Neurodegeneration and cognitive decline slow with Anavex 2-73

Benefits include slower rate of brain shrinkage, amyloid-beta protein reductions

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Anavex Life Sciences’ investigational oral therapy Anavex 2-73 (blarcamesine) significantly slows cognitive and functional decline in people with early Alzheimer’s disease, according to a new data analysis of a Phase 2b/3 clinical trial.

The cognitive benefits were accompanied by a slower rate of brain shrinkage, a marker of neurodegeneration, and reductions in blood levels of the disease-associated amyloid-beta protein.

“These data are very exciting, particularly in a study that can demonstrate objective slowing of markers of neurodegeneration,” Michael Weiner MD, a professor at the University of California, San Francisco and principal investigator of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), said in an Anavex press release, which notes that Anavex is preparing to meet with regulatory authorities in the U.S., Europe, and Asia-Pacific to discuss approving Anavex 2-73’s for Alzheimer’s.

In Alzheimer’s, the amyloid-beta protein forms toxic clumps that disrupt nerve cell function. A brain affected by Alzheimer’s is also marked by neuroinflammation, energy imbalances, and oxidative stress, a type of cellular damage.

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What is Anavex 2-73 and how does it work?

Anavex 2-73 is an orally available small molecule that activates sigma-1 receptor, a brain protein associated with a range of neuroprotective effects including preventing toxic protein accumulation and reducing neuroinflammation and oxidative stress.

Levels of sigma-1 receptors normally increase with age, but people with Alzheimer’s have lower levels than healthy peers of a similar age.

By increasing the receptors’ activity, Anavex 2-73 may prevent the neurological changes that lead to Alzheimer’s-associated cognitive declines, Anavex believes. The therapy is also being developed for other neurological conditions, including Rett syndrome and Parkinson’s disease.

The global Phase 2b/3 trial, called Anavex 2-73-AD-004 (NCT03790709), enrolled 509 people, ages 60-85, with mild cognitive impairments or mild dementia due to Alzheimer’s. The participants were randomly assigned to receive oral capsules of either one of two doses of Anavex 2-73 (338 patients) or a placebo (170 patients), once daily for 48 weeks, almost a year.

The trial’s main goals were to evaluate the therapy’s effects on cognition — using the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) — and overall function, via the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), after a year.

Top-line trial data, announced in December 2022, indicated both goals were met.

Those treated with Anavex 2-73 were 84% more likely to see a meaningful cognitive improvement — a drop of at least 0.5 points on the ADAS-Cog score — over those on a placebo. The treatment also was associated with a 45% slower cognitive decline relative to a placebo and was 167% more likely to lead to clinically meaningful improvements in overall function — a ADCS-ADL score increase of 3.5 points or more — over a placebo. It was also associated with a 27% slower decline in cognitive function as assessed by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), meeting a key secondary goal.

Further benefits of Anavex 2-73

The new analyses showed patients on Anavex 2-73 saw significantly greater score reductions in the ADAS-Cog (by 1.78 points) and CDR-SB (by 0.46 points) throughout the study than those on a placebo. The findings reflect a slowing of cognitive declines with the therapy.

Also, blood analyses indicated a significantly increased ratio of two forms of amyloid-beta — AB42 and AB40 — with Anavex 2-73. A lower ratio generally reflects a greater toxic amyloid burden and is linked to Alzheimer’s risk.

Moreover, brain MRI imaging showed a significant reduction in brain volume loss with active treatment relative to a placebo.

“There is hope that new therapies for Alzheimer’s that target the disease beyond amyloid … may slow progression … for many people with the earliest forms of the disease,” said Marwan Noel Sabbagh, MD, professor of neurology at the Barrow Neurological Institute in Arizona and chairman of the scientific advisory board at Anavex. “The advantage of … Anavex 2-73 … is that it is a small oral molecule that exerts clinical benefits on cognition and neurodegeneration and could be appealing because of its route of administration and excellent safety profile.”

The treatment was generally safe and well tolerated, with dizziness being the most common side effect, which was usually mild or moderate in severity. It was more common in the Anavex 2-73 group.

Participants who completed the trial were able to enroll in an ongoing open-label extension study, called ATTENTION-AD (NCT04314934), wherein all will receive Anavex 2-73 for about two years. It’s expected to finish next year.

“Alzheimer’s disease is such a devastating disease that affects tens of millions worldwide, and Anavex’s clinical development is a testament to our determination to follow the science,” said Christopher U. Missling, PhD, Anavex’s president and CEO. “We like to thank all the people involved in the study for their invaluable contributions and we look forward to advancing [Anavex 2-73] as a potential new convenient orally available treatment option for Alzheimer’s disease.”