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

a technology of epothilone d and alzheimer's disease, which is applied in the direction of biocide, drug composition, metabolic disorder, etc., can solve the problems of severe emotional distress and turmoil, many patients do not respond, and the epothilone d has a devastating impact on patients and their family members, and achieves a high level of brain penetration and selective retention. high, the effect of a favorable profil

Inactive Publication Date: 2009-10-29
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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 ...

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...

Method used

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

Examples

Experimental program
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Effect test

example 1

[0172]The design of the Tg4510 experiment with epothilone D (Compound I) as described above is depicted in FIG. 1. In this experiment, mice were tested at 2.5 months in the MWM and assigned to one of three groups (N=12, 13, 16) such that the pre-treatment performance of each group was determined to be similar. Starting at 2.5 months, mice were administered a weekly intraperitoneal (IP) injection of either vehicle alone or vehicle with 1 mpk or 10 mpk of epothilone D (Compound I). At 4.5 months, the mice were again tested in the MWM to determine the effect of treatment on cognitive performance. After 5.5 months, mice were euthanized and brains were collected for subsequent analysis.

[0173]In tumor xenograft experiments, investigators typically administer epothilone D (Compound I) intraperitoneally at 30 mpk every other day for 5 days, yielding a cumulative dose of 150 mpk. (Chou et al., 1998) Hence, treatment with 1 mpk epothilone D (Compound I) for 12 weeks, as described herein, is c...

example 2

[0176]FIG. 4 shows probe data 18 h after 5 days of training in the 4.5 month-old Tg4510 mice dosed for 2 months with epothilone D (Compound I) at 1 mpk, 10 mpk, and with vehicle. In FIG. 4, “TQ” stands for target quadrant, “AR” stands for adjacent right, “AL” stands for adjacent left, and “OP” stands for opposite quadrant. Two measures of performance, namely % pathlength (A) and number of platform crossings (B) in each quadrant, are indicated in FIG. 4. A preference for the target quadrant indicates that the mouse remembered the location where the platform was located during the acquisition phase of the study. As can be seen from the data, the vehicle-treated mice performed at chance with similar results for each of TQ, AR, AL, and OP, for both the pathlength (A) and platform crossing (B) measures, and they did not show a quadrant preference. However, the mice treated with 1 mpk (Compound I) showed statistically significant differences in both measures as compared with the vehicle g...

example 3

[0177]To determine the effect of epothilone D (Compound I) on brain pathology, brain tissue was examined from a subset (N=5) of the Tg4510 mice from the preceding experiment. Previous studies had shown that Tg4510 mice lost about 60% of their neurons in the CA1 region of the hippocampus at 5.5 months (Santacruz et al. 2005). Thus, the present inventors first examined the number of the neurons in the CA1 region of the hippocampus, followed by examination of the CA3 region. FIG. 5 depicts neuronal counts in the CA1 and CA3 regions of hippocampus in the mice at 5.5 months following treatment with vehicle, 1 mpk of epothilone D (Compound I), and 10 mpk of epothilone D (Compound I).

[0178]Surprisingly, as can be seen in FIG. 5, the Tg4510 mice treated with 1 mpk epothilone D (Compound I) had substantially more CA1 neurons than vehicle-treated animals. In fact, the difference between the mice treated with vehicle and the mice treated with 1 mpk of epothilone D (Compound I) shows that the 1...

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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...

Claims

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Application Information

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IPC IPC(8): A61K31/427
CPCA61K31/427A61P21/00A61P25/00A61P25/02A61P25/16A61P25/28A61P27/00A61P27/02A61P27/06A61P31/12A61P43/00A61P9/10A61P3/10
Inventor ALBRIGHT, CHARLES F.BARTEN, DONNA MARIELEE, FRANCIS Y.
Owner BRISTOL MYERS SQUIBB CO
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