1. Project profile

2.SIGMAR1 agonists have reached a clinical ceiling in AD

Genotype dependency: only effective in SIGMAR1 wild-type patients (post-hoc analysis);Q2P variant completely unresponsive (up to 40%of AD patients);
CNS tolerability:high rates of dizziness,confusion,dropout.

3.Differentiated mechanism-not another SIGMAR1 agonist, superior to Blarcamesine

Mechanistically, ADdrives APP MAM accumulation through a palmitoylation-dependent mechanism. APP recruits the ERAD machinery (SYVN1), and accelerates SIGMAR1 degradation, which directly inhibits SIGMAR1, disrupting mitochondrial-ER crosstalk and calcium homeostasis, resulting in Aβpathology and AD-related synaptic deficits.
Unlike Blarcamesine, which has limited efficacy in Q2P carriers and causes CNS toxicities including dizziness and confusion, Assetexhibits no such side effects or receptor overactivation. It uniquely blocks the pathological interaction between APP and SIGMAR1, restores normal SIGMAR1 function, and is effective against the Q2P variant while avoiding agonist-related safety risks.
In 5×FAD mice, Assetoutperforms Blarcamesine in memory improvement, synaptic recovery and Aβ reduction.

4. Results and Data

In-vitro studies: Asset(1423)reverses cognitive pathology in patient organoid models including Q2P variants

Head-to-head data in 5×FAD mice show Asset(1423)superior to Blarcamesine across memory, synaptic recovery, and Aβ Asset demonstrates efficacy in the Q2P variant;
Asset(1423)mono/combination with Blarcamesinereduces Aβ deposition and Aβ42 in cortex and hippocampus;