To evaluate the cognitive effects of oral valiltramiprosate in MCI subjects over 156 weeks.

Valiltramiprosate/ALZ-801, an oral inhibitor of beta-amyloid oligomer formation, is in late-stage development as a disease-modifying Alzheimer’s disease (AD) treatment. Whereas the 78-week Phase 3 trial (NCT04770220) did not meet the primary endpoint in the overall APOE4/4 Early AD population, the prespecified MCI group showed clinically-meaningful, nominally-significant benefits  with significant slowing of hippocampal and brain atrophy. A Phase 2, 104-week study in APOE4 carriers with Early AD (NCT0493520) had a long term extension of 104 weeks.

The Phase 2 trial in Early AD (MMSE 22-30) enrolled 84 APOE4 carriers (31 APOE4/4, 53 APOE3/4) with positive CSF amyloid/p-tau biomarkers who received valiltramiprosate 265mg BID over 208 weeks. Cognitive (RAVLT+DSST summed score) and hippocampal volume (HV) changes at 156 weeks were compared to matched external control from Alzheimer’s Disease Neuroimaging Initiative (ADNI). In the MCI group (N=36), Change from baseline of clinical and HV measures were evaluated at 156 weeks versus 56 matched ADNI-controls, with Pearson correlations of cognitive vs HV drug effects.

In MCI RAVLT+DSST remained above baseline in APOE4 carriers at 2 years with ~5% decline at year 3. Compared to matched-control, there was slowing of cognitive decline over 3 years in APOE4 carriers (78% slowing, delta=20.7, p≤0.001) and homozygotes (84% slowing, delta=21.0, p=0.002). Cognitive benefit correlated significantly with slowing of HV atrophy (r=0.75, p=0.0001). Valiltramiprosate showed no ARIA-E or symptomatic ARIA-H.

Valiltramiprosate effects in MCI APOE4 carriers, including APOE4/4 homozygotes, over 3 years showed similar cognitive benefits to the MCI APOE4/4 group from the Phase 3 study. These clinical benefits are supported by significant correlations to slowing of hippocampal atrophy. These long-term clinical benefits and favorable safety support oral valiltramiprosate as a promising potential treatment for APOE4 carriers with MCI.