Oral AMX0035 found to improve core Alzheimer’s-related biomarkers
Analysis of PEGASUS data suggests therapy 'engages important pathways'
Amylyx Pharmaceuticals‘ investigational oral therapy AMX0035 reduces the levels of several biomarkers associated with Alzheimer’s disease, according to an analysis of data from the PEGASUS trial.
“The results from this exploratory analysis suggest that AMX0035 engages important pathways implicated in the [development] of Alzheimer’s disease and other neurodegenerative diseases,” Steven E. Arnold, MD, professor of neurology at Harvard Medical School, in Massachusetts, said in a company press release.
Despite these results, data from the Phase 2 clinical (NCT03533257) study, which enrolled 95 adults with mild cognitive impairment or early dementia due to Alzheimer’s, showed that six months of oral treatment failed to slow cognitive decline compared with a placebo.
According to the authors of the study, titled “Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer’s disease,” the lack of efficacy was “most likely due to the small sample size and relatively short treatment duration.” The study was published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions.
AMX0035 tested for Alzheimer’s in PEGASUS trial
Alzheimer’s is a disease caused by the loss of brain cells due to the toxic buildup of misfolded protein clumps called amyloid plaques and tau tangles.
Emerging evidence suggests that nerve cell death in Alzheimer’s is also linked to other factors, including inflammation, altered metabolism, the dysfunction of energy-producing mitochondria, and oxidative stress, a type of cellular damage.
“Alzheimer’s disease is defined by amyloid plaques and tau tangles, but it’s now understood that these [features] are accompanied by alterations in multiple cell and molecular pathways, including neuronal dysfunction, neurodegeneration, and oxidative stress, driving the progression of this relentless disease,” said Arnold, who is also the translational neurology head and managing director of the Interdisciplinary Brain Center and the E. Gerald Corrigan, PhD endowed chair at Massachusetts General Hospital.
AMX0035 is an oral combination of two small molecules: sodium phenylbutyrate, called PB, and taurursodiol, known as TURSO. PB is thought to help prevent proteins from unfolding, while TURSO helps limit cellular energy loss by boosting the function of mitochondria, which serve as the powerhouses of cells.
The therapy had previously been approved for the neurodegenerative condition amyotrophic lateral sclerosis (ALS), sold under the brand name Relyvrio in the U.S., and as Albrioza in Canada. However, Amylyx voluntarily discontinued the medicine in April of this year after it failed to demonstrate benefits in a confirmatory Phase 3 trial.
PEGASUS tested AMX0035’s safety, tolerability, and preliminary efficacy against a placebo over 24 weeks, or about six months, in Alzheimer’s. The trial’s main goal was a combined change in three outcome measures of cognition, function, and the volume of the hippocampus, a region of the brain where nerve cell death begins in early Alzheimer’s, as assessed by MRI.
Cerebrospinal fluid (CSF), which surrounds the brain and spinal cord, also was collected before and after 24 weeks of treatment to measure various biomarkers associated with the disease.
Key biomarkers linked to Alzheimer’s reduced with treatment
Before treatment, the level of cognitive impairment was significantly greater among patients randomly assigned to AMX0035 than to the placebo.
After six months of treatment, the combined outcome measure failed to demonstrate a significant difference between the treatment and placebo groups.
Despite these findings, AMX0035 significantly reduced the levels of core Alzheimer’s CSF biomarkers — such as total tau protein and p-tau 181, a key biomarker associated with tau tangles — compared with the placebo.
These results suggested that “AMX0035 has the potential to treat neurodegenerative diseases associated with tau dysfunction and tau aggregation,” said Camille L. Bedrosian, MD, Amylyx’s chief medical officer.
Treatment also reduced levels of neurodegeneration biomarkers, specifically neurogranin and FABP3, and YKL-40, a biomarker linked to the rate of cognitive decline and brain volume loss.
[These results suggest that] AMX0035 has the potential to treat neurodegenerative diseases associated with tau dysfunction and tau aggregation.
However, the oxidative stress marker 8-OHdG increased in the AMX0035 group compared with the placebo. The amyloid-beta 42/40 ratio, which indicates toxic clumps of the amyloid-beta protein, trended upward, and there was an increase in interleukin-15, a signaling protein associated with inflammation.
Statistical analysis confirmed significant differences in biomarker levels between the AMX0035 and placebo groups for total tau, p-tau181, neurogranin, FABP3, YKL-40, amyloid-beta 42/40 ratio, interleukin-15, and 8-OHdG.
A final sensitivity analysis showed that the effects of treatment on these biomarkers were not influenced by age, sex, scores on the Montreal Cognitive Assessment, or the Alzheimer’s genetic risk variant called APOEe4.
“The findings of our analysis provide support for further clinical development of PB and TURSO for [Alzheimer’s] and may be used to inform the design of subsequent trials,” the authors wrote.
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