Memory Enhancer Succeeds in Phase II Alzheimer’s Trial

SEATTLE — A first-in-class oral compound targeting N-methyl-D-aspartate (NMDA) receptors proved beneficial in a mid-stage clinical trial in Alzheimer’s disease, setting the groundwork for a full safety and efficacy study, a researcher said here.

SAGE-718, a positive allosteric modulator (PAM) of NMDA receptor activity, improved mean scores on five standard memory tests in 26 Alzheimer’s patients with mild cognitive deficits, reported Aaron Koenig, MD, of drugmaker Sage Therapeutics in Cambridge, Massachusetts.

These included a 2.3-point gain in Montreal Cognitive Assessment (MoCA) score over the 28-day study, a 50% improvement in digit symbol substitution, an average 6.9 fewer errors relative to baseline performance on a multitasking test, and a 1.1-point increase on a 5-point verbal recognition test scale, Koenig told attendees at a late-breaking abstract session during the American Academy of Neurology annual meeting.

Moreover, these improvements came without a change in psychomotor performance, meaning that participants were not simply hitting buttons faster during the cognitive tests, he noted.

Sage is developing the agent for several types of cognitive deficits, including those related to Huntington’s and Parkinson’s diseases, as well as Alzheimer’s. A placebo-controlled phase II study is now underway in patients with Huntington’s disease, and Sage said it plans to open similar trials for other indications this year.

For the current open-label study, Koenig and colleagues enrolled patients with mild cognitive impairment or mild dementia (Clinical Dementia Rating [CDR] of 0.5-1.0) believed to stem from Alzheimer’s disease, and MoCA scores of 15 to 24 at baseline. Patients initially completed the battery of five cognitive tests and the psychomotor evaluation, then received SAGE-718 (no generic name has been officially assigned yet) at 3 mg each morning for 2 weeks. The drug was stopped for 2 weeks, and patients repeated the test suite on day 28.

Mean patient age was 67. About 70% were women, and 80% were white. MoCA scores at baseline averaged 20.7, and about 90% of the group had a CDR score of 0.5.

Seven of the 26 participants had adverse events during the study, with six of the events considered drug-related. Koenig did not give specifics, but he noted that none were considered serious and no one discontinued the treatment because of them. Lab values were all normal, and there were no signs of suicidal ideation or behavioral changes.

“These results support further clinical evaluation of SAGE-718” for memory deficits related to neurodegenerative diseases, Koenig said.

It’s certainly a fertile territory for drug development. Attention and research money in recent years has been heavily weighted toward disease-modifying therapies, such as those targeting beta-amyloid for Alzheimer’s disease. Payoffs have been slow in coming, however. Meanwhile, currently available drugs that aim to boost memory are only moderately effective and not for very long.

Among the latter is memantine (Namenda), which is a broad NMDA receptor antagonist. Because it is not highly effective, memantine is usually paired with an acetylcholinesterase inhibitor, bringing the risks that come with polypharmacy. Researchers have more recently come to believe that PAMs are a better way to modify receptor activity and may prove more effective. That, however, will only be known when randomized placebo-controlled studies are completed.