journal articles
PHASE 3 RANDOMIZED CLINICAL TRIALS OF SIMUFILAM IN MILD-TO-MODERATE ALZHEIMER’S DISEASE
James W. Kupiec, Anton P. Porsteinsson, Raymond S. Turner, Suzanne Hendrix, Craig Mallinckrodt, Arifulla Khan, Ian Cohen, Jonathan Liss, Roger Clarnette, Kee Hyung Park, Antonio M. Hernandez, Lindsay H. Burns
BACKGROUND: Soluble amyloid β1–42 (Aβ42) 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.
CITATION:
James W. Kupiec ; Anton P. Porsteinsson ; Raymond S. Turner ; Suzanne Hendrix ; Craig Mallinckrodt ; Arifulla Khan ; Ian Cohen ; Jonathan Liss ; Roger Clarnette ; Kee Hyung Park ; Antonio M. Hernandez ; Lindsay H. Burns (2025): Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer’s disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2025.100469