PBT2: From C. elegans Screening to Clinical Trials

PBT2, a metal-protein attenuating compound (MPAC), was developed for Alzheimer's and Huntington's diseases. Its journey began with Caenorhabditis elegans screening, where researchers generated a transgenic strain expressing amyloid-beta (Aβ1-42). This model showed that PBT2 significantly protected against Aβ-induced toxicity. The ease and efficiency of using C. elegans enabled a high-throughput screening of potential therapeutic compounds.

Following promising results in C. elegans, PBT2 was tested in mouse models of Alzheimer's and Huntington's diseases. These studies showed improved synaptic health and motor performance, encouraging further clinical investigation.

In a Phase 2 clinical trial for Alzheimer's disease, PBT2 was found safe and well-tolerated, with higher doses showing some cognitive benefits. However, a partial clinical hold by the U.S. FDA due to safety concerns at clinically useful doses led to the discontinuation of its development for Alzheimer's disease.

This journey underscores the critical role of C. elegans in early-stage drug discovery, paving the way for testing in more complex models and ultimately in clinical trials.

McColl G, Roberts BR, Pukala TL, et al. Utility of an improved model of amyloid-beta (Aβ₁₋₄₂) toxicity in Caenorhabditis elegans for drug screening for Alzheimer's disease. Molecular Neurodegeneration. 2012 Nov;7:57. DOI: 10.1186/1750-1326-7-57.

Cherny RA, Ayton S, Finkelstein DI, Bush AI, McColl G, Massa SM. PBT2 Reduces Toxicity in a C. elegans Model of polyQ Aggregation and Extends Lifespan, Reduces Striatal Atrophy and Improves Motor Performance in the R6/2 Mouse Model of Huntington's Disease. J Huntingtons Dis. 2012;1(2):211-9. doi: 10.3233/JHD-120029

https://www.alzforum.org/therapeutics/pbt2