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Leuprolide Acetate Stabilises Cognitive Decline in Women With Alzheimer's Disease: Presented at AAT

By Chris Berrie

GENEVA, SWITZERLAND -- April 24, 2006 -- Leuprolide acetate, a drug that is commonly used to treat prostate cancer, appears to produce a significant stabilisation of cognitive function in women with mild-to-moderate Alzheimer's disease (AD).

According to a substudy analysis of a placebo-controlled, double-blind, randomised, phase 2 clinical trial, the gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate can significantly stabilise cognitive and global functions in women with mild-to-moderate Alzheimer's disease (AD) who are on concomitant cholinesterase inhibitors (ChEIs).

The findings were presented here on April 22^nd at the 9^th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT).

In presenting this study, Brian Reynolds, PhD, director of medical and scientific information, Voyager Pharmaceuticals, Raleigh, North Carolina, United States, indicated that leuprolide acetate already has more than 20 years of safety history and use, as it is at present indicated for patients with prostate cancer.

"Indeed, the observation that was made that led to these trials came from when a practicing physician was treating a patient with Alzheimer's disease who also showed prostate cancer," he said, "So he started treating him with this prostate cancer medication, and he seemed to see benefits for this patient's Alzheimer's disease."

Pharmacologically, leuprolide acetate is a GnRH agonist, although at doses used in the clinic it functions as a GnRH antagonist, in that it eliminates the GnRH signalling, Dr. Reynolds said. Thus, the agent is believed to act on the hypothalamus-pituitary-gonadal axis, although how this equates to its AD-related effects remains to be properly clarified.

Recent preclinical studies have shown that leuprolide acetate reduces brain levels of beta-amyloid 42 (A-beta₄₂) and beta-amyloid 40 (A-beta₄₀) by about 40% in mice, an effect that correlates with improved cognition in a transgenic mouse model for AD, he said.

However, recent studies using a transgenic mouse model showed that leuprolide acetate also reduces brain beta-amyloid 42 (A-beta₄₂) and beta-amyloid 40 (A-beta₄₀) by about 40%, an effect that correlates with improved cognition.

GnRH antagonism at the level of the pituitary is known to promote increased levels of luteinizing hormone (LH), Dr. Reynolds said. In effect, researchers have seen evidence of a link between LH and AD in transgenic mice that over-expressed LH, which were shown to suffer AD-like cognitive decline but which were shown to improve through knockout of the LH receptor. Similarly, Dr. Reynolds said researchers have shown that treatment of neuronal cell lines with LH results in rapid Tau phosphorylation, which is itself associated with AD.

Dr. Reynolds and colleagues therefore conducted a phase 2 trial in 108 women who were older than 65 years with mild-to-moderate AD, defined as a Mini-Mental State Examination (MMSE) score 12 to 24. These patients were randomised to 3 treatment groups (n = 36 for each), who received placebo or leuprolide acetate 11.25 mg or 22.5 mg, every 12 weeks by microsphere injection. Concomitant ChEI therapy was permitted, and was taken by 72% of patients in the study.

Primary efficacy endpoints were for cognitive and global function, as measured by AD Assessment Scale-cognitive subscale (ADAS-cog), AD Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC), and ADCS - Activities of Daily Living (ADCS-ADL).

Overall, for all of the intention-to-treat (ITT) population, and with a number of the placebo group patients showing unexpectedly high improvements, the researchers observed no significant differences in ADAS-cog scores between placebo and either of the 2 treatment groups.

However, some specific relationships regarding patients using ChEIs became apparent during analysis, so the researchers performed a subgroup analysis on these patients.

The subgroup analysis showed that patients treated with low dose leuprolide acetate plus a ChEI performed similarly to those treated with placebo plus ChEI. Although these analyses were on small patient group sizes, data for high-dose leuprolide acetate + ChEI (n = 24) were compared with those for placebo + ChEI (n = 26).

The ADAS-cog score on the ITT population did indeed show significant (unadjusted P [uP] =.009; adjusted P [aP] =.027) improvement with leuprolide acetate 2 weeks after the 24-week dosing schedule, whereby 2-drug combination clearly promoted maintenance of ADAS-cog scores, Dr. Reynolds said.

A similar situation was seen at week 48 for ADCS-GCIC scores (uP =.031; aP =.093), while significant improvements with leuprolide acetate were more pronounced for ADCS-ADL scores at both week 26 (uP =.016; aP =.048) and week 48 (uP =.014; aP =.044). Again, these latter data showed clear maintenance of ADCS-ADL scores for the full 48-week study period.

Dr. Reynolds and colleagues are hoping that these encouraging results from the women's trial will be reflected in their ongoing trial in men with mild-to-moderate AD, where a higher dose of 33.75 mg leuprolide acetate is being evaluated.

Although AChEIs were allowed but not required in this study, their 2 new phase 3 trials currently underway require at least 120 days of AChEI use as a result of the subgroup analysis in women, he said. These phase 3 trials are using their new implant formulation of leuprolide acetate, which has already been through its own phase 1 trial with success, Dr. Reynolds said.

Voyager Pharmaceutical Corporation provided financial support for this study.


[Study title: Stabilisation of Cognitive Decline in Alzheimer's Disease Following Treatment With Leuprolide Acetate. Abstract 72]

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