Allopregnanolone, a first-in-class regenerative therapeutic, has the potential to delay neurodegeneration in early Alzheimer’s disease (AD) by promoting endogenous systems of renewal and repair, early clinical data show.
In a small phase 1b/2a study, the drug was safe and well-tolerated and increases in hippocampal volume and beneficial structural and functional brain changes were noted with once-weekly treatment.
In presenting the findings at the 16th Clinical Trials on Alzheimer’s Disease (CTAD) conference, study investigator Roberta Brinton, PhD, with The Center for Innovation in Brain Science at the University of Arizona in Tucson, gave a “whirlwind tour of decades of research” into allopregnanolone — “from discovery to translation to now in clinical trials.”
She explained that allopregnanolone is a pleiotropic neuro-steroid that promotes neurogenesis, oligogenesis, and synaptogenesis, as well as mitochondrial function and has anti-inflammatory effects. It also promotes cholesterol efflux, which then leads to a reduction in beta-amyloid generation.
“Collectively, these phototropic actions of allopregnanolone promote regenerative and disease modifying outcomes,” said Brinton, founder and president of NeuTherapeutics, LLC, which is developing the drug.
Reduction in Amyloid
In preclinical studies, the drug reduced amyloid burden in the brain. Brinton reported results of a double-blind, randomized, controlled phase 1b/2a multiple ascending-dose trial of allopregnanolone in 12 men and 12 women with early AD (Mini-Mental State Examination score > 20; 62% APOE ε4 carriers).
Intravenous allopregnanolone or placebo were administered once weekly for 12 weeks, with brain MRI conducted before and after 12 weeks of treatment.
Allopregnanolone was safe and well tolerated in all participants. There were no indications of toxicity and no evidence of amyloid-related imaging abnormalities (ARIA), Brinton reported.
Exploratory MRI data revealed that the rate of decline in hippocampal volume was slowed, and in some cases reversed, with allopregnanolone compared with placebo.
Gain of hippocampal volume was evident in APOE ε4 carriers (range: 0.6% to 7.8% increase) and multiple measures of white matter integrity indicated evidence of preserved or improved integrity, Brinton noted.
With allopregnanolone, there was also evidence of significantly increased fractional anisotropy (FA), a measure of the integrity of brain white matter.
Consistent with structural changes, the drug also strengthened local, inter-regional, and network level functional connectivity in AD-vulnerable regions, including in the default mode network and limbic system, the researchers note in their conference abstract.
Based on these data, the National Institute on Aging has funded a phase 2b randomized controlled clinical trial (REGEN-BRAIN), which is set to get underway next month.
“Exciting” Early Data
Commenting on this research for Medscape Medical News, Rebecca Edelmayer, PhD, senior director of scientific engagement for the Alzheimer’s Association, said that allopregnanolone “may potentially have a neuroprotective effect, or even regenerative effect, within the brain.”
“Work in preclinical animal models suggests allopregnanolone may reduce some of the hallmarks of Alzheimer’s disease, like amyloid plaque buildup, and even have an effect on learning and memory,” Edelmayer explained.
The early clinical data reported at CTAD builds off that initial work, “demonstrating that there may be the potential for delaying disease progression and treating Alzheimer’s disease with this type of approach,” she said.
“There is still more work that needs to be done. It’s still very early days still for this medication, but it’s innovative and it’s exciting to see because we also know that combining approaches in the future might be really the most effective way that will treat Alzheimer’s,” Edelmayer told Medscape Medical News.
Support for the trial was provided in part by the National Institute on Aging, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Association, and NeuTherapeutics, LLC. Brinton has a financial relationship with NeuTherapeutics. Edelmayer reports no relevant financial relationships.
16th Clinical Trials on Alzheimer’s Disease (CTAD) conference: Abstract OC10. Presented October 26, 2023.
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