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APOLLOE4

Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer's Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial

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Year of Publication: 2025

Authors: Abushakra S, Power A, Watson D, ..., Tolar M

Journal: Drugs

Citation: Drugs (2025) 85:1455-1472

Link: https://doi.org/10.1007/s40265-025-02250-5

PDF: https://link.springer.com/content/pdf/10...025-02250-5.pdf

Clinical Question

Does oral valiltramiprosate slow clinical decline and brain atrophy in APOE4/4 homozygotes with early Alzheimer's disease without causing ARIA?

Bottom Line

Valiltramiprosate did not meet its primary cognitive endpoint in the overall early AD APOE4/4 population at 78 weeks but showed significant hippocampal atrophy slowing and nominally significant clinical and imaging benefits in the prespecified MCI subgroup with a favorable safety profile and no ARIA risk, supporting future MCI-focused trials.

Major Points

  • Primary endpoint (ADAS-Cog13) not met in the overall early AD population (11% slowing, p=0.607)
  • Significant slowing of hippocampal atrophy by 18% (p=0.017) in overall population
  • Prespecified MCI subgroup (MMSE >26) showed nominally significant ADAS-Cog13 benefit (52% slowing, p=0.041) and DAD benefit (96%, p=0.016)
  • MCI subgroup showed 26% hippocampal atrophy slowing (p=0.004) with positive DTI grey/white matter effects
  • No increased risk of ARIA-E (brain edema) or microhemorrhages compared with placebo
  • Most common adverse events were GI symptoms (nausea, vomiting, decreased appetite) at more than double placebo rate
  • Mild AD subgroup (MMSE ≤26) showed no significant clinical effects
  • Subject-level correlations between clinical and imaging outcomes in MCI subgroup support mechanism of action

Design

Study Type: Phase III randomized, double-blind, placebo-controlled, multi-center trial

Randomization: 1

Blinding: Double-blind (participants, site, CRO, and Sponsor staff blinded; DSMB unblinded for safety reviews)

Allocation: 1:1 randomization via IRT system, block size of 4 per site, stratified by AChEi use, age (50-65 or >65), sex, and disease severity (MMSE ≤26 or >26)

Follow-up Duration: 78 weeks with safety follow-up at week 82

Centers: 0

Countries: United States, Canada, United Kingdom, European Union (6 countries)

Sample Size: 325

Analyzed: 320

Analysis: Full analysis set; prespecified subgroup analyses by disease severity (MCI vs mild AD)

Power Calculation: Sample size of 125 participants per arm provided 80-90% power to detect 2.0-2.5 point ADAS-Cog13 difference at 2-sided α=0.05, assuming SDs of 8.1 and 5.6; ~320 subjects assuming 22% early termination

Registration: NCT04770220; EudraCT 2020-005755-20

Inclusion Criteria

  • Age 50-80 years
  • APOE4/4 genotype
  • Clinical diagnosis of AD at early stage (MCI or mild dementia)
  • MMSE score 22-30
  • CDR-Global Score of 0.5 or 1
  • CDR Memory Box score ≥0.5
  • RBANS delayed memory index ≤85
  • Evidence of progressive memory loss over previous 12 months
  • Brain MRI consistent with MCI or AD
  • Stable medical conditions or good medical health
  • Acceptable hematology/chemistry/coagulation labs
  • Normal TSH and B12 levels
  • GFR ≥40 mL/min
  • Stable AChEi dose for ≥3 months prior to randomization if applicable

Exclusion Criteria

  • Other neurodegenerative or psychiatric disorders
  • Seizures within last 10 years
  • Cerebral infarct or TIA within last year
  • Untreated major depression
  • Inadequately treated or unstable medical conditions
  • Brain MRI showing tumors, vascular malformations, cortical infarcts
  • More than two lacunar infarcts (each >1.5 cm)
  • Confluent white matter disease (Fazekas score >2)
  • ARIA-E on baseline MRI
  • Macrohemorrhage >1 cm
  • More than three superficial siderosis lesions
  • Anti-amyloid antibody use in prior 6 months
  • Lifetime use of any anti-amyloid vaccines
  • Use of memantine, anticoagulants, CNS-penetrant anti-cholinergics, atypical anti-psychotics, or anti-epileptics (except low-dose for sleep)

Baseline Characteristics

CharacteristicValiltramiprosatePlacebo
N163162
Age (years)68.4 ± 6.468.5 ± 5.9
Female (%)5251
White (%)8890
Non-Hispanic/Latino (%)9087
BMI (kg/m²)25.8 ± 4.025.2 ± 4.5
MCI diagnosis (%)4137
AChEi use (%)3338
MMSE screening25.69 ± 2.5525.52 ± 2.39
MMSE randomization25.34 ± 3.1424.73 ± 3.49
ADAS-Cog1323.54 ± 8.3024.31 ± 8.79
CDR-SB3.04 ± 1.532.97 ± 1.45
Bilateral hippocampal volume (mm³)7067.3 ± 1035.16998.1 ± 990.5
Cortical thickness (mm)2.41 ± 0.102.41 ± 0.12
Whole brain volume (mL)1078.4 ± 120.01069.4 ± 107.6
Ventricular volume (mL)40.2 ± 21.542.4 ± 21.9
Plasma Aβ42/400.053 ± 0.010.053 ± 0.01
Plasma p-tau181 (pg/mL)29.9 ± 30.2531.5 ± 18.10

Arms

FieldValiltramiprosateControl
N163162
InterventionOral valiltramiprosate 265 mg twice daily with 2-week titration period from daily to BID dosingMatching placebo tablets twice daily
Duration78 weeks78 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Change from baseline in ADAS-Cog13 (13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale)Primary11% slowing vs placebo in overall population; 52% slowing in MCI subgroup0.607 (overall, N=320); nominal p=0.041 (MCI subgroup, N=125)
CDR-Sum of Boxes (CDR-SB)Secondarynominal p=0.053 (MCI subgroup)
Amsterdam-Instrumental Activities of Daily Living (A-IADLw)SecondaryTime Point: 78 weeks · No significant effect in overall population
Disability Assessment for Dementia (DAD)Secondarynominal p=0.016 (MCI subgroup)
Hippocampal volume (main imaging outcome)Secondary0.017 overall; 0.004 (MCI subgroup)
Cortical thicknessSecondaryTime Point: 78 weeks · Significant slowing of cortical atrophy in MCI subgroup
MRI-DTI (grey/white matter microstructural integrity)SecondaryTime Point: 78 weeks · Positive grey/white matter effects in MCI subgroup
Amyloid-related imaging abnormalities (ARIA-E and ARIA-H)SafetyNo increased risk of brain edema or microhemorrhages vs placebo
Treatment-emergent adverse eventsSafetyMost common were nausea, vomiting, and decreased appetite at more than double placebo rate; overall safety profile favorable with mild/moderate intensity
Most common AEs (>2x placebo)AdverseNausea, vomiting, decreased appetite (mild/moderate)
ARIA-EAdverseNo increased risk vs placebo
MicrohemorrhagesAdverseNo increased risk vs placebo

Subgroup Analysis

Prespecified analyses by disease severity (stratification variable): Mild AD subgroup (MMSE ≤26, N=195) showed no significant clinical effects. MCI subgroup (MMSE >26, N=125) showed nominally significant positive effects on ADAS-Cog13 (52% slowing, p=0.041), DAD (96%, p=0.016), positive trend on CDR-SB (102%, p=0.053), significant hippocampal atrophy slowing (26%, p=0.004), and positive grey/white matter MRI-DTI effects. Subject-level correlations between positive ADAS-Cog13 drug effects and positive imaging outcomes were significant in the MCI group.

Criticisms

  • Primary endpoint not met in overall early AD population
  • Positive findings in MCI subgroup are nominal p-values from prespecified subgroup analyses, not adjusted for multiplicity
  • Statistically significant baseline imbalance in MMSE at randomization (p=0.041) favoring valiltramiprosate arm
  • Amyloid PET or AD fluid biomarkers not required for enrollment (though APOE4/4 symptomatic patients have high amyloid positivity rates)
  • MCI subgroup (N=125) is smaller than originally powered for the primary efficacy population
  • Predominantly White (88-90%) population limits generalizability

Funding

Alzheon (Sponsor designed the trial, provided trial drug, oversaw conduct, and analyzed data)

Based on: APOLLOE4 (Drugs, 2025)

Authors: Abushakra S, Power A, Watson D, ..., Tolar M

Citation: Drugs (2025) 85:1455-1472

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