dose of acetylcholinesterase inhibitor (donepezil, galantamine, or rivastigmine) for at least 4 months, a modified Hachinski score of 4 points or less, and CT or MRI results that were consistent with AD. The principal outcomes were safety and tolerability. Secondary outcomes were plasma and CSF biomarkers and cognition. Analysis was intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00471211.

Findings

78 patients were randomly assigned (29 to placebo, 20 to PBT2 50 mg, and 29 to PBT2 250 mg) and 74 (95%) completed the study. 42 (54%) patients had at least one treatment emergent adverse event (10 [50%] on PBT2 50 mg, 18 [62%] on PBT2 250 mg, and 14 [48%] on placebo). No serious adverse events were reported by patients on PBT2. Patients treated with PBT2 250 mg had a dose-dependent (p=0·023) and significant reduction in CSF Aβ42 concentration compared with those treated with placebo (difference in least squares mean change from baseline was −56·0 pg/mL, 95% CI −101·5 to −11·0; p=0·006). PBT2 had no effect on plasma biomarkers of AD or serum Zn2+ and Cu2+ concentrations. Cognition testing included ADAS-cog, MMSE, and a neuropsychological test battery (NTB). Of these tests, two executive function component tests of the NTB showed significant improvement over placebo in the PBT2 250 mg group: category fluency test (2·8 words, 0·1 to 5·4; p=0·041) and trail making part B (−48·0 s, −83·0 to −13·0; p=0·009).

Interpretation

The safety profile is favourable for the ongoing development of PBT2. The effect on putative biomarkers for AD in CSF but not in plasma is suggestive of a central effect of the drug on Aβ metabolism. Cognitive efficacy was restricted to two measures of executive function. Future trials that are larger and longer will establish if the effects of PBT2 on biomarkers and cognition that are reported here translate into clinical effectiveness.

Funding

Prana Biotechnology.

Introduction

Alzheimer's disease (AD) is the most common form of dementia.1 Current treatments for AD have restricted symptomatic benefit2 and do not affect the underlying disease process. AD is characterised pathologically by the accumulation of various amyloid beta (Aβ) peptides, including the 40 and 42 amino acid cleavage products (Aβ40 and Aβ42) of the amyloid precursor protein (a neuronal membrane protein).3 Oligomeric soluble forms of Aβ40 and Aβ42 have toxic properties and are thought to cause synaptic degeneration in stereotypic areas of the cerebral cortex in patients with AD.4, 5 Toxic oligomers of Aβ are formed by dimerisation or trimerisation of Aβ monomers, a process that is mediated, in part, by Zn2+ and Cu2+, which are normally found in high concentrations near excitatory NMDA synapses.6, 7 Aβ–Zn2+ interactions drive Aβ towards fibrillogenesis and amyloid plaque formation.8 Aβ–Cu2+ interactions initiate a series of redox reactions centred around the histidine residues at the N terminus of Aβ, resulting in the formation of soluble, toxic oligomers of Aβ.9, 10

Other therapeutic strategies to modify the underlying pathology of AD have focused on inhibiting the biogenesis of Aβ (eg, the inhibition of secretases) or promoting its clearance (eg, Aβ immunotherapy); however, an alternative approach was to develop a library of compounds that can inhibit Zn2+-induced and Cu2+-induced Aβ oligomers. These are typically hydrophobic, low-affinity-metal-complexing compounds that do not perturb essential transition-metal homoeostasis. To differentiate the compounds from high-affinity, medicinal metal chelators, they were termed metal-protein attenuating compounds (MPACs). As proof of concept, we took the prototype of this drug class, iodochlorhydroxyquin (clioquinol, PBT1), through preclinical11 and clinical12 development. PBT2 is a second generation 8-OH quinoline MPAC that was selected for clinical development because of its pharmacological properties and equivalent or superior efficacy to clioquinol for targeting Aβ oligomers in preclinical models.13

We report the results of a clinical study of the safety, tolerability, and the biological and cognitive effects of PBT2 in a group of patients with early AD. The primary objective of this study was to establish the safety and tolerability of PBT2 at two different doses. Secondary objectives were to assess the effect of PBT2 on putative blood and CSF biomarkers that are thought of as important surrogate measures for disease modification in AD,14 and to establish the effect of PBT2 on specific cognitive activity associated with early AD.

Section snippets

Patients

Eligible patients in Sweden (eight centres) and Australia (seven centres) were recruited to this phase II, double-blind, placebo-controlled trial between December 6, 2006, and September 21, 2007. Final patient assessments were completed on December 28, 2007. Eligible patients were community dwelling, aged over 55 years, and satisfied the following criteria: had a mini-mental state examination (MMSE)15 score between 20 and 26 points or Alzheimer's disease assessment scale-cognitive subscale

Results

88 patients were screened; 78 patients were randomly assigned to treatment, and 74 patients (95%) completed the study. Figure 1 lists the reasons for screening failure and withdrawal from the trial. No patient withdrew from the PBT2 treatment arms of the study because of adverse events or other problems with tolerability.

Four patients withdrew from the study before completion: three in the PBT2 group (one patient on 50 mg PBT2 was withdrawn because they received an excluded medication; one

Discussion

Both doses of PBT2 were well tolerated over the 12-week study period. No clinically significant adverse findings were attributable to PBT2 with respect to laboratory tests or physical assessment (including neurological, neuropsychiatric, ophthalmological or electrocardiographic tests), nor any effects on any of these parameters that were attributable to PBT2. Specifically, there was no evidence of any features that are consistent with subacute myelo-optic neuropathy, which supports earlier

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