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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
Susan R. Abushakra, Aidan Power, David Watson, Anton P. Porsteinsson, Marwan Sabbagh, Emer MacSweeney, Sharon Cohen, Merçé Boada et al.. Drugs, 2025-09-28
Topic: Amyloid, tau and blood-test diagnosis
A total of 325 participants enrolled and received study drug. At 78 weeks, the overall efficacy population did not show significant effects on ADAS-Cog13 or other clinical outcomes compared with placebo (ADAS-Cog13: 11% slowing; p = 0.607, N = 320), but showed significant slowing of hippocampal atrophy (18%, p = 0.017, N = 290). Prespecified analyses by disease severity (stratification variable) showed no significant clinical effects in mild AD (MMSE ≤26, N = 195). The prespecified MCI group (MMSE >26, N = 125) showed nominally significant positive effects on ADAS-Cog13 (52%, nominal p = 0.041) and DAD (96%, nominal p = 0.016), positive trend on CDR-SB (102%, nominal p = 0.053), with significant hippocampal atrophy slowing (26%, p = 0.004), and positive grey/white matter effects on MRI-DTI. In the MCI group, positive ADAS-Cog13 drug effects showed significant subject-level correlations with positive effects on imaging outcomes. The most common adverse events were nausea, vomiting, and decreased appetite (more than double placebo rate), with no increased risk of brain edema or microhemorrhages. The APOE4/4 Early AD population did not show significant clinical efficacy at 78 weeks but showed significant brain atrophy slowing. Prespecified analyses at the MCI stage showed nominally significant slowing of clinical decline with significant hippocampal atrophy slowing. Oral valiltramiprosate may provide a favorable benefit-risk profile and simple treatment paradigm for homozygotes with MCI. These results will inform the design of future MCI trials. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04770220; EudraCT Number: 2020-005755-20.
Key findings
- A total of 325 participants enrolled and received study drug.
- At 78 weeks, the overall efficacy population did not show significant effects on ADAS-Cog13 or other clinical outcomes compared with placebo (ADAS-Cog13: 11% slowing; p = 0.607, N = 320), but showed significant slowing of hippocampal atrophy (18%, p = 0.017, N = 290).
- Prespecified analyses by disease severity (stratification variable) showed no significant clinical effects in mild AD (MMSE ≤26, N = 195).
- The prespecified MCI group (MMSE >26, N = 125) showed nominally significant positive effects on ADAS-Cog13 (52%, nominal p = 0.041) and DAD (96%, nominal p = 0.016), positive trend on CDR-SB (102%, nominal p = 0.053), with significant hippocampal atrophy slowing (26%, p = 0.004), and positive grey/white matter effects on MRI-DTI.
- In the MCI group, positive ADAS-Cog13 drug effects showed significant subject-level correlations with positive effects on imaging outcomes.
Why it matters
In this phase III trial of 325 participants with early Alzheimer's disease who were APOEε4/ε4 homozygotes, the drug did not show significant effects on cognitive outcomes compared with placebo at 78 weeks, but did significantly slow hippocampal atrophy. In a prespecified mild cognitive impairment subgroup, nominally significant positive effects on some clinical measures were seen.
Study details
- Participants320
- Evidence strengthHigh
How this study scored 58/100
Published in a peer-reviewed journal. Scored zero for study design and effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Drugs) |
| Journal's citation record | 3 / 4 | Drugs: journal h-index 260 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 320 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 2 / 2 | Randomised and blinded or placebo-controlled (as stated in the record) |
| Times cited | 3 / 7 | Cited 21 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 7.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 4 / 6 | Cited 11.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 2 / 4 | Cited 21 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Martin Tolar: h-index 20 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Duke University: institution h-index 1,541 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 6 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41015981) |
| Free to read | 2 / 2 | Free to read |
| Total | 58 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Abushakra, S. R., Power, A., Watson, D., Porsteinsson, A. P., Sabbagh, M., MacSweeney, E., et al. (2025). 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. Drugs. https://doi.org/10.1007/s40265-025-02250-5
Vancouver
Abushakra SR, Power A, Watson D, Porsteinsson AP, Sabbagh M, MacSweeney E, et al. 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. Drugs. 2025. doi:10.1007/s40265-025-02250-5. PMID: 41015981.
BibTeX
@article{abushakra2025-41015981,
author = {Abushakra, Susan R. and Power, Aidan and Watson, David and Porsteinsson, Anton P. and Sabbagh, Marwan and MacSweeney, Emer and Cohen, Sharon and Boada, Merçé and others},
title = {{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}},
journal = {Drugs},
year = {2025},
doi = {10.1007/s40265-025-02250-5},
pmid = {41015981},
url = {https://doi.org/10.1007/s40265-025-02250-5}
}
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