Background & Objectives
The apolipoprotein ε4 allele (APOE4) is a major genetic risk factor for Alzheimer’s disease (AD), with APOE4 carriers (homozygotes and heterozygotes) comprising ~65% of AD patients. APOE4 gene dose-dependently increases the burden of beta amyloid (Aβ) soluble oligomers, which are thought to be primary drives of neurotoxicity. APOE4/4 homozygotes have shown high rates of hippocampus atrophy (Abushakra et al. CTAD 2018) and early cognitive decline. Therefore, APOE4/4 homozygotes are an optimal target population for drugs that inhibit Aβ oligomer formation, such as tramiprosate or its prodrug ALZ-801 (Abushakra et al. 2017, Kocis et al. 2017, Hey et al. 2018,Tolar et al. 2019).
Background on ALZ-801
- An oral pro-drug of tramiprosate, with improved oral absorption and gastrointestinal tolerability
- Shows improved brain penetration of tramiprosate, 40% of drug in plasma enters brain (Hey et al. 2018)
- Tramiprosate and its active metabolite, 3-SPA, inhibit formation of Aβ42 oligomers (Kocis et al. 2017))
- Tramiprosate showed significant efficacy in APOE4/4 homozygotes in a Phase 3 study (Abushakra 2016 and 2017)
- Tramiprosate showed favorable safety in ~2000 AD patients, with no organ toxicity or ARIA-E (Abushakra 2016)
- Main adverse events with tramiprosate were mild to moderate nausea and vomiting
- Tramiprosate showed dose dependent protection of hippocampus atrophy in a prior AD study (Gauthier et al. 2009)
- ALZ-801 development program for AD, has received Fast Track Status from the FDA
- We are planning a Phase 3 study of ALZ-801 in APOE4/4 homozygotes with Early AD (MCI due to AD and Mild AD)
- Hippocampus volume on MRI will be designated as main imaging biomarker in the Phase 3 study
Our objectives are to:
- Optimize imaging biomarker selection for the planned ALZ-801 Phase 3 trial in APOE4/4 patients
- Evaluate rates of cortical thickness loss in APOE4/4 and APOE3/3 subjects
- Evaluate correlations of cortical thickness loss to clinical decline in APOE4/4 patients
We analyzed clinical and imaging datasets from ADNI-1, and the subset of a tramiprosate Phase 3 study with serial volumetric MRI. We compared clinical and imaging data from APOE3/3 versus APOE4/4 subjects in late MCI and Mild AD groups of ADNI-1.
- Enrolled 722 subjects: 255 Cognitively Normal (CN), 301 Late Mild Cognitive Impairment (LMCI) and 166 Mild AD.
- LMCI group had 228 APOE3/3 non-carriers and 73 APOE4/4 carriers.
- Mild AD group had 101 APOE3/3 and 65 APOE4/4 subjects. • Clinical scores (MMSE, ADAScog13, CDR-SB) were collected at Baseline and Months (M) 3, 6, 9, 12, 18 and 24.
- Data from MRI subgroup was evaluated at baseline, 12 and 24 months (http://adni.loni.ucla.edu), and included: LMCI (93 APOE3/3, 29 APOE4/4) and AD (29 APOE3/3, 21 APOE4/4).
- 3D T1-weighted MRI collection consisted of MP RAGE (Siemens), 3D TFE (Philips) and 3D Fast SPGR (General Electric) pulse sequences, with 1.25×1.25×1.2 mm3 voxel resolution in sagittal orientation.
- Cortical thickness (Mayo Index) was measured using FreeSurfer, Mayo AD signature ROI (Jack 2017) was calculated at baseline and changes from baseline (CBL) were analyzed by a Jacobian-based method.
- Whole brain volume (WBV) and hippocampus volume (HV=L+R) were derived & CBL assessed using Boundary Shift Integral
- Baseline volumetric measures were adjusted for age, years of education, and head size.
- Clinical score CBL were estimated by fitting a linear model for each subject. Correlations between baseline cortical thickness, clinical decline, and changes in cortical thickness at M24 were analyzed by Pearson’s correlations.
ADNI-1 analysis comparing APOE4/4 to APOE3/3 AD subjects showed the following:
- Baseline cortical thickness was significantly different between APOE4/4 and APOE3/3 subjects in Mild AD, but not MCI
- In contrast, hippocampus volume was significantly smaller in APOE4/4 subjects with MCI and Mild AD
- Rates of cortical thickness loss at 12 and 24 months were significantly higher in APOE4/4 with MCI
- Differences between APOE4/4 and APOE3/3 in cortical thickness loss were larger at MCI than AD stage
- Cortical thickness is strongly correlated with cognitive decline in the MCI, but not Mild AD stage
- Correlations between cortical thickness and cognitive decline are stronger in APOE4/4 MCI subjects
- These analyses highlight cortical thickness as a useful biomarker of neurodegeneration in APOE4/4 population
- Cortical thickness may complement & support use of hippocampus volume as imaging biomarker in Early AD trials
- In the planned Phase 3 trial of ALZ-801 in Early AD, cortical thickness will be a secondary imaging biomarker