PBT2 for the Treatment of Alzheimer's Disease
PBT2 for the Treatment of Alzheimer's Disease
Abstract & Commentary
By Norman R. Relkin, MD, PhD, Director, Memory Disorders Program, and Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Relkin reports that he receives grant/research support from Baxter Bioscience, and is a consultant to Eisai, Pfizer, Myriad, and Smart Genetics.
Synopsis: This novel agent, which inhibits interactions between beta amyloid (Ab) and metal ions, holds promise as a therapeutic agent for Alzheimer's disease.
Source: Lannfelt L, et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Ab as a modifying therapy for Alzheimer's disease: A phase IIa, double-blind, randomized, placebo-controlled trial. Lancet Neurology 2008;7:779-786.
Results of a phase II clinical study of PBT-2, an orally administered anti-amyloid agent, suggest that altering the interaction of beta amyloid (Ab) with the metal ions may be a viable way to treat Alzheimer's disease (AD). PBT2 is a second-generation metal-protein attenuating compound (MPAC) that is designed to reduce Ab aggregation and toxicity by interfering with the association of the Ab peptide with ions such as zinc and copper. PBT2 is a successor to clioquinol, a now defunct antifungal agent that was the first MPAC to be tested as a potential AD therapeutic. Clioquinol is neurotoxic at high doses and caused optic neuropathy, whereas PBT2 was designed to be more easily synthesized, safer, and improved in its metal-peptide attenuating effects.
This Phase IIa study of PBT2 was a double-blind, placebo-controlled trial in 78 patients with mild AD (mini-mental score = 20–26) who were given either placebo or one of two oral, daily doses of PBT2 (50 mg or 250 mg) for 12 weeks. There were no serious adverse events in this study. Patients treated with PBT2 had reduced CSF Ab42 concentrations compared with those treated with placebo, but no differences in the concentrations of plasma amyloid or serum zinc and copper. Among several tests of cognition administered, outcomes favoring the 250mg dose of PBT2 were found on two executive function subtests of the Neuropsychological Test Battery (NTB), namely Category Fluency and Trail-Making part B.
The investigators interpreted the changes in cerebrospinal fluid (CSF), but not plasma amyloid levels, after treatment, to indicate a specific effect on central processing of Ab42. They concluded that the safety and tolerability of PBT2 were good and its further development as a potential AD treatment is warranted.
Commentary
The concept that Ab–metal interactions may be relevant to AD is less well known nor as widely accepted as the amyloid hypothesis itself. Zinc and copper ions are present in increased concentration in brain synapses, where they play important roles in neurotransmission and other functions. Binding of zinc or copper to Ab makes these metal ions less available for physiologic functions and also fosters the formation of potentially toxic Ab aggregates. PBT-2 is not a metal chelator but does function as an ionophore, making copper and zinc more available for normal neuronal function. By attenuating the interaction of Ab with metals, it also reduces the formation of soluble and potentially toxic aggregates. These novel mechanisms of action distinguish PBT-2 from other anti-amyloid therapies now under development.
The stated primary goal of this Phase II study was to assess PBT-2's safety in treating mild AD. In that regard, this study was positive. In the PBT-2 Phase II trial, there were no serious side effects and no visual disturbances resembling the demyelinating optic neuropathy associated with its predecessor, clioquinol. Larger clinical trials will be needed to establish its safety.
PBT2 treatment also brought about changes in CSF Ab consistent with an amyloid-related mechanism of action. No attempt was made to correlate the observed biomarker changes with clinical outcomes, leaving unresolved the question of whether changes in CSF amyloid brought about by PBT-2 are relevant to any therapeutic effect.
In the aftermath of the failure of the first two anti-amyloid agents to complete Phase 3 trials (tramiprosate and tarenflurbil), better outcome on two tests of executive function in a 12-week trial with multiple other cognitive measures is modestly encouraging. However, this trial was too short and involved an inadequate number of subjects to draw conclusions about clinical efficacy. Given PBT2's novel mechanisms of action, oral dosing, excellent tolerability, and the changes it invoked in CSF Ab42 levels, this is an agent that could well find a place in future AD therapeutics if larger, longer-term trials prove positive.
This novel agent, which inhibits interactions between beta amyloid (Ab) and metal ions, holds promise as a therapeutic agent for Alzheimer's disease.Subscribe Now for Access
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