Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease

Abstract

Introduction: ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.

Methods: The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau₁₈₁, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aβ42 and Aβ40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau₁₈₁ at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test.

Results: The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau₁₈₁ reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks.

Conclusions: The effect of ALZ-801 on reducing plasma p-tau₁₈₁ over 2 years demonstrates target engagement and supports its anti-Aβ oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD.

Trial registration: https://clinicaltrials.gov/study/NCT04693520 .

Fig. 1

Phase 2 study design, visit schedule, and outcomes. The study was designed to enroll 80 subjects with early AD with APOE4/4 and APOE3/4 genotypes and positive CSF AD biomarkers (A+/T+). Early AD included subjects with MCI (MMSE > 26) and those with mild AD (MMSE 22-26); 84 subjects were enrolled (31 APOE4/4; 53 APOE3/4), and all received ALZ-801 at 265 mg BID dose for 104 weeks. The schedule of assessments is described in Sect. 2.3. Aβ amyloid beta, AD Alzheimer’s disease, APOE apolipoprotein E, CSF cerebrospinal fluid, DSST digit symbol substitution test, MMSE Mini-Mental State Examination, MRI magnetic resonance imaging, RAVLT Rey Auditory Verbal Learning Test

Fig. 2

Screening, randomization, and follow-up (CONSORT diagram for ALZ-801-201): number of subjects screened, randomized, and those completing 52 and 104 weeks of the study. Medic medications, HT APOE3/4 heterozygotes, HM APOE4/4 homozygotes

Fig. 3

Plasma biomarker changes from baseline over 104 weeks of ALZ-801 treatment. a Plasma p-tau₁₈₁ change from baseline at each study visit (observed case analysis). The p values are for LS mean difference in the change from baseline at each visit with SEM. b Plasma Aβ42 change from baseline at each study visit (observed case analysis). The p-values are for LS mean difference in the change from baseline at each visit with SEM. c Plasma Aβ40 changes from baseline (144.1 pg/ml) at each study visit (observed case analysis). The LS means for changes from baseline were not significant at any visit with SEM. % CBL, Visit_X value − baseline value/baseline value × 100; N number of subjects at each visit, LS mean least squares means, SEM standard error of the mean; * p < 0.05, ** p < 0.01, *** p < 0.001

Fig. 4

Hippocampal volume (HV) change from baseline in ALZ-801-treated group compared with matched ADNI control at 52 and 104 weeks (MMRM analysis). The ALZ-801 arm is for the phase 2 group with valid HV measures. The ADNI arm is for the matched APOE4/4 and APOE3/4 subjects with early AD. The dashed line is for the ADNI arm of APOE4/4 and APOE3/4 subjects with normal cognition (not part of formal MMRM analysis, shown for clinical context). The p values are for the LS mean difference in the % change from baseline. The % reductions in HV atrophy are calculated as: Visit_X value − baseline value/baseline value × 100; N number of subjects with HV measure from each group, AD Alzheimer’s disease, ADNI Alzheimer’s Disease Neuroimaging Initiative, LS mean least squares means, MMRM mixed-effects model for repeated measures. * p < 0.05, ** p < 0.01, *** p < 0.001

Fig. 5

Changes from baseline in RAVLT—total scores in ALZ-801-treated group compared with matched ADNI control at each visit (MMRM analysis). The ALZ-801 arm is the phase 2 group with an RAVLT—total score at any post-baseline visit. The ADNI arm is from the matched APOE4/4 and APOE3/4 subjects with early AD with RAVLT—total score at any post-baseline visit. The p values are for the LS mean difference in the % change from baseline. The % change from baseline for each group is calculated as Visit_X value − baseline value/baseline value × 100; N number of subjects with RAVLT—total score from each group, ADNI Alzheimer’s Disease Neuroimaging Initiative, MMRM mixed-effects model for repeated measures, RAVLT Rey Auditory Verbal Learning Test. * p < 0.05, ** p < 0.01, *** p < 0.001