Waiting for memantine

The glutamate activity blocker promises relief to AD sufferers. Not yet approved here, the drug's backers are already pushing the envelope

By Owen Dyer

Initial results from an as-yet-unpublished US study, show that the new Alzheimer's drug memantine is safe and effective for the early stages of Alzheimer's disease. Coincidentally, it makes its first appearance in US pharmacies, under the brand name Namenda this month. The FDA approval is only for severe AD.

In Europe, where it goes by the brand names of Axura and Ebixa, memantine was approved nearly two years ago for advanced Alzheimer's. Memantine is not yet approved in Canada, but likely will be in the next six to nine months.

Current treatments for early Alzheimer's disease, such as donepezil (Aricept) or rivastigmine (Exelon), improve the function of the cholinergic system that uses acetylcholine to transmit signals. Memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, works differently. It blocks the activity of glutamate, an essential neurotransmitter in memory and learning. In Alzheimer's, a glutamate imbalance overstimulates neurons in the brain, leading to an influx of toxic calcium, which degrades and eventually kills the neurons. Memantine seems to counteract this imbalance without impairing the signalling efficiency of the glutamate system.

The latest study, conducted by Forest Laboratories, which has the US licence for memantine, appears to suggest that it is effective in mild to moderate Alzheimer's as well. It's still unknown whether the twice-daily pill can actually slow the course of the disease or merely control symptoms.

This US Phase III study was designed to evaluate the safety and efficacy of memantine given as 10mg monotherapy to patients with mild to moderate Alzheimer's disease. It was conducted at 35 US centres and included 403 patients. Results from the study showed that patients receiving memantine performed significantly better than patients receiving placebo on both primary outcome measures: the Alzheimer's Disease Assessment Scale -- cognitive subscale (ADAS-cog) (p=0.003), a measure of cognitive function, and the Clinician's Interview Based Impression of Change --Plus version (CIBIC-plus), a global measure of overall status (p=0.004).

A European Phase III memantine study released its preliminary results simultaneously. This trial, conducted by H Lundbeck, a Danish pharma company, randomized a total of 470 patients with mild to moderate Alzheimer's disease from 65 centres to 20mg memantine daily or placebo for six months. In this prospective study, the memantine treatment group saw statistically significant improvement in ADAS-cog and the CIBIC-plus scores at multiple time points. At week 24, however, although numerical improvement was observed, statistical significance was not reached, a fact the testers attributed to higher than expected response in the placebo group.

While there is still no clinical evidence on memantine's effects after six months, the drug has convinced most researchers that it is a step forward from cholinesterase inhibitors. It need not be an alternative, however, as research published last year in Neurology showed that memantine in combination with donepezil is effective in advanced Alzheimer's. Memantine at 10mg daily costs about the same as donepezil, while at 20mg daily it costs about 80% more.

Intriguingly, memantine has repeatedly shown efficacy in vascular dementia despite the fact that its mechanism of action is squarely aimed at Alzheimer's. In fact, in trials involving patients with both Alzheimer's and vascular dementia, the two groups have benefited equally from treatment. This could imply that the drug has some extra, unsuspected mechanism. Just as likely, however, it shows that the classification of dementia remains a hit-and-miss process.