Working on the principle that EX 527 metal ions aid the pathological aggregation of AB, specific metal protein attenutating compounds, have been developed. Cloquinol, PBT1, was not found to be of clinical benefit and there were safety concerns in keeping with the drug's previous profile. Development has been halted. A newer generation compound, PBT2, has exhibited a more favourable safety profile and further Phase 2 testing is ongoing [50].
3.1.4. Antitau therapies
The pathological aggregation of tau has also been the focus of therapeutic attempts. Once again strategies are based on a shifting pathophysiological understanding, with target pathways including the hyperphosphorylation and aggregation of tau. Reflecting tau's stabilising role as a microtubule associated protein, supplementing this function with microtubule stabilisers has also been proposed.
The enzyme glycogen synthase kinase (GSK) 3β has been targeted in an attempt to interrupt its role in the hyperphosphorylation of tau. A Phase 3 study of sodium valproate, a known GSK3B inhibitor, showed it to be detrimental in those with AD [51]. Lithium has also been considered however results from a Phase 3 trial showed no benefit in those with mild AD [52].
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