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APOLLOE4

APOLLOE4 Phase 3 Study of Oral ALZ-801/Valiltramiprosate in APOE ε4/ε4 Homozygotes with Early Alzheimer's Disease: Trial Design and Baseline Characteristics

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Year of Publication: 2024

Authors: Susan Abushakra, Anton P. Porsteinsson, Marwan Sabbagh, ..., Martin Tolar

Journal: Alzheimer's & Dementia: Translational Research & Clinical Interventions

Citation: Alzheimer's Dement. 2024;10:e12498

Link: https://doi.org/10.1002/trc2.12498

Clinical Question

Does ALZ-801/valiltramiprosate, an oral amyloid beta oligomer inhibitor, slow cognitive and functional decline in APOE ε4/ε4 homozygotes with early AD (MCI or mild AD) compared to placebo over 78 weeks?

Bottom Line

Design paper with baseline characteristics - results expected 2024. This is the first disease-modification AD trial focused exclusively on APOE ε4/ε4 homozygotes, a population at highest risk for ARIA with approved antibodies. ALZ-801 has shown no ARIA in prior studies and may offer a safer alternative for this high-risk population.

        Major Points
        First Phase 3 trial focused exclusively on APOE ε4/ε4 homozygotes with early AD
325 subjects enrolled (May 2021-December 2022) from ~6500 screened
Mean age 69 years, 51% female, mean MMSE 25.6, 65% MCI, 35% mild AD
High baseline CAA burden: 32% with ≥1 microhemorrhage, 8% with >4 microhemorrhages, 10% with siderosis
CAA lesions more prevalent in males (63% vs 37% for microhemorrhages, 68% vs 32% for siderosis)
Unique study design allows enrollment of subjects with large burden of CAA (unlike antibody trials)
ALZ-801 is a prodrug of tramiprosate; inhibits Aβ oligomer formation via electrostatic interactions
Prior tramiprosate Phase 3 data showed dose-dependent efficacy signals in APOE ε4/ε4 subgroup
Phase 2 ALZ-801 data showed significant reduction in plasma p-tau181 sustained at 2 years
No symptomatic ARIA events reported in blinded safety reviews to date

      

Design

Study Type: Phase 3 randomized controlled trial

Randomization: 1

Blinding: Double-blind; sponsor, investigators, site personnel, subjects all blinded; independent DSMB meets every 6 months to review unblinded safety data; central ratings group (Medavante-ProPhase) reviews ADAS-Cog and CDR tests

Enrollment Period: May 2021 - December 2022

Follow-up Duration: 78 weeks

Centers: 78

Countries: United States, Canada, Czech Republic, France, Germany, Iceland, Netherlands, Spain, United Kingdom

Sample Size: 325

Analysis: Full analysis set (FAS); likelihood-based MMRM on observed cases; model includes treatment, age group, sex, baseline MMSE, use of ChEi, baseline value, visit, treatment-by-visit interaction; graphical testing for Type 1 error control on key secondary outcomes

Inclusion Criteria

APOE ε4/ε4 homozygotes confirmed by genotyping
Age 50-80 years
MCI or mild AD per NIA-AA clinical criteria
MMSE ≥22
CDR-G = 0.5 or 1.0
Stable acetylcholinesterase inhibitors or none

Exclusion Criteria

ARIA-E on screening MRI
Large macrohemorrhage on MRI
Severe white matter disease on MRI
Memantine use
Anticoagulant use

Arms

Field	ALZ-801	Control
Intervention	ALZ-801 (valiltramiprosate) 265 mg oral tablet twice daily	Matching placebo oral tablet twice daily
Duration	78 weeks	78 weeks

Outcomes

Outcome	Type	Control	Intervention
Change from baseline in ADAS-Cog13 at 78 weeks (powered to detect 2.0-2.5 point difference)	Primary	Design paper - results pending	Design paper - results pending
CDR-SB change from baseline at 78 weeks (key secondary)	Secondary	Design paper - results pending	Design paper - results pending
Amsterdam-IADL (A-IADL) change from baseline at 78 weeks (key secondary)	Secondary	Design paper - results pending	Design paper - results pending
Hippocampal volume change (volumetric MRI)	Secondary	Design paper - results pending	Design paper - results pending
Plasma p-tau181	Secondary	Design paper - results pending	Design paper - results pending
Plasma Aβ42 and Aβ40	Secondary	Design paper - results pending	Design paper - results pending
CSF biomarkers (subgroup ~45 subjects)	Secondary	Design paper - results pending	Design paper - results pending
Note	Adverse	Blinded safety reviews to date show no symptomatic ARIA events; overall safety similar to Phase 2 and prior tramiprosate datasets; most common TEAE is mild nausea

Subgroup Analysis

Randomization stratified by sex, age (50-65 or >65 years), disease stage (MMSE ≤26 or >26), and cholinesterase inhibitor use. Correlations of clinical effects to imaging and plasma biomarkers planned.

Criticisms

Design paper with baseline characteristics only - efficacy results not yet available
No amyloid PET confirmation required (relies on APOE ε4/ε4 genotype as surrogate for amyloid positivity)
Only 9% non-White or Hispanic enrolled despite outreach efforts; COVID-19 pandemic impacted diversity enrollment
Relatively small sample size (325) compared to antibody trials
78-week duration may be shorter than optimal for detecting disease modification
CSF biomarker subgroup (~45 subjects) is small

Funding

Alzheon, Inc.; National Institute on Aging (Grant R01-AG065253)

Based on: APOLLOE4 (Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2024)

Authors: Susan Abushakra, Anton P. Porsteinsson, Marwan Sabbagh, ..., Martin Tolar

Citation: Alzheimer's Dement. 2024;10:e12498

Content summarized and formatted by NeuroTrials.ai.

APOLLOE4

(2025)

Objective

Valiltramiprosate – To evaluate the efficacy, safety, and neuroprotective effects of the oral amyloid oligomer inhibitor valiltramiprosate (ALZ-801) in APOE4/4 homozygotes with early Alzheimer's disease.

Study Summary

• Primary cognitive endpoint not met in overall population
• Cognitive and functional benefits observed in prespecified MCI subgroup
• Slowed brain atrophy across multiple regions

Intervention

Randomized, double-blind, placebo-controlled Phase 3 trial. 325 patients with mild cognitive impairment or mild dementia due to Alzheimer’s disease and APOE4/4 genotype received oral valiltramiprosate 265 mg BID or placebo for 78 weeks. Primary endpoint: ADAS-Cog13; secondary endpoints included CDR-SB, A-IADL, DAD, MMSE, and MRI-based hippocampal volume and brain atrophy. Subgroup analyses conducted in prespecified MCI cohort.

Inclusion Criteria

Adults aged 50–80 with early Alzheimer's disease (MCI or mild dementia) and confirmed APOE4/4 genotype. Amyloid positivity confirmed. Exclusion criteria not detailed in the release.

Study Design

Arms: Valiltramiprosate vs. Placebo

Patients per Arm: Valiltramiprosate: 162; Placebo: 158

Outcome

• Primary Endpoint (ADAS-Cog13): Not met in overall population (difference –0.504; p=0.607)
• Prespecified MCI subgroup: ADAS-Cog13 difference –2.144 (p=0.041); CDR-SB –0.646 (p=0.053); DAD +6.093 (p=0.016); all favor valiltramiprosate
• MRI volumetrics: Slower atrophy in hippocampal volume (18% benefit; p=0.0174), cortical thickness (20%; p=0.0020), and whole brain volume (16%; p=0.0400) in full cohort; greater effects in MCI subgroup
• No increased risk of ARIA-E, ARIA-H, or serious adverse events; nausea was most common side effect
• Dropout rate: 19% (active) vs. 9% (placebo)

Bottom Line

Major Points

First Phase 3 trial focused exclusively on APOE ε4/ε4 homozygotes with early AD
325 subjects enrolled (May 2021-December 2022) from ~6500 screened
Mean age 69 years, 51% female, mean MMSE 25.6, 65% MCI, 35% mild AD
High baseline CAA burden: 32% with ≥1 microhemorrhage, 8% with >4 microhemorrhages, 10% with siderosis
CAA lesions more prevalent in males (63% vs 37% for microhemorrhages, 68% vs 32% for siderosis)
Unique study design allows enrollment of subjects with large burden of CAA (unlike antibody trials)
ALZ-801 is a prodrug of tramiprosate; inhibits Aβ oligomer formation via electrostatic interactions
Prior tramiprosate Phase 3 data showed dose-dependent efficacy signals in APOE ε4/ε4 subgroup
Phase 2 ALZ-801 data showed significant reduction in plasma p-tau181 sustained at 2 years
No symptomatic ARIA events reported in blinded safety reviews to date

Study Design

Study Type: Phase 3 randomized controlled trial
Randomization: Yes
Blinding: Double-blind; sponsor, investigators, site personnel, subjects all blinded; independent DSMB meets every 6 months to review unblinded safety data; central ratings group (Medavante-ProPhase) reviews ADAS-Cog and CDR tests
Sample Size: 325
Follow-up: 78 weeks
Centers: 78
Countries: United States, Canada, Czech Republic, France, Germany, Iceland, Netherlands, Spain, United Kingdom

Primary Outcome

Definition: Change from baseline in ADAS-Cog13 at 78 weeks (powered to detect 2.0-2.5 point difference)

Control	Intervention	HR/OR	P-value
Design paper - results pending	Design paper - results pending	-

Limitations & Criticisms

Design paper with baseline characteristics only - efficacy results not yet available
No amyloid PET confirmation required (relies on APOE ε4/ε4 genotype as surrogate for amyloid positivity)
Only 9% non-White or Hispanic enrolled despite outreach efforts; COVID-19 pandemic impacted diversity enrollment
Relatively small sample size (325) compared to antibody trials
78-week duration may be shorter than optimal for detecting disease modification
CSF biomarker subgroup (~45 subjects) is small

Citation

Alzheimer's Dement. 2024;10:e12498

View Original Publication →

APOLLOE4

APOLLOE4 Phase 3 Study of Oral ALZ-801/Valiltramiprosate in APOE ε4/ε4 Homozygotes with Early Alzheimer's Disease: Trial Design and Baseline Characteristics

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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