Background

AGB101 is a proprietary, once-daily, extended-release, low-dose formulation of the FDA-approved atypical anti-convulsant medication levetiracetam. According to AgeneBio, AGB101 corresponds to roughly 1/12 of the dose typically prescribed for epilepsy, and the drug's mechanism of action is inhibition of the synaptic protein SV2A. The rationale for AGB101’s use in MCI stems from suggestions that tamping down hippocampal neuron hyperactivity in people in the early stages of AD dementia may prevent the spread of tau pathology and disease progression.

Findings

In September 2015, AgeneBio received a $7.5 million grant from the National Institutes on Aging toward evaluating AGB101, and announced that it intended to begin a Phase 3 trial of this formulation in 2016 (company press release; Nov 2015 conference news). Further NIA funds were received in September 2017, a trial start announced for 2018 (press release), and the first patient enrolled in January 2019 (press release).

Conducted at 23 sites in the U.S. and Canada, the HOPE4MCI trial was intended to evaluate AGB101 safety, and its efficacy at slowing cognitive and functional impairment, in 830 people who fulfill criteria for MCI and had a positive PET scan for brain amyloid. Participants receive 220 mg AGB101 or placebo once daily for 18 months. The primary outcome is change in CDR-SB score at 18 months; secondary measures include change on the MMSE and Functional Activities Questionnaire. An imaging substudy includes structural MRI and tau PET imaging with MK-6240 in 160 participants at baseline and after treatment; plasma p-217 will be measured at 78 weeks (Rosenzweig-Lipson et al., 2020). In August 2020, the trial registration was changed from Phase 3 to Phase 2/3. In April 2021, AgeneBio announced completion of enrollment in HOPE4MCI, with only 164 participants and 609 screen failures (press release; AAIC presentation). The company now refers to the trial as a Phase 2b, rather than Phase 3, study. It finished in November 2022, and results are published (Mohs et al., 2024). There was no difference between AGB101 and placebo on the primary outcome or any secondary clinical outcomes. In a prespecified analysis based on ApoE4 status, noncarriers showed 40 percent slower decline on the CDR-SB on AGB101 compared to placebo; this slowing was not seen in carriers. A subsequent analysis of imaging and biomarkers in only the 44 noncarriers found a significant reduction in atrophy of the left entorhinal cortex in AGB101 treated participants compared to placebo. The effect correlated with slower decline on the CDR-SB and lower neurofilament light chain, although neither of those measures differed significantly between treated or placebo groups (Bakker et al., 2024).

In April 2019, a Phase 2 research study on AGB101 began at Medical College of Wisconsin. This crossover trial compares the effects of two weeks of 220 mg/day AGB101 or placebo on functional brain networks. It will enroll 50 healthy older people, half ApoE4 carriers and half noncarriers. The primary endpoint will be change in functional connectivity in the hippocampus and default mode networks, assessed by functional MRI; secondary measures include tests of episodic memory. The study was completed in March 2021. The CTAD 2022 program listed an abstract but the poster was not shown.

In August 2023, AgeneBio registered a Phase 2 trial for people with mild cognitive impairment due to Alzheimer’s disease. The trial plans to enroll 60 patients for an 18-month course of 220 mg AGB101 or placebo, against a primary endpoint of change in entorhinal cortex volume from baseline. Secondaries are change in CDR-Sum of Boxes and CDR-Memory Box score from baseline. ApoE4 carriers are excluded from this trial. The study is planned to run from December 2024 to December 2028.

In September 2023, a trial began at Johns Hopkins University to assess AGB101 in people with Parkinson’s disease and psychosis. Thirty patients will be treated with 220 mg daily or placebo for six weeks, in a crossover trial design, with a primary endpoint of change in hallucinations or delusions. Change in hippocampal overactivity on fMRI will serve as the secondary endpoint. The trial will run until September 2026.

For details on AGB101 trials, see clinicaltrials.gov.