Xanamem Shows Potential in Slowing Alzheimer Progression in Patients With Elevated Plasma pTau181

Jack Taylor, PhD

(Credit: LinkedIn)

Findings from the phase 2a XanADu biomarker trial presented at the 2025 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), held April 1-5 in Vienna, Austria, suggest that elevated plasma pTau181 levels may help identify patients with Alzheimer disease (AD) who are more likely to experience clinical progression, and that xanamem (Actinogen Medical) may offer potential benefits in slowing disease worsening in these individuals.¹

The double-blind analysis included 72 participants with clinically diagnosed AD who had available plasma samples from the XanADu trial of xanamem versus placebo. Presented by lead author Jack Taylor, PhD, senior clinical scientist at Actinogen Medical, patients were categorized based on plasma pTau181 levels, with those above the median (>6.74 pg/mL) classified as "High (H)" and those below as "Low (L)."

The study assessed cognitive and behavioral outcomes across multiple clinical scales, revealing that placebo-treated participants in the H group experienced significant worsening over 12 weeks. Xanamem, however, appeared to prevent clinical decline, particularly in the H group, showing a notable benefit on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score.

Participants in the H placebo group exhibited clinically significant cognitive decline over 12 weeks, with worsening observed across all assessed scales. Compared with the L group, these patients showed greater declines in CDR-SB (d = 0.63), Alzheimer's Disease Composite Score (d = 0.55), Mini-Mental State Examination (MMSE, d = 0.52), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (d = 0.53), indicating that elevated plasma pTau181 may be associated with a faster rate of disease progression.

Xanamem appeared to prevent clinical deterioration in the H group, particularly showing a clinically significant benefit on the CDR-SB score (d =0 .41) compared with placebo. However, this effect was not observed in the L group, suggesting that patients with higher plasma pTau181 levels may be more responsive to treatment.

Across both H and L groups, xanamem demonstrated improvements in measures of executive function and global cognition. Executive function scores favored xanamem treatment, with effect sizes of d = 0.34 in the H group and d = 0.26 in the L group. Similarly, MMSE scores improved with xanamem in both groups (d = 0.32 and d = 0.16, respectively), further supporting potential cognitive benefits.

These findings suggest that plasma pTau181 could serve as a valuable biomarker for patient enrichment in future AD clinical trials. By identifying individuals more likely to progress, researchers may be able to design more efficient studies that require smaller sample sizes, lower costs, and shorter durations.² Additionally, the potential clinical benefits of xanamem observed in this study warrant further exploration in larger, more robust trials.

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REFERENCES
1. Taylor J, Jaros M, Harrison J, Chen C, Hilt D. Plasma P-tau181 predicts clinical progression in mild Alzheimer's in a randomized controlled trial. Presented at: 2025 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD); April 1-5. Vienna, Austria. Abstract 1588.
2. Taylor J, Jaros M, Chen C, Harrison J, Hilt D. Plasma pTau181 Predicts Clinical Progression in a Phase 2 Randomized Controlled Trial of the 11β-HSD1 Inhibitor Xanamem® for Mild Alzheimer's Disease. J Alzheimers Dis. 2024;100(1):139-150. doi:10.3233/JAD-231456