Use of epothilone d in treating tau-associated diseases including alzheimer's disease

Abstract

Methods of treating Tau-associated diseases, preferably tauopathies, are described using epothilone D that exhibit good brain penetration, long half-life, and high selective retention in brain, and provides effective therapies in treating tauopathies including Alzheimer's disease.

Description

FIELD OF THE INVENTION[0001]This invention relates generally to the treatment of Tau-associated diseases using epothilone D, and more specifically, to the treatment of Alzheimer's Disease using epothilone D.BACKGROUND OF THE INVENTION[0002]Alzheimer's disease (AD) is the most common form of dementia, affecting an estimated 27 million people worldwide in 2006. Age is the greatest known risk factor for AD with an incidence of 25-50% in people aged 85 years or older. As the average age of the population increases, the number of patients with AD is expected to rise exponentially. AD is the fifth leading cause of death in people aged 65 and older, and most patients eventually need nursing home care. Consequently, AD has an enormous economic impact, e.g., estimated direct and indirect costs for 2005 in the US only were $148 billion. Besides the economic costs, AD has a devastating impact upon patients and their family members, causing severe emotional distress and turmoil.[0003]Patients a...

AI Technical Summary

Benefits of technology

[0021]The present inventors have discovered based on multiple in vivo studies including behavioral and neuropathological studies, that epothilone D achieves a surprisingly advantageous profile in treating Tau-associated diseases, including AD. The inventors have discovered that epothilone D exhibits a remarkable combination of advantageous properties, making the compound particularly well-suited to treat such diseases. These properties include not only a high level of brain penetration across the BBB, but also a surprisingly long half-life in the brain and a surprisingly high selective retention rate in the brain as compared with drug levels found in peripheral tissues, most notably, the liver, over extended periods of time. Additionally, the inventors have further discovered that surprising, therapeutic advantages in treating Tau-associated diseases, particularly, AD, can be achieved with low dosages of epothilone D, e.g., with dosages that are approximately 100-fold less than those administered to achieve chemotherapeutic effects. Consequently, the inventors have discovered methods that allow for therapies in treating Tau-associated diseases with epothilone D, particularly treatment of AD, without causing drug-induced side effects and / or drug-plasma concentration levels that would require use of the epothilone D to be discontinued. Given the low dose as compared with chemotherapeutic treatments, any side effects are greatly reduced as compared with side effects that are induced upon administration of the epothilones and analogs for treatment of cancer.

Problems solved by technology

Besides the economic costs, AD has a devastating impact upon patients and their family members, causing severe emotional distress and turmoil.

Although these two classes of therapeutics show some clinical benefit, many patients do not respond, and these drugs only ameliorate the symptoms of AD (e.g., cognitive function) with little or no modification of disease progression.

Paclitaxel has proven highly effective as a microtubule-stabilizing agent in treating cancer patients; however, it presents brain-penetration and peripheral neuropathy issues when considered for AD (further described below), and has not emerged as a viable therapy to treat AD.

While certain of the epothilone compounds and analogs have been clinically evaluated for treating cancers, it is highly unpredictable whether a cancer drug may be effectively used to treat neurodegenerative diseases including AD.

There are various factors affecting this unpredictability.

One factor is the substantial difficulty of achieving good brain penetration due to the blood-brain barrier (BBB).

For a compound to be useful in treating neurodegenerative brain diseases, it is necessary that the compound cross the BBB; however, since a function of the BBB is to protect the brain from external substances and toxins, discovering a useful drug that has good BBB penetration is challenging.

Additionally, BBB penetration is an undesirable feature for a cancer drug (other than brain cancer drugs).

Thus, for example, while paclitaxel is a highly-successful cancer drug, it has not emerged as a useful therapy to treat brain diseases such as AD, as it has a low rate of brain penetration through the BBB.

Additionally, measuring brain penetration, retention and selective brain accumulation with microtubule-stabilizers is complex because these compounds are typically rapidly cleared from plasma but more slowly cleared from microtubule-containing tissues, making it important to set appropriate time windows for comparisons of plasma and tissue levels.

Yet further challenges involved with looking to cancer drugs for potential application to neurodegenerative diseases involve the mode of administration and the bioavailability and cytotoxicity associated therewith.

However, Andrieux et al. disclaimed and thereby taught against use of these compounds for treating AD, stating that diseases associated with neuronal connectivity defects (i.e., those claimed in that application) “are different from progressive dementing disorders like Alzheimer, which involve neuronal degeneration.

Lichtner et al. are not able to report comparative data against paclitaxel on brain-to-plasma levels because their paclitaxel brain levels were below the level of detection, and they do not report data relating to brain-to-liver ratios, half-life, or brain retention for any of the compounds (e.g., concentration of drug in brain tissue over extended periods of time).

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