New Drug Offers Hope As Alzheimer’s Treatment

Two new studies suggest that memantine, an investigational new drug for the treatment of moderate to severe Alzheimer’s disease, appears to significantly improve cognitive function as well as patients’ ability to perform everyday tasks like dressing themselves, bathing and toileting, and eating.

Memantine, currently under review by the Food and Drug Administration, targets a different chemical pathway than the existing medications approved to treat Alzheimer’s disease. The drug blocks the binding of glutamate—the brain’s primary excitatory neurotransmitter—to N-methyl-D-aspartate (NMDA) receptors.

It is thought that glutamate plays a significant role in the neuronal cell death that is common to all neurodegenerative diseases. As neurons are damaged—in Alzheimer’s, for example, by the deposition of amyloid—that damage leads to an excess release of glutamate, which neuroscientists refer to as “overexcitation.”

High levels of glutamate can drastically alter the cell’s internal levels of calcium, leading to toxicity and cell death. By blocking the action of glutamate at NMDA receptors, the drug directly short-circuits that “over-excitation.”

The two recent studies include data from two separate clinical trials of the drug, presented at the annual meeting of the American Academy of Neurology last month, expanding on a report in the April 3 New England Journal of Medicine (NEJM).

Memantine, studied as a single therapeutic medication in the first trial, slowed both the mental and physical deterioration of patients with moderate to severe Alzheimer’s, according to Barry Reisberg, M.D., a professor of psychiatry at New York University School of Medicine and princpal investigator of the study. Reisberg was the lead author on the NEJM report and updated those data during a presentation at the neurology meeting.

“The patients we studied were all functional stage six in Alzheimer’s,” Reisberg told Psychiatric News. “They are having problems with putting on their clothes, they can no longer handle the mechanics of bathing and toileting, and eventually they deteriorate further, becoming incontinent.”

Patients who were assigned to receive memantine, Reisberg noted, “seem to be declining much less, about half as much as ordinarily expected, over the six months of the study. The drug greatly slowed their decline, which we hope translates into increased functionality and quality of life, and although we didn’t look at it in this specific study, presumably a delay in institutionalization.”

Neil Buckhotlz, Ph.D., chief of the Dementias of Aging Branch at the National Institute on Aging (NIA), noted in a press release regarding the NEJM report, “This study shows that treatment in the very late stages of Alzheimer’s can be beneficial in a number of ways, for both patients and caregivers.”

Reisberg’s team at New York University coordinated the study, which enrolled 252 patients at 32 medical centers nationwide. A total of 181 patients completed the study, which was funded by the German pharmaceutical company Merz (which discovered memantine), as well as a grant from NIA. (Forest Laboratories holds marketing rights for the drug domestically, pending its approval by the FDA.)

The average age of the patients was 76, and 67 percent were women. All of the patients lived in the community, but while they had trouble with dressing, bathing, toileting, and continence, all patients could still communicate to some degree and were able to walk. The average baseline score on the Mini-Mental State Examination (MMSE) was 7.9.

The study was a randomized, placebo-controlled, stage III clinical trial. Over a period of 28 weeks patients received either 10 mg memantine twice a day, or placebo.

The primary outcome measurements were the global score on the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) at 28 weeks, and the change from baseline to week 28 on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory, modified for more severe dementia (ADCS-ADLsev). Assessments were completed at baseline, at week 12, and at completion (week 28) or upon a patient’s early withdrawal from the study.

Secondary measures included the MMSE, the Neuropsychiatric Inventory, and scores on the Severe Impairment Battery (SIB) and the Functional Assessment Staging (FAST) scale.

Improvements for patients who received memantine were statistically significant on the ADCS-ADLsev, the SIB, and the FAST and approached statistical significance on the CIBIC-Plus.

Open-Label Extension

In a separate presentation at the neurology meeting, Frederick Schmitt, Ph.D., a professor of neurology at the University of Kentucky and a co-author of the NEJM report, detailed data from a 24-week, open-label extension of the 28-week randomized clinical trial.

One hundred and seventy-five patients continued into the second phase. Patients who switched to memantine from the placebo group in the first 28 weeks of the study saw statistically significant improvement. In addition, the benefits seen in the initial 28-week trial for those taking memantine were sustained throughout the 52-week study period, using the same assessment scales.

Combination Therapy

Also presented during the neurology meeting were data on the use of memantine as adjunctive therapy to donepezil (Aricept).

In a study of more than 400 patients in a six-month phase III randomized placebo-controlled clinical trial, the combination of memantine and donepezil demonstrated significant improvement in patients’ cognition relative to baseline and as compared with donepezil plus placebo.

Again the patients in this trial had moderate to severe Alzheimer’s and used the same outcome measures: CIBIC-Plus, ADCS-ADLsev, and the SIB. Patients taking the memantine-donepezil combination also showed significantly less decline in activities of daily living.

Notably, in each of the studies fewer patients taking memantine dropped out of the trial for adverse events, compared with placebo. The most frequently cited adverse event for those taking placebo was agitation, which was markedly improved in those receiving memantine.

“The results of this combination-therapy study point the way toward a new standard of care in the treatment of moderate to severe Alzheimer’s,” said Martin Farlow, M.D., lead investigator of the study and a professor of neurology at the Indiana University School of Medicine, during a press conference. “The findings are encouraging since they suggest that memantine’s mechanism of action, which is unique and different from cholinesterase inhibitors [such as donepezil], will really let us attack the disease on another front.”

A spokesperson for Forest Laboratories, which submitted its New Drug Application to the FDA in January, said that the company expects an action letter from the agency by the end of 2003. If approved, the spokesperson indicated, the drug could be available to patients in the United States by the summer of 2004.

“This drug is really a major advance in two ways,” Reisberg concluded. “One, it is the first effective treatment for the severe stages of Alzheimer’s, and two, it represents a whole new way to treat neurodegenerative diseases—it is really a first proof of concept.”

An abstract of “Memantine in Moderate-to-Severe Alzheimer’s Disease” is posted on the Web at http://content.nejm.org/cgi/content/abstract/348/14/1333. ▪

N Engl J Med 2003 348 1333