Early Promise Seen From Experimental Alzheimer’s Drug

Researchers are working on a pill that might safely help people with early Alzheimer’s disease improve their thinking and memory skills and possibly even live independently longer.

The new study was only designed to gather data on the experimental drug’s safety, but when 26 patients with mild to moderate Alzheimer’s disease took SAGE-718 daily for two weeks, they showed marked improvements in tests measuring thinking function as quickly as one week. Not only that, these improvements lasted for at least a month.

“We are seeing an improvement in symptoms that will be meaningful to patients, and being able to see improvements so early on is a really exciting thing,” said study author Dr. Aaron Koenig, vice president of early clinical development at Sage Therapeutics in Cambridge, Mass. Sage is the drug’s maker and study sponsor.

SAGE-718 is a positive allosteric modulator of N-methyl-D-aspartate (NMDA) receptors. “Over the course of the disease, there is a deficit in the NMDA receptor, and the new drug helps the receptor function normally,” explained Koenig.

The drug is also in clinical trials for the treatment of thinking impairments due to Parkinson’s disease and Huntington’s disease.

For the study, participants took SAGE-718 daily for two weeks and were followed for another two weeks. When the study began, they had an average score of 20.7 points on a standard cognitive test, which suggests mild cognitive impairment or mild dementia. After one month, scores on the cognitive test had gone up by an average of 2.3 points.

Some people also showed improvement in performing complicated activities such as using a computer, performing household chores, driving, cooking and managing their medications. These gains dovetailed with improvements seen on multiple tests of executive functioning.

“These are meaningful things for patients,” Koenig noted.

The drug is also extremely safe, he said: No patient stopped early due to adverse events, while five people had mild or moderate side effects such as headache or constipation.

The company plans to begin conducting larger randomized, controlled studies to see if these findings hold up.

There are other medications that can help ease some symptoms of Alzheimer’s disease such as memory loss for a limited time, but they are largely approved for later stages of the disease, Koenig said. These drugs include cholinesterase inhibitors that increase levels of acetylcholine, a brain chemical that sends signals from one brain cell to another.

“Available drugs don’t slow the progress or affect higher-order cognitive deficits,” Koenig said. “We know that Alzheimer’s disease is a progressive disease and that there are stages that increase in severity and character, and that treating early in the disease probably has the highest chance of success.”

The study will be presented at the American Academy of Neurology’s annual meeting, held in Seattle April 2-7. Findings presented at medical meetings should be considered preliminary until published in a peer-reviewed journal.

Dr. Howard Fillit is founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation in New York City. “This is a really potentially interesting drug directed toward the NMDA receptor,” he commented.

Another approved Alzheimer’s drug, Namenda (memantine), also targets this receptor, but goes about it differently. “The investigational drug regulates how the receptor works, and this is really a novel mechanism of action, and the efficacy is pretty impressive,” said Fillit, who has no ties to the new research.

The study was small and short in duration, so more research is needed to confirm these findings, but there is reason for optimism, he said.

“The data are provocative and combined with the relative safety profile, this drug will move into a larger trial and may bring a new class of therapies for the treatment of Alzheimer’s disease,” Fillit said.

The bigger picture is that the Alzheimer’s disease treatment pipeline is filling up at long last, he added.

“We are seeing a tremendous number of diverse mechanisms being tested,” Fillit noted. The newest Alzheimer’s drug, aducanumab [Aduhelm], works by removing amyloid plaques from the brain, which may help stave off cognitive decline, and others in this class are also under development, he said. Amyloid plaques are clumps of misfolded proteins in the brain that are hallmarks of Alzheimer’s disease.

“We still need more drugs with different mechanisms of action and combination therapy to ultimately conquer this disease,” Fillit said.

More information

The Alzheimer’s Drug Discovery Foundation has more on Alzheimer’s disease treatments,

SOURCES: Aaron Koenig, MD, vice president, early clinical development, Sage Therapeutics, Cambridge, Mass; Howard Fillit, MD, founding executive director and chief science officer, Alzheimer’s Drug Discovery Foundation, New York City; presentation, American Academy of Neurology annual meeting, Seattle, April 2-7, 2022

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