The first published description of ‘neurofibrillary tangles’ was in 1906 by Dr Alois Alzheimer, a German neurologist.1 He presented the case of a female patient with mysterious tangles in the brain at a scientific meeting of psychiatrists in Münich. Alzheimer considered this ‘presenile dementia’ to be a new type of psychiatric disorder characterized by the presence of neurofibrillary tangles. It is this disease which would later be named Alzheimer’s disease as the same tangles came to be identified in older cases with dementia as well.
In 1985, PhD student Claude Wischik, while at the University of Cambridge, set out to identify the structure of the paired helical filaments (PHFs) which make up the tangles associated with Alzheimer’s disease. In 1988, he published his discovery that the PHFs are composed of tau protein. 2,3 Until then, a number of proteins had been identified as bound up in tangle structures within neurons, but it had not been possible to determine which were part of the core structure of the PHF. The body of work published in 1988 defined for the first time the core structure of the PHF and showed that a short fragment from the microtubule-binding domain of tau was a structural building-block of the PHF. Later work showed that this fragment of tau accounted for at least 90% of the protein mass of the PHF.
Claude Wischik and colleagues at Cambridge University published the first report of inhibitors of tau aggregation in 1996.4
LMTX® is a second-generation tau aggregation inhibitor (TAI) and is the first TAI to enter Phase 3 clinical studies in Alzheimer’s disease and in the related neurodegenerative disorder, behavioural variant frontotemporal dementia.
The FDA did not require us to do additional Phase 2 studies with LMTX®. This is because LMTX® delivers the same active moiety into the blood as rember®, namely MT. LMTX® is a new chemical entity which has been engineered to deliver MT with better availability, tolerability and safety.
Yes, from 2008 to 2011 the company conducted a large number of in vitro and animal studies, as well as 6 human Phase 1 clinical trials on LMTX®. These enabled a bridge to be established linking dosing and safety information to that already obtained with rember® and LMTX® In addition, these studies defined the levels of MT required for engagement with the tau-aggregation target, and the corresponding levels of MT in plasma and brain. The studies also defined the main metabolism steps whereby MT is cleared from the body.
We have an active pipeline program, with a prime focus on primarily tau aggregation inhibitors, tau-based immunotherapeutics and diagnostic ligands. We have patented a number of chemical entities that have efficacy in tauopathies such as frontotemporal dementia, and other disorders of protein aggregation including Parkinson’s and Huntington’s. Additionally, we have screened a library of 2.8 million compounds to identify new leads for future drug and diagnostic development.
We are conducting discovery studies on a number of different compounds. Some are ready for formal pre-clinical studies with a view to Phase 1 studies, specifically for Alzheimer’s and Parkinson’s.