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Updated 29 September 2004
Memantine: Implications for Treating Alzheimer's
Steven T. DeKosky | 
Bengt Winblad | |
Steven T. DeKosky and Bengt Winblad led this live discussion on 10 February 2004, co-organized by the Alzheimer's Association and the Alzheimer Research Forum, on how the addition of memantine to the clinician's toolbox will change the management of Alzheimer's disease. |
 View list of participants and disclosure information.
See Transcript—Posted 2 March 2004
View Q&A—Updated 12 July 2004
View additional references—Posted 29 September 2004
Following its FDA approval last October, memantine is due to arrive in pharmacies this month.
- How should physicians use it?
- For whom should it be prescribed?
- What are good drug combinations?
- What side effects should doctors watch out for?
- Just how much of an improvement does this drug offer?
- Will this drug work for related forms of dementia?
- How long does its effect last?
- What is the best way to titrate the dose?
Bring your questions, concerns, and experience to these two leaders in the field during this live discussion.
We have posted our summary adapted from the briefing document (.pdf) that the drug's U.S. distributor, Forest Laboratories Inc., submitted to the Food and Drug Administration (FDA) last September. Our recent news story reports on the results of a trial of memantine combined with AChE inhibitors. You may also be interested in our previous live discussion on cholinesterase inhibitors.
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Q & A
Adapted from the FDA brief by Forest Laboratories Inc., New York. Download Full Text (.pdf). Please note that this text was originally prepared by the sponsor of the drug.
The Medical Need
Alzheimer's disease is the most common form of dementia in the elderly and is the fourth-leading cause of death for patients aged 65 or older. The prevalence of AD is estimated to be about four million people in the U.S. alone, and approximately one million elderly Americans have severe dementia. Moderate to severe AD represents an identifiable stage of AD and can be reliably diagnosed. A hallmark of the transition to the moderate and severe stages of AD is the progressive loss of the ability to perform activities of daily living.
The current therapeutic options for AD approved by the FDA are the cholinesterase inhibitors (ChEIs), which are indicated for the treatment of mild to moderate AD. However, it is believed that seventy percent of diagnosed dementia patients already have advanced dementia symptoms. The time that the average AD patient spends in the mild stages, where episodic memory loss is the primary clinical finding, is relatively brief. Once the patient reaches the moderate stage, the remaining three to 12 years of life (depending on the age of onset, see related ARF news story) are spent experiencing further deterioration in cognition and activities of daily living (ADLs). There is no approved anti-dementia treatment in the U.S. for patients with advanced AD (MMSE <10).
During the mild-to-moderate stages, cognitive skills show deterioration and this decline leads to impaired ADLs. Instrumental ADLs begin to be affected in the mild-to-moderate stages of AD, followed by pronounced deterioration in physical or self-care functions during the moderate-to-severe stage. The progressive decline in the patient's ADLs ultimately lead to nursing home placement. Decline in ADLs and cognition further burden caregivers. In severe AD, all intellectual functions are severely compromised, and the clinical picture is dominated by the patient's limited function and disruptive behavior. The estimated annual cost of patient care rises from $18,408 in mild to $36,132 in severe stages. Thus, there is a need for therapeutic agents that will slow decline, potentially reduce care costs, and delay institutionalization.
Preclinical and postmortem studies of AD have associated changes in glutamatergic function with memory deficits, a hallmark of AD. Moreover, the excitotoxicity hypothesis holds that chronic glutamatergic overstimulation leads to neurodegeneration.
Thus, the glutamatergic neurotransmitter pathway has been implicated in AD pathology and serves as a target for therapeutic intervention.
About Memantine
Memantine is a novel therapeutic agent that represents a new class of AD treatment options. Memantine has shown efficacy and safety in the symptomatic treatment of patients with moderate-to-severe AD. Memantine has recently been approved for the treatment of moderately severe to severe AD in the European Union and Australia. (Section 2.1 of the full briefing summarizes the history of the clinical development of memantine.)
Memantine has been available in Germany since 1982 (originally approved for the treatment of organic brain syndrome) and is currently available outside the U.S. in 42 countries. As of February 2003, there were over 600,000 patient-years of exposure to memantine.
Memantine is a low-to-moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage dependency and rapid blocking/unblocking kinetics. These pharmacological features appear to allow memantine to block the sustained activation of the receptor by glutamate that may occur under pathological conditions, and to rapidly leave the NMDA receptor channel during normal physiological activation. In humans, memantine is 100 percent bioavailable after an oral dose, undergoes minimal metabolism, and exhibits a terminal elimination half-life of 60 to 80 hours (75 percent or more of the dose is eliminated intact in the urine). It rapidly crosses the blood-brain barrier with a CSF/serum ratio of 0.52. Memantine does not inhibit cytochrome P-450 (CYP 450) isoenzymes in vitro, and its pharmacokinetics are not affected by food, sex, or age.
Efficacy
Memantine demonstrated efficacy in the treatment of moderate-to-severe AD using a dose of up to 20 mg/day in two key double-blind, placebo-controlled trials (Trials 9605 and MD-02) of 6-month duration in patients with probable AD. Also, efficacy of 10 mg/day of memantine was shown in an earlier trial (Trial 9403) of 12-week duration in dementia patients. AD patients were defined as having Hachinski Ischemia Scale [HIS] scores ² 4; (see Panel 1 in briefing pdf). In these studies, memantine was titrated from a starting dose of 5 mg/day (weekly titration by 5 mg/day increments) to a target dose of 20 mg/day administered as 10 mg twice daily in the two six-month trials, and a target dose of 10 mg/day administered once daily in the 12-week trial. Patients were diagnosed with probable AD using National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria in Trials 9605 and MD-02, and with dementia using the Diagnostic and Statistical Manual for Mental Disorders, 3rd revised edition (DSM-III-R) criteria in Trial 9403. AD stages were identified as moderate to severe based on scores on the Mini Mental State Examination (MMSE scores of 3-14 in Trial 9605; 5-15 in Trial MD-02; and <10 in Trial 9403), Global Deterioration Scale (GDS; overall range 5-6 in Trial 9605 and 5-7 in Trial 9403), Functional Assessment Staging (FAST ³ 6a in Trial 9605), and/or Clinical Global Impression of Severity (CGI-S; range 5-7 in Trial 9403).
These three key memantine clinical trials are the first to evaluate the treatment of moderate-to-severe AD. Outcome measures were chosen to reflect the symptomatology of the more severe dementia patient. Specifically, in Trials 9605 and MD-02, the Severe Impairment Battery (SIB) and the 19-item version of the ADCS-Activities of Daily Living Inventory (ADCS-ADL19), which is modified for more advanced AD patients, were used as the indices of cognitive and functional change, respectively, and a global assessment of change was made by the clinician using the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC+).
When Trial 9403, the earliest of the three, was conducted, the ADCS-ADL19 and SIB instruments were not generally available. Trial 9403 used the care dependency subscale of the Behavioral Rating Scale for Geriatric Patients (BGP) as a functional assessment, along with a co-primary measure of global change, the Clinical Global Impression of Change (CGI-C). The BGP-cognitive subscale, which was a subset of items from the BGP-care dependency subscale, was retrospectively defined and analyzed as a cognitive measure. (Panel 1 in briefing .pdf summarizes efficacy of memantine as measured in cognition, function, and global status from these three trials. See simplified Table below, full table in .pdf)
Efficacy Results from 3-Key, Double-Blind, Placebo-Controlled Dementia Studies
| Trial
Randomized
Patients N
|
Treatment
Duration/
Groups/
Dosage
|
Patient
Population/
Diagnostic & Inclusion Criteria
|
Efficacy Outcome Measures (Protocol Defined Primary Endpoints) P-values for 3 Key Domains
|
| Cognition | Function | Global |
|
| 9605 Total
N=252 Memantine
N=126 |
28-week Placebo
Memantine
10mg BID |
Diagnosis: Probable AD
(DSM-IV and NINCDS-ADRDA)
Severity: Moderate to Severe
MMSE 3-14
GDS 5-6
FAST ≥ 6a
HIS ≤ 4
≥ 50 years of age |
| SIB | ADCS-ADL19
(Primary) | CIBIC+
(Primary) |
| <0.001(LOCF) 0.002(OC) | 0.022 (LOCF) 0.003 (OC) | 0.064 (LOCF) 0.025 (OC) |
|
| MD-02 Total
N=404 Memantine
N=203 |
24-week Placebo
Memantine
10mg BID |
Diagnosis: Probable AD
(NINCDS-ADRDA)
Severity: Moderate to SevereMMSE 5-14
≥ 50 years of age
Ongoing donepezil therapy
≥ 6 months at a stable dose (5-10 mg/day) for the past 3 months |
SIB
(Primary) | ADCS-ADL19
(Primary) | CIBIC+ |
| <0.001(LOCF) 0.001(OC) | 0.028 (LOCF) 0.020 (OC) | 0.027 (LOCF) 0.028 (OC) |
|
| 9403 Total
N=166 Memantine
N=82 |
12-week Placebo
Memantine
10 mg QD |
Diagnosis: Dementia
(DSM-111-R)
Severity: SevereMMSE < 10
GDS 5-7
CGI-S 5-7
HIS ≤ 4 (AD patients)
> 60-80 years of age |
| BGP-Cognitive | BGP-Care
Dependency
(Primary) | CGI-C
(Primary) |
| <0.001(LOCF) 0.001(OC) | 0.012 (LOCF) 0.010 (OC) | <0.001 (LOCF) <0.001 (OC) |
|
Safety
Memantine has exhibited an acceptable safety and tolerability profile in 2,297 patients in 27 clinical trials involving a variety of neurodegenerative disorders (e.g., dementia, neuropathic pain, spasticity, and Parkinson's disease). This overall safety database, including studies with limited safety information, European postmarketing clinical practice experience, and other postmarketing drug experience studies, contains no evidence for rare, serious safety findings. A total of 1,748 patients were exposed to memantine in the core dementia and neuropathy safety studies. Adverse events, vital signs, and laboratory tests were systematically evaluated in the core safety trials, and electrocardiograms (ECGs) were assessed in two dementia (Trials MD-02 and 9605) studies and the two neuropathic pain studies.
The core double-blind, placebo-controlled dementia trials (AD or VaD patients) included 922 placebo patients and 940 memantine patients. Approximately 80 percent of patients in both treatment groups completed the studies. Serious adverse events that were reported in more than 1 percent of either treatment group were confusion (memantine 1.6 vs. placebo 0.9 percent), inflicted injury (memantine 1.1 vs. placebo 1.7 percent), cerebrovascular disorder (memantine 1.0 vs. placebo 1.5 percent), fall (memantine 0.6 vs. placebo 1.1 percent), and agitation (memantine 0.5 vs. placebo 1.1 percent). Most of these were considered unrelated or unlikely to be related to the trial drug. The most common reason for discontinuation in both placebo and memantine patients was adverse events (11.5 percent in the placebo group and 10.1 percent in the memantine group). The most frequent adverse events (AEs) leading to discontinuation in this trial group were agitation (memantine 1.2 vs. placebo 2.0 percent), confusion (memantine 1.2 vs. placebo 1.1 percent), and cerebrovascular disorder (memantine 0.7 vs. placebo 1.1 percent).
Treatment-emergent adverse events (TEAE) reported most frequently (>5 percent in incidence) by memantine-treated dementia patients and at an incidence greater than placebo patients were dizziness, confusion, headache, and constipation. None of the TEAEs were reported by >7 percent of memantine-treated patients or at a rate two times higher than in the placebo group (see Table below, or Panel two in .pdf). Most TEAEs were considered mild or moderate in severity and not related to the trial drug in either the placebo- or memantine-treated patients. The percentage of AD patients reporting TEAEs was similar in placebo- and memantine-treated groups. Patients with moderate to severe dementia had an overall TEAE profile similar to that of the entire dementia group. The profile and incidence of TEAEs (as compared to placebo) reported for AD patients receiving memantine as concomitant treatment with donepezil (Trial MD-02) was not different overall from that observed in AD patients receiving memantine alone (Trial 9605).
Analyses of vital sign measurements, clinical laboratory data, and ECG results in the placebo-controlled trials revealed no clinically relevant differences between treatment groups. There was no evidence for any special safety concerns based on the preclinical safety trial results and specific assessments of possible psychotomimetic, neurologic, ophthalmologic, and cardiovascular effects from the clinical trials.
In summary, the sponsor writes, memantine at its recommended dosage of 10 mg BID is well-tolerated with a safety profile similar to that of placebo treatment and is effective in providing clinical benefit for patients with moderate-to-severe AD. —Edited by Gabrielle Strobel.
TEAEs in ≥ 5.0 of Patients in Either Treatment Group—Core Double-Blind, Placebo-Controlled Dementia Trials
| Adverse Events |
Placebo
(N=922)
n (%) |
Memantine
(N=940)
n (%) |
| Dizziness |
49 (5.3) |
64 (6.8) |
| Agitation |
98 (10.6) |
63 (6.7) |
| Confusion |
42 (4.6) |
58 (6.2) |
| Headache |
31 (3.4) |
54 (5.7) |
| Constipation |
28 (3.0) |
50 (5.3) |
| Fall |
50 (5.4) |
48 (5.1) |
| Inflicted Injury |
64 (6.9) |
44 (4.7) |
Additional References—Posted 29 September 2004
Note: Please see original references in Briefing Document Full Text (.pdf)
Periclou AP, Ventura D, Sherman T, Rao N, Abramowitz WT. Lack of Pharmacokinetic or Pharmacodynamic Interaction Between Memantine and Donepezil (September). Ann Pharmacother. 2004 Sep ; 38(9):1389-94. Abstract
Doody, R, Wirth, Y, Schmitt, F, Möbius, HJ. Specific Functional Effects of Memantine Treatment in Patients with Moderate to Severe Alzheimer's Disease. Dement Geriatr Cogn Disord. 2004 ; 18(2):227-32. Abstract
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