Background:

Emestedastat is an oral, selective 11β-HSD1 inhibitor that decreases brain cortisol. Clinical trials of a 10mg daily dose have demonstrated adequate target engagement and/or clinical benefit by PET imaging, antidepressant activity, improvements in cognitive performance in healthy older adults, and attenuation of CDR-SB decline in pTau181-elevated clinically diagnosed Alzheimer’s Disease (AD) patients (Fig. 1).

As shown in Fig. 1, and by other groups ptau181 selects for progressive AD

 

Methods:

placebo-controlled Phase 2B/3 trial in mild to moderate AD.

Inclusion criteria include age ≥ 50, CDR global score 0.5-1.0, MMSE 18-26, and elevated plasma pTau181 (≥ 1.6 pg/ml; LumiPulse). Stable symptomatic AD medications were allowed. Participants were randomised 1:1 to daily emestedastat 10mg or placebo for 36 weeks, with 4 weeks blinded follow up.

The trial used a 2-staged screening process comprising a pre-screening visit followed by a screening visit. The primary purpose of the pre-screening was to exclude participants without elevated pTau181 early to improve efficiency and reduce participant screening burden.

The primary endpoint is change from baseline to Week 36 in CDR-SB. Key secondary endpoints include a digital cognitive test battery (CTB) assessing global cognition and the Amsterdam Instrumental Activities of Daily Living (A-iADL). Emestedastat’s effect on plasma biomarkers of AD (pTau181, pTau217), neurodegeneration (NfL, GFAP), other markers of neuroinflammation will also be evaluated.

 

Reducing cost and patient burden:

The XanaMIA trial’s 2-staged screening approach improved trial efficiency. By excluding participants with low pTau181 at the pre-screening visit, a total of 819 full patient screening visits were saved. This equates to a 42.9% reduction in screening costs compared to a single screening visit approach (Fig. 3).

 

Conclusions:

- 2-staged method improved screening efficiency in this contemporary AD trial

- Plasma pTau181 selects for a progressive AD population ideal for evaluating potential emestedastat benefits over 36-weeks

- The enrolled population is typical for a mild / moderate AD population

- Topline results are expected in November 2026