R&D Capabilities
Tau Aggregation Inhibitors as
Therapeutic Agents
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Tau Aggregation Inhibitors as Therapeutic Agents
Introduction
Marketed AD therapeutics act on disease symptoms only, they do not target or modify the cause of the disease. They exert their effects by influencing neurotransmitter-mediated pathways. Such therapies can offer some transient reduction in symptoms for patients, but they cannot influence the eventual degenerative course of the disease. An objective for AD therapeutics now in development is to target the underlying pathology of the disease in order to alter the course of the disease: either by reducing the rate of disease progression or by halting the disease or preventing it. The discovery and development of such drugs, known as disease modifying therapies, requires an understanding of the biological processes that lead to the development of the disease, that is, the pathophysiology of the disease.
Two main hypotheses have been developed by the scientific community to describe the pathophysiology of progressive neuronal cell dysfunction, cell death and its relationship with dementia in Alzheimer’s disease: the Tau protein aggregation hypothesis implicating a causal role for Tau aggregates that form within neurons and the beta-amyloid (Aß) hypothesis that proposes a causal role for Aß aggregation that occurs outside of neurons. The Tau-hypothesis of Alzheimer’s disease pathogenesis proposes that age-related malfunctions in the cellular processing of Tau proteins, which are normal components of healthy cells, leads to Tau protein misfolding and loss of neuronal function, then to the formation of neurotoxic aggregates and ultimately disease symptoms.
Non-Clinical Rationale for Drugs Targeting Tau Aggregates
Neuronal cell degeneration is a very slow, multi-stage process of cumulative neuronal cell dysfunction that culminates in cell death. In degenerating cells, signal transduction between neuronal cells across the intercellular gap, or synapse, begins to deteriorate many years before neuronal cell death occurs. Initially Tau proteins aggregate, next Tau tangles form and eventually cell death is seen. The progression of a patient through these phases correlate strongly with loss of memory or cognitive decline. Preliminary evidence from active immunization studies suggests that a reduction in brain tissue amyloid does not reliably influence symptom development in AD.
The predominant initial clinical symptom of Alzheimer’s Disease is the impairment of memory, although a wide range of other higher functions, such as personality and judgment, are also affected. Yet in very early, asymptomatic Alzheimer’s Disease, pre-tangle Tau aggregates and Tau protein tangles are already present in the entorhinal cortex and hippocampus regions of the brain. These are the same regions where neuronal degeneration and loss of neuronal cells eventually occurs. With time, Tau tangles also form in the parieto-temporal and frontal region of the cortex resulting in neuronal dysfunction and correlating with the worsening of clinical symptoms.
Tau Protein Aggregation Leads to Neuronal Cell Dysfunction and Eventually Cell Death
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This relationship between Tau Protein Aggregate accumulation and the emergence of Alzheimer’s disease symptoms combined with additional evidence from a large body of non-clinical research supports the proposal that drugs that target the Tau Protein Aggregation cascade would have clinical utility in Alzheimer’s disease and related disorders. Two of the most compelling non-clinical studies include those conducted in murine Alzheimer’s disease models. In one study, Alzheimer’s disease related behavioural changes and memory loss were prevented by partially reducing levels of Tau protein expression while overproducing human amyloid protein. This finding suggests that only partial changes to the levels of intracellular Tau aggregates could be therapeutically beneficial even in the presence of high levels of amyloid. Furthermore, in other studies, reduction or eradication of amyloid levels in animal models did not protect against the development of symptoms. Conversely overproduction of Tau protein aggregates leads to behavioural deficits and their reduction by treatment with prototype Tau Aggregation Inhibitors leads to relief of these deficits. Preliminary evidence from active immunisation studies in humans suggests that a reduction in the brain tissue amyloid load does not reliably influence symptoms or disease progression in AD. See Resources for related publications.
Clinical Rationale for Drugs Targeting Tau Aggregates
The most relevant and compelling data to support a role for drugs targeting Tau pathophysiology and particularly the utility of Tau Aggregation Inhibitors, is that gathered in patients.
Braak Staging System : Tau Aggregates Correlate with Cognitive Impairment
During the 1990s, Braak and his colleagues reported a tool that directly measured the development of Alzheimer’s disease related pathology in patients. Braak graded the presence, distribution and density of Tau tangles in the brain and defined six distinct stages of AD progression (“Braak stages”). The TauRx research team built on the findings of Braak and demonstrated, in a clinical setting, that there is a strong correlation between the degree of Tau protein neurofibrillary pathology in the brain as measured using Braak staging, the amount of aggregated Tau in pre-tangle brain regions and the degree of cognitive incapacitation as measured by “mini mental state exam” (MMSE) scores. The Braak neuropathological staging system for Alzheimer’s disease thus provides a means for the direct measurement of the relationship between Tau aggregate formation and cognitive decline.
Braak Stage Relationship to MMSE Scores
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The Braak neuropathological staging system has been used to demonstrate that in the human clinical context:
- The spread of Tau protein aggregates in the brain correlates with clinically observed cognitive deficit and progression of functional brain scan deficit.
- The pattern of distribution and the density of Tau protein aggregates throughout the brains of Alzheimer’s disease patients are very similar.
- Neurofibrillary tangles first form in the medial temporal lobe regions of the brain then spread into the limbic and neocortical regions.
In contrast:
- Aß deposits do not correlate with disease progression.
- Aß plaques are frequently found in the cortex of non-demented individuals.
See Resources for related publications.
TauRx’s TAIs: rember™ and Second Generation TAIs
TauRx’s pipeline of therapeutics includes a range of compounds that have arisen from research, preclinical and clinical investigations the Company first performed using rember™. rember™ is TauRx’s ultrapure Tau Aggregation Inhibitor (TAI), with patents pending, a version of methylene blue (methylthionine chloride), a comparatively crude and poorly tolerated compound previously used to treat a variety of conditions. TauRx has discovered and is developing alternative forms of the same active moiety present in rember™ that have been chemically optimized to afford enhanced tolerability and bioavailability, enabling their use at higher doses than rember™. TauRx’s TAIs are backed by a robust patent estate.
TauRx’s lead “second generation” TAI has the potential to achieve greater clinical efficacy than the striking effects already shown with rember™. Delivering the same active moiety in the blood as rember™, the clinical tolerability profile of LMTX, one of TauRx’s second generation TAIs, is currently being investigated clinically in trials conducted under an open US IND. TauRx is now preparing to advance LMTX into pivotal international phase 3 trials in mild and moderate AD and related neurodegenerative diseases.
TAIs Show Promise in Disease Modification: Clinical Results
TauRx has evaluated rember™, in a large, double-blind, long-duration international phase 2 clinical trial in patients with mild or moderate AD. This study provided the first clinical indication that treatment with the Company’s proprietary Tau Protein Aggregation Inhibitors holds promise in modifying the progression of AD. rember™ showed evidence in the phase 2 trial of a significant reduction in the rate of clinical decline: 80% by weeks 50 and 102 of this trial, relative to controls, as measured using psychometric tools. Functional neuroimaging results from the trial supported the psychometric data: in patients exposed to rember™, the loss of function occurring in the areas of the brain known to be particularly affected by the Tau-tangle pathology of disease was eliminated over 6 months. Functional brain scan benefits seen at 6 months were predictive of clinical benefit at 12 months.
Molecular imaging (SPECT/PET) has provided a key result in the phase 2 rember™ clinical trial by identifying regions within the brain that were protected by this drug. These regions are coincident with regions known to be affected by Alzheimer’s disease neuropathology and provide significant support for the TAI strategy for treating the disease.
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The central figure demonstrates the locations of Tau pathology in AD. The surrounding images show the locations that rember™ appears to protect. These images were created using data from a randomized placebo controlled trial using rCBF SPECT. The areas are the statistically significant regions of difference between the active and control groups.
Results suggesting similar benefits have been seen in an ongoing open label trial in a small number of patients with Frontotemporal dementia, a progressive, lethal neurodegenerative disease characterized by Tau or TDP-43 pathology for which no effective therapy is available.
Clinical studies with diverse therapies directed at Aß pathology and other targets have not demonstrated clinical benefit when evaluated in large patient populations. Indeed, in one trial, dementia persisted in patients whose levels of Aß aggregates were reduced by the therapy to non-detectable levels. See Resources for related publications.
For more information on TauRx’s clinical trial program see Pipeline.
Clinical Potential of TAIs in Disease Prevention
Research reported by the TauRx team compared levels of Tau protein aggregates in various regions of the brain versus MMSE scores and Braak stage. It was shown that Tau tangle-mediated neuronal death is a relatively late stage event. As described previously, the level and nature of Tau aggregates correlates with cell death, the hallmark of which is the appearance of “ghost tangles” composed of Tau protein. In the affected brain region, Tau protein aggregation precedes the appearance of neurofibrillary tangles and measurable symptoms by 10 – 20 years. In the neocortex, for example, there is evidence of Tau protein aggregation and loss of neuronal function from Braak stage 2 onwards, but tangle-mediated cell death is not seen in neocortex until Braak stage 6. In light of the constant improvement of diagnostic tools for ever earlier stages of AD and cognitive decline that in some cases evolves into AD, this analysis indicates the potential use of Tau protein aggregation inhibitors in disease prevention. See Resources for related publications.
A Therapeutic Window for Preventative Treatment?
Comparison between:
- Concentrations of Aggregated Tau Protein
- Severity of symptoms measured using the MMSE scale
- Years since graded as Braak stage 1
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Key: ‘erc.’ entorhinal cortex where Tau aggregation pathology begins; ‘hipp.’ hippocampus, the memory critical brain region immediately adjacent to entorhinal cortex; ‘cortex’ the neocortical hemispheres of the brain
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