Blarcamesine sustains benefits in early Alzheimer’s patients over year
Oral therapy found to slow cognitive, functional decline in Phase 2b/3 trial
Nearly one year of treatment with blarcamesine (Anavex 2-73), a once-daily oral small molecule being developed by Anavex Life Sciences, slowed cognitive and functional decline in people with early Alzheimer’s disease, according to data from a global Phase 2b/3 clinical study.
Researchers also observed that patients on blarcamesine had less atrophy in multiple areas of the brain compared with those on a placebo, and that the therapy led to a reduction of blood markers of neurodegeneration, with mostly mild and transient side effects.
“These data are very exciting, particularly in a study that can demonstrate objective slowing of markers of neurodegeneration,” Marwan Noel Sabbagh, MD, a professor of neurology at Barrow Neurological Institute in Phoenix, said in a press release.
Sabbagh, who chairs the scientific advisory board of Anavex, shared these data in an oral presentation, titled “Blarcamesine in Early Alzheimer’s Disease: Phase IIb/III Randomized Clinical Trial,” at the 2024 Alzheimer’s Association International Conference, held in Philadelphia and online.
In Alzheimer’s, misfolded proteins build up into toxic clumps that disrupt the normal functioning of nerve cells, leading to brain damage. This slowly impairs memory and thinking skills, and eventually the ability to carry out the simplest tasks in daily life.
“People living with early Alzheimer’s disease have the desire to maintain their sense of self for as long as possible,” said Juan Carlos Lopez-Talavera, MD, PhD, head of research and development at Anavex. “The study results provide the potential for people with more time to engage in meaningful activities.”
Blarcamesine designed to activate SIGMAR1 that helps nerve cells stay healthy
Being investigated in the form of an oral capsule, blarcamesine is designed to activate SIGMAR1, a protein that supports the health of nerve cells by helping them cope with stress and by increasing autophagy, which is a clearance mechanism that removes misfolded and clumped proteins, including those that cause Alzheimer’s.
“The advantage of blarcamesine 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 good comparative safety profile,” Sabbagh said.
The Phase 2b/3 study (NCT03790709) included 508 patients, ages 60 to 85, with mild dementia or mild cognitive impairment due to Alzheimer’s. They were randomly assigned to blarcamesine at a dose of 30 or 50 mg, or to a placebo, once daily for 48 weeks, or nearly one year.
The study’s main goals were to evaluate the benefits of blarcamesine on cognition, using the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog13), and its effects on overall function, as assessed with the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL), over 48 weeks.
Researchers found blarcamesine significantly slowed cognitive decline by 34.6% at the 30 mg dose and by 38.5% at the 50 mg dose compared with the placebo. According to the March 2024 FDA Guidance for Early Alzheimer’s Disease, a cognitive test like ADAS-Cog13 can be used as the primary endpoint in early Alzheimer’s studies.
No significant differences in ADCS-ADL scores were observed between the blarcamesine and placebo groups, perhaps because the test is better suited for more advanced Alzheimer’s and may not capture changes in early stages as well, according to the company.
Blarcamesine found to slow cognitive worsening
One of the study’s secondary goals was to watch for changes in the Clinical Dementia Rating Scale Sum of Boxes, which measures the degree of dementia and cognitive impairment. Blarcamesine was found to slow cognitive worsening by 28.6% at the 30 mg dose and by 26.5% at the 50 mg dose.
The blood levels of amyloid-beta 42/40 ratio — a measure that indicates less toxic clumps of the amyloid-beta protein, a hallmark of Alzheimer’s — were significantly reduced upon treatment with blarcamesine, as were those of neurofilament light protein, a marker of nerve cell damage.
Blarcamesine also slowed brain atrophy, which refers to the loss of nerve cells, including in the whole brain by 37.6%, in total gray matter by 63.5%, and in the lateral ventricles by 25.1%. The the lateral ventricles house cerebrospinal fluid, the liquid that flows around the brain and spinal cord.
“We believe the scalable and convenient features of blarcamesine could reduce crucial barriers within the currently complex healthcare ecosystem for Alzheimer’s disease and provide broader access to a diverse population with early Alzheimer’s disease,” Sabbagh said.
Safety data revealed no neurological tissue damage, such as bleeding or amyloid-related imaging abnormalities, a serious complication that has been reported with medications targeting the amyloid-beta protein.
Dizziness was most common side effect reported
Consistent with earlier data, side effects tended to occur within the first 24 weeks, or six months, of treatment, and were mostly mild and transient, lasting for up to 11 days. The most common side effect reported with blarcamesine was dizziness.
“We like to thank all the people involved in the study for their invaluable contributions and we look forward to continuing our journey to address the high unmet need for Alzheimer’s disease patients with a potential new convenient orally available treatment option,” said Christopher Missling, PhD, Anavex’s president and CEO.
In addition to Alzheimer’s, the company is exploring the potential benefits of blarcamesine for other neurological diseases, such as Parkinson’s, Rett syndrome, and fragile X syndrome.
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