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Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer's disease
Kupiec JW, Porsteinsson AP, Turner RS, Hendrix S, Mallinckrodt C, Khan A, Cohen I, Liss J et al.. The journal of prevention of Alzheimer's disease, 2026-01-06
Topic: Amyloid, tau and blood-test diagnosis
Background Soluble amyloid β 1-42 (Aβ 42 ) signals via the α7 nicotinic acetylcholine receptor to hyperphosphorylate tau in Alzheimer's disease (AD). Simufilam disrupts this pathogenic signaling by binding filamin A and disrupts its linkages with inflammatory receptors to reduce neuroinflammation. We assessed simufilam in two Phase 3 clinical trials in mild-to-moderate AD. Methods Participants were age 50-87 with Stage 4 or 5 CE, a mini-mental state exam (MMSE) ≥16 and ≤27 and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. The criterion supporting AD pathology was plasma phosphorylated (p)-tau181 or prior amyloid PET. RETHINK randomized participants to simufilam 100 mg or placebo for 52 weeks. REFOCUS evaluated simufilam 50 and 100 mg versus placebo for 76 weeks. Co-primary endpoints were change from baseline on ADAS-Cog12 and ADCS-ADL. Sub-studies assessed exploratory plasma biomarkers and, in REFOCUS only, CSF and imaging biomarkers. Results Both trials failed to meet co-primary, secondary or exploratory biomarker endpoints. REFOCUS was terminated early, with 22% of participants still active in the trial. In the predefined mild subgroup in REFOCUS, simufilam was associated with slower cognitive decline than placebo through Week 64 (p = 0.019). This finding disappeared at Week 76 with 45% missing data and did not replicate in RETHINK. Favorable nominal exploratory post-hoc findings amongst participants with the highest half of screening plasma p-tau181 levels occurred in RETHINK but not REFOCUS. The plasma p-tau181 entry criterion did not reliably exclude amyloid PET negativity in the sub-study. Conclusions Simufilam did not meet co-primary or secondary endpoints in these Phase 3 trials. Simufilam was safe and well tolerated. Trials registered at clinicaltrials.gov: NCT04994483 and NCT05026177.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Kupiec, J. W., Porsteinsson, A. P., Turner, R. S., Hendrix, S., Mallinckrodt, C., Khan, A., et al. (2026). Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer's disease. The journal of prevention of Alzheimer's disease. https://doi.org/10.1016/j.tjpad.2025.100469
Vancouver
Kupiec JW, Porsteinsson AP, Turner RS, Hendrix S, Mallinckrodt C, Khan A, et al. Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer's disease. The journal of prevention of Alzheimer's disease. 2026. doi:10.1016/j.tjpad.2025.100469. PMID: 41500915.
BibTeX
@article{kupiec2026-41500915,
author = {Kupiec, J. W. and Porsteinsson, A. P. and Turner, R. S. and Hendrix, S. and Mallinckrodt, C. and Khan, A. and Cohen, I. and Liss, J. and others},
title = {{Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer's disease}},
journal = {The journal of prevention of Alzheimer's disease},
year = {2026},
doi = {10.1016/j.tjpad.2025.100469},
pmid = {41500915},
url = {https://doi.org/10.1016/j.tjpad.2025.100469}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
Key findings
- REFOCUS evaluated simufilam 50 and 100 mg versus placebo for 76 weeks.
- Results Both trials failed to meet co-primary, secondary or exploratory biomarker endpoints.
- In the predefined mild subgroup in REFOCUS, simufilam was associated with slower cognitive decline than placebo through Week 64 (p = 0.019).
Why it matters
In two Phase 3 trials, RETHINK and REFOCUS, simufilam failed to meet its main or secondary goals for slowing decline in mild-to-moderate Alzheimer's. An early hint of benefit in a mild subgroup disappeared later and did not repeat in the other trial, though the drug was safe and well tolerated. These results do not support simufilam as an Alzheimer's treatment.
Study details
- Study designpost-hoc analysis
- Evidence strengthHigh
How this study scored 58/100
Published in a peer-reviewed journal, and it is a large phase 3 trial. Scored zero for sample size and effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The journal of prevention of Alzheimer's disease) |
| Journal's citation record | 0 / 4 | The Journal of Prevention of Alzheimer s Disease: journal h-index 63 (OpenAlex, 2026-10-29) |
| Study design | 11 / 12 | A large phase 3 trial (from PubMed type “Clinical Trial, Phase III”) |
| 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 | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| 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 (pubmed indexes it as a clinical or observational study) |
| Randomized / blinded | 1 / 2 | Randomized (as stated in the record) |
| Times cited | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 16.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Lindsay H. Burns: h-index 30 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Rochester: institution h-index 1,195 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41500915) |
| 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
- DOI: 10.1016/j.tjpad.2025.100469
- PubMed: 41500915
- Original source →
- Free full text: The Journal of Prevention of Alzheimer s Disease →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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