Background

Allopregnanolone is a neurosteroid metabolite of progesterone. It is an allosteric modulator of inhibitory γ-aminobutyric acid (GABA-A) receptors on neural stem cells and other cell types in the brain (Luchetti et al., 2011). Allopregnanolone levels have been reported to be reduced in the temporal cortices of people with Alzheimer's disease (Naylor et al., 2010).

In transgenic Alzheimer's mouse models, allopregnanolone has been reported to increase neurogenesis, reduce amyloid deposition, and improve performance on learning and memory tests (e.g., Wang et al., 2010; Chen et al., 2011; Zhang et al., 2015). The drug also has been proposed to promote neuron and oligodendrocyte maturation and improve mitochondrial function in AD mice (Chen et al., 2020; Wang et al., 2020). In mouse models of the lipid storage disease Niemann-Pick Type C, restoring low allopregnanolone levels lengthened survival, a neuroprotective effect thought to be mediated by the pregnane X steroid receptor (Sep 2006 news).

The rationale behind evaluating allopregnanolone in Alzheimer's is that a combined regenerative and neuroprotective effect may counteract ongoing neuronal cell loss in this neurodegenerative disease (Brinton and Wang, 2006; Brinton, 2013; Irwin et al., 2014). However, other studies have reported that allopregnanolone can impair learning function in two different AD mouse strains (e.g., Bengtsson et al., 2013). Newer data indicate that continuous elevation of allopregnanolone in mice worsens amyloid load and learning, while intermittent dosing has opposite, beneficial effects (Bengtsson et al., 2020).

Findings

From August 2014 to February 2018, an NIH-funded Phase 1 study compared 2, 4, and 6 up to 18 mg of allopregnanolone to placebo, all infused once a week for three months. Conducted at the University of Southern California, the study enrolled 24 men and women with a clinical diagnosis of MCI due to AD or mild AD; 18 received allopregnanolone and 6, placebo. Primary outcome measures include various safety parameters including brain MRI; secondary outcomes are pharmacokinetics, cognitive batteries, and structural and functional MRI. Both drug and placebo were being manufactured at the University of California, Davis (see Dec 2014 conference news; Aug 2013 conference news).

According to trial results presented at the 2018 CTAD meeting, the 2, 4, and 6 mg doses produced no adverse events or amyloid-related imaging abnormalities on MRI, and clinical results remained in the normal range. The drug caused sleepiness at 10 mg in women and 6 mg in men. Treatment was associated with less atrophy of the left hippocampus compared to placebo, more so in APOE4 carriers. The 4 and 6 mg doses improved functional connectivity in some brain regions. Exploratory cognitive measures found high variability and no significant differences between drug and placebo groups (Nov 2018 conference news). Results were published (Hernandez et al., 2020). Additional analysis of exploratory imaging data indicated that allo treatment improved white matter integrity and functional connectivity in some brain regions (Raikes et al., 2022). Data presented at the October 2023 CTAD conference showed slowing or reversing of hippocampal atrophy in ApoE4 carriers with amyloid pathology and loss of hippocampal volume at the start of the study.

In October 2019, a Phase 1 dose-finding study at the University of Southern California began testing intramuscular injections of allopregnanolone in lieu of infusions. The trial is enrolling 12 people with MCI due to AD or mild AD to receive 4 to 18 mg of drug weekly for up to four weeks, with pharmacokinetic analysis to determine the equivalent dose to the 4 mg infusion. Participants will continue that dose for a total of 12 weeks. Endpoints are safety, pharmacokinetics, patient satisfaction, and feasibility. Other outcomes include MRI measures of brain volume, standard tests of cognition, daily function, sleep quality, and physical activity. The trial was slated to finish in June 2023.

A 200-participant Phase 2 trial began in August 2023. Participants have probable AD and carry an ApoE4 allele, but the trial requires no biomarker confirmation of Alzheimer's as underlying etiology. Participants will be randomized to 4 mg allopregnanolone or placebo infusion once weekly for 12 months, followed by a six-month, open-label extension. The primary outcome is hippocampal volume. Secondary outcomes include measures of cognition and function, safety, and tolerability. Blood markers, various MRI modalities, as well as clinical measures will serve as exploratory outcomes.

Allopregnanolone is also being evaluated in traumatic brain injury, as well as post-traumatic stress, depression, anxiety disorders, Tourette syndrome, and tinnitus.

For all trials of allopregnanolone, see clinicaltrials.gov.