To assess the potential of XPro1595 treatment in early Alzheimer’s disease, specifically in persons with increased risk of ARIA.

Alzheimer’s disease (AD) pathophysiology involves chronic neuroinflammation driven by tumor necrosis factor (TNF). XPro1595 selectively neutralizes pathological soluble TNF while preserving neuroprotective transmembrane TNF signaling, offering a mechanistically distinct approach from current amyloid-targeting therapies. The approved amyloid-targeting therapies for AD provide an elevated risk of ARIA, particularly in those with APOE e4 homozygosity, on anti-thrombotic treatments, and/or with previous cerebral microbleeds.

MINDFuL (NCT05318976) was a proof-of-concept Phase 2, multicenter, randomized, double-blind, placebo-controlled study conducted across 35 centers in 8 countries. Participants aged 50-85 years with early AD (mild cognitive impairment or mild dementia) and elevated inflammatory biomarkers received weekly subcutaneous injections of XPro1595 (1.0 mg/kg) or placebo for 24 weeks. Endpoints included cognition (EMACC), neuropsychiatric behaviors (NPI), plasma biomarkers (pTau-217 and GFAP), and imaging. The overall analysis from MINDFuL has been presented, however we have not yet shared the results from this important ‘ARIA-at-risk’ AD subpopulation, which were only recently analyzed.

MINDFuL included 140 participants with an elevated risk for ARIA (SAF of n=206), defined as participants with APOE e4 homozygosity (n=26), on anti-thrombotic treatments (n=58), and/or with previous cerebral microbleeds (n=70). Over the 6-month duration of the trial, there were no occurrences of ARIA and the most frequent adverse event were injection site reactions. While acknowledging the smaller sample size of these subpopulations, directional changes favoring XPro1595 treatment were observed across cognitive, neuropsychiatric, and biomarker endpoints. Statistically significant (nominal) beneficial effects were observed on the NPI overall, specifically with APOE e4 homozygotes, and on the subfactor of mood/depression.

With its favorable safety and the consistent directional benefits, we will continue to clinically develop XPro1595 as a treatment for this ARIA-at-risk early Alzheimer’s disease population.