AAN 2023: Memantine fails to slow disease progression in Phase 2b trial

The approved Alzheimer's drug also did not reduce biomarkers in ALS patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Daily oral treatment with memantine did not slow disease progression nor did it reduce biomarker changes among people with amyotrophic lateral sclerosis (ALS) enrolled in a Phase 2b trial.

Approved under the brand name Namenda to treat cognitive problems in people with Alzheimer’s disease, memantine has also been shown to help people with Parkinson’s disease, but evidence for the therapy’s benefits in ALS has been conflicting.

Researchers discussed the data in a poster presentation at the American Academy of Neurology (AAN) 2023 Annual Meeting, held April 22-27 in Boston and virtually.

The poster was titled “A 40-week Phase 2B Randomized, Multicenter, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Memantine in Amyotrophic Lateral Sclerosis.”

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Memantine designed to prevent toxic effects of excitotoxicity

Excitotoxicity, a type of cell death driven by the excessive activity of glutamate — a chemical signaling molecule — in the brain has been implicated in ALS and other neurodegenerative diseases. Glutamate exerts its effects in several ways, one of which involves binding to N-methyl-D-aspartate (NMDA) receptors.

Memantine is a small molecule that blocks NMDA receptors, thereby working to prevent the toxic effects of excessive glutamate signaling.

Consequently, the drug has been associated with reductions in inflammation, prevention of protein misfolding, and reduced production of toxic oxidative molecules, all of which are implicated in ALS.

Preclinical studies have indicated that memantine may prolong survival in a mouse model of ALS. A few small clinical studies testing memantine in ALS patients have been conducted, but yielded conflicting results, according to the scientists.

For example, a pilot open-label study (NCT01020331) involving 19 ALS patients found the treatment reduced the rate of clinical decline by 38% compared with a historical untreated control group. However, another placebo-controlled study (NCT00353665) involving 60 patients did not see any slowing of disease progression.

Memantine did not slow the progression of ALS nor did it ameliorate the neurocognitive or behavioral effects of ALS.

Phase 2b trial tested memantine’s safety and efficacy in 89 adults with ALS

To learn more, the researchers conducted a larger Phase 2b trial (NCT02118727), called TAME, evaluating memantine’s safety and efficacy among 89 adults with ALS, ages 18-85, who had started experiencing symptoms of the neurodegenerative disease in the last three years.

In the trial, which took place from December 2018 to September 2020, participants were randomly assigned to receive oral memantine (58 people) or a placebo (31 people) for 40 weeks, or about nine months. The dose of memantine was increased to a maximum of 20 mg twice daily (40 mg total) or to the highest dose tolerated by each patient.

Patients were allowed to continue treatment with approved ALS therapies Radicava (edaravone) and riluzole (sold as Rilutek among others) if they had been stable on treatment for more than a month.

The trial’s main goal was to assess changes in disease progression, as assessed by the Revised ALS Functional Rating Scale (ALSFRS-R), over 36 weeks. Secondary outcomes included changes in disease biomarkers and behavioral measures.

Results showed that monthly rates of functional decline were similar in the two groups, with those given memantine seeing a 1.26-point monthly drop in ALSFRS-R scores, compared with a 1.23-point monthly decline among those in the placebo group.

Likewise, scores on the ALS Cognitive Behavioral Screen and the Neuropsychiatric Inventory Questionnaire, two measures of cognitive and neuropsychiatric function, did not differ between the two groups.

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No differences found in blood levels of ALS-associated biomarkers

There also were no differences in blood levels of neurofilament light chain, a biomarker of nerve damage, or other disease-associated biomarkers.

“Memantine did not slow the progression of ALS nor did it ameliorate the neurocognitive or behavioral effects of ALS,” the researchers wrote.

The most frequently reported side effects among those treated with memantine included falls (26%), dizziness (26%), confusion (17%), and constipation (14%). Three deaths occurred in each group and were attributed to disease progression.

While the findings overall do not support the use of memantine in ALS, the researchers noted that the study, which allowed remote enrollment because of the COVID-19 pandemic, “demonstrated the feasibility of an almost entirely remote clinical trial that can be used for future trials.”

Memantine, taken as an oral solution, is also being examined in the ongoing multi-arm Phase 2/3 MND-SMART clinical trial (NCT04302870), which is recruiting adults with ALS at sites in the U.K. Its main goals are to assess changes in ALSFRS-R scores and survival with daily memantine compared with a placebo over 18 months, or about 1.5 years.