#AAN2018: New Data Largely Supports Memantine Combo Easing Alzheimer’s Symptoms

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Namenda combo trials

New data on how Allergan’s Namenda (memantine) — given in combination with cholinesterase inhibitors — works to help ease some symptoms of Alzheimer’s disease will be presented at the American Academy of Neurology annual meeting in Los Angeles, April 21-27.

The data, the results of five studies supported by Allergan, will be presented through scientific posters on April 27 at the conference, which Alzheimer’s News Today is covering remotely.

Namenda works by blocking the action of a natural substance (glutamate) in the brain. Although it does not cure Alzheimer’s disease, it may improve memory, awareness, and the ability to perform daily functions.

Namenda, alone or in combination with a cholinesterase inhibitor (ChEI) — such as Aricept (donepezil) — has been shown to improve global and cognitive functions in Alzheimer’s patients. Increasing evidence supports that Namenda-ChEI combination therapy brings more clinical benefits than monotherapy with either drug or drug class.

The studies being presented involved post-hoc (after-the-fact) analysis on the data of several randomized clinical trials.

Two studies focused on the cognitive function of Alzheimer’s patients — assessed through the Severe Impairment Battery (SIB) test — as seen in the Phase 3 clinical trial MEM-MD-50 (NCT00322153), which evaluated the addition of Namenda to a cholinesterase inhibitor therapy in 676 patients.

Researchers examined SIB score changes in five-points increments that were defined as “improvement/decline” at five-point changes, “notable improvement/decline” at 10-point changes, and “remarkable improvement/decline” at 15-point changes.

In the study “Memantine ER With an AChEI Improves Individual SIB Scores Compared With AChEI Alone: Post Hoc Analyses From a Randomized, Double-blind, Placebo-controlled Study,” about twice as many patients receiving Namenda/ChEI combo therapy had notable and remarkable improvements on the SIB scores, compared to patients on placebo/ChEI. Likewise, fewer patients receiving the combo therapy experienced a decline in cognition compared to those on ChEIs alone.

In the study “Memantine ER and Donepezil Treatment Maintains Cognitive Improvements Versus Donepezil Monotherapy: Post Hoc Analyses From a Placebo-controlled Study in Patients with Moderate-to-Severe Alzheimer’s Disease,”  similar benefits were found for patients given Namenda/Aricept (187 patients) compared to those on placebo/Aricept (183 patients). Also, significantly greater proportions of patients in the Namenda/Aricept group maintained their cognitive improvements (SIB changes), compared to patients in the placebo/Aricept group.

Notably, results showed that the higher the level of cognitive improvement achieved, the better were the chances of maintaining it.

The study “Memantine With Cholinesterase Inhibitors Maintains Improvements of Psychiatric Symptoms vs Cholinesterase Inhibitors Alone: Post Hoc Analyses From 3 Randomized, Double-blind, Placebo-controlled Studies in Patients With Alzheimer’s Disease” evaluated the maintenance of improvements in neuropsychiatric symptoms — behavioral and psychological — between patients given either Namenda/ChEI or placebo/ChEI.

In Alzheimer’s, neuropsychiatric symptoms include apathy, depression, anxiety, delusions and hallucinations, agitation/aggression, irritability/lability, euphoria, disinhibition, sleep disturbance, and eating disorders.

Researchers analyzed the Neuropsychiatric Inventory (NPI) scores  of 1,121 patients with moderate to severe Alzheimer’s disease in three Phase 3 clinical trials (MEM-MD-02, MEM-MD-50, and MEM-MD-12) at weeks 12 and 24. Significantly more patients in the Namenda/ChEI group maintained neuropsychiatric improvements from weeks 12 to 24 than in the placebo/ChEI group.

The study “Memantine Added to Background Cholinesterase-Inhibitors Reduces Agitation in Alzheimer’s Disease” assessed the improvement in Alzheimer’s-associated agitation in 1,140 patients from other three Phase 3 clinical trials at weeks 12 and 24. The trials included people with mild to moderate and moderate to severe Alzheimer’s treated with either Namenda/ChEI (576 patients) or placebo/ChEI (564 patients).

Using the agitation subscale of the NPI, researchers found that combining Namenda with cholinesterase inhibitors significantly reduced agitation severity and emergence, and stabilized agitation symptoms at both 12 and 24 weeks, compared with ChEI alone.

In contrast with these positive data, recent studies evaluating the addition of novel therapies to cholinesterase inhibitors and/or Namenda have failed to see clinical benefits. Researchers believe it is possible that, in some cases, a real effect may be missed due to treatment interaction or confounding by indication – when the clinical indication for selecting a treatment also affects the outcome.

In the final study presented, “Memantine and Cholinesterase Inhibitor Use in Alzheimer Disease Trials: Potential for Confounding by Indication,” researchers investigated whether the use of ChEIs and/or Namenda in trials with Alzheimer’s patients were associated with different rates of cognitive and functional decline.

Data from 1,423 people with mild to moderate Alzheimer’s disease, who participated in five randomized studies of the Alzheimer’s Disease Cooperative Study (ADCS) from 2003 to 2013, were analyzed.

Cognitive function was assessed through the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Mini Mental State Examination (MMSE), and the ability to perform general daily tasks such as eating, dressing, shopping, and household chores were measured using the Alzheimer’s Disease Cooperative Study—Activities of Daily Living Inventory (ADCS-ADL).

All measures were found to decrease more over the course of one year in patients receiving Namenda —  alone or in combination with cholinesterase inhibitors — than in those given neither treatment. This finding might have been unexpected, and the researchers suggested further study.

This type of treatment may be indicated for patients with specific characteristics that are yet to be understood, supporting the need for further research to evaluate whether biological differences could explain what the scientists thought might be “confounding by indication.”