Abstracts & Commentary
Synopsis: The hundreds of presentations at this meeting provided encouraging evidence that existing Alzheimer’s therapies may have greater benefits than first realized, and that a new generation of potential disease-modifying therapies for AD may be on the way.
Sources: Petersen R, et al. "Donepezil and Vitamin E as Treatments for Mild Cognitive Impairment" 9th ICADRD Presentation Number: O1-05-05; Pomara N, et al. "Memantine Monotherapy is Effective and Safe for the Treatment of Mild to Moderate Alzheimer’s Disease: A Randomized Controlled Trial, 9th ICADRD, presentation O1-05-04; Aisen PA, et al. Clinical Data On AlzhemedTM After 12 Months Of Treatment In Patients With Mild To Moderate Alzheimer’s Disease. 9th ICADRD Presentation Number: O1-05-06; Gilman S, et al. Neuropsychological, CSF, and Neuropathological Effects of A-Beta Immunotherapy (AN1792) of Alzheimer’s Disease in an Interrupted Trial, 9th ICADRD Presentation O4-05-07; Fox N, et al. Effects of A-Beta Immunotherapy (AN1792) on MRI Measures of Brain, Ventricle and Hippocampal Volumes in Alzheimer’s Disease. 9th ICADRD Presentation O4-05-08.
The 9th International Congress on Alzheimer’s Disease and Associated Disorders (ICADRD), held in Philadelphia during July 2004, was attended by several thousand Alzheimer’s researchers and clinicians from around the world. The hundreds of presentations at this meeting provided encouraging evidence that existing Alzheimer’s therapies may have greater benefits than first realized, and that a new generation of potential disease-modifying therapies for AD may be on the way.
This was the first ICADRD meeting in which the results of MCI prevention trials were available. Dr. Ronald Petersen presented the results of a large-scale AD prevention study that compared the effect of 2000 IU/day of vitamin E, 10 mg/d of donepezil, or placebo on progression from Mild Cognitive Impairment (MCI) to AD. This 3-year trial involved 769 patients with amnestic MCI from 69 centers in the United States and Canada. Petersen and colleagues documented progression from MCI to possible or probable AD in over 200 cases, representing a cumulative conversion rate of 13% per year. No significant differences were observed in rate of development of AD in vitamin E, donepezil, and placebo-treated patients at the 3-year study endpoint. However, donepezil-treated patients showed a significant delay in the progression to AD over the first 18 months of the study, equivalent to approximately 6 months difference relative to placebo. While these findings could be interpreted as evidence of a purely symptomatic effect of donepezil in MCI, it is noteworthy that 4 other agents (vioxx, celebrex, vitamin E, and galanthamine) have been studied in similar large-scale MCI trials. Thus far, only donepezil has been reported to significantly decrease conversions from MCI to AD over an 18-month period.
Memantine, an NMDA-receptor antagonist, is currently approved in the United States for treatment of moderate-to-severe AD, but not for treating mild cases. Dr. Nunzio Pomera presented results of a 24-week, double-blind, placebo-controlled trial testing the safety and efficacy of memantine in mild to moderate AD. A total of 403 patients enrolled, and 82% completed the trial. Patients treated with 10 mg b.i.d. of memantine, declined less over 24 weeks than placebo-treated patients on the ADAS-cog (P = 0.003) and the CIBIC+ (P = 0.004). At this dosage, memantine was found to be safe and well-tolerated. The effect of memenatine monotherapy in mild AD patients was not compared to that of the already-approved cholinesterase inhibitors. However, memantine’s mechanism of action is different from the cholinesterase inhibitors, which could lead to its approval for mild AD, even if it is found not to have equal efficacy.
Several agents that target amyloid production, fibrillogenesis, and clearance were discussed at the ICADRD. Dr. Paul Aisen reported results from a 21-month open-label extension of a double-blind, Phase 2 AD treatment trial of the Alzhemed, a small molecule that is reported to function as an amyloid fibrillogenesis inhibitor. Results from a 3-month double-blind period indicated that the drug was safe and well-tolerated at all doses, with only mild dose-related side effects. Results of tests of cognitive function (MMSE and ADAS-Cog) in the first 3 months were not significantly different in Alzhemed-treated patients than those who received placebo. In 14 patients followed up to 21 months, possible benefits were reported relative to extrapolated controls. Dr. Aisen reported that a large scale, 18-month Phase III trial of Alzhemed is now being initiated.
Among the most interesting series of presentations at the 9th ICADRD, were those in follow-up to the Elan/Wyeth’s Phase IIa AN-1792 immunotherapy trial, which was discontinued in 2002, owing to the development of meningoencephalitis in 18 (6%) of 300 immunized AD patients. Dr. Sid Gilman presented neuropsychological and laboratory test results from this trial. The primary cognitive outcome measures (including the MMSE, ADAS-Cog, and CDR) were not significantly different in immunization responders than placebo-treated patients, although a possible difference in delayed verbal memory was observed favoring responders. Concentrations of tau protein in cerebrospinal fluid were relatively reduced in responders, suggesting possible improvement. However, CSF Ab-42 levels were not significantly different at month 12 between responders and matched placebo treated patients. Dr. James Nicoll presented results from autopsy studies of 4 patients who died several months after receiving their last injection in AN-1792 trials. Substantial reduction in amyloid burden, and evidence of amyloid clearance, was observed in 3 of the 4 autopsies. These neuropathological studies provide some of the strongest evidence, to date, that immunotherapy can reverse amyloid-related pathology in actual patients with AD. Dr. Nick Fox reported on changes in brain volume over the 12 months after immunization, based on quantitative volumetric MRI studies. Much to everyone’s surprise, there was a significantly greater amount of volume reduction observed over 1 year in the whole brain of those who were treated and responded to immunization, compared to those who went untreated. A greater increase in ventricular volume was also observed in successfully immunized patients. Dr. Fox suggested that this increased rate of shrinkage of the brain could be the result of removal of beta-amyloid, which occupies a substantial volume of the brain in AD. An alternative explanation not discussed is that the ventricular volume increased disproportionate to parenchymal shrinkage, as a result of a mild reactive hydrocephalus, which can result from subclinical meningoencephalitic inflammation, brought about by immunization. Further studies of the AN-1792 preparation are not planned, however, Elan has begun a Phase 1 trial of an anti-amyloid monoclonal antibody involving a passive immunization strategy. — Norman Relkin
Dr. Relkin, Associate Professor of Clinical Neurology and Neuroscience, New York Presbyterian Hospital- Cornell Campus, is Assistant Editor of Neurology Alert.