New Useful Insights: Analysis of Data From Phase 3 Clinical Trials Evaluating Simufilam for Mild-to-Moderate Alzheimer Disease

Cassava Sciences today announced the publication of a detailed analysis of data from 2 phase 3 randomized clinical trials, RETHINK-ALZ and REFOCUS-ALZ, examining the use of simufilam to treat mild-to-moderate Alzheimer disease. While these 2 studies did not meet their prespecified coprimary, secondary, or exploratory biomarker endpoints, exploratory post-hoc analysis of the studies offers informative insights for future research.¹

Simufilam is a proprietary, investigational, oral small molecule that is believed to modulate activity of the filamin A protein.

The phase 3 RETHINK-ALZ (NCT04994483) and REFOCUS-ALZ (NCT05026177) trials were designed as multi-center, double-blinded, placebo-controlled, randomized parallel group studies to evaluate the safety and efficacy of simufilam compared with placebo across distinct clinical sites in the US, Canada, and Asia. The prespecified coprimary endpoints for the studies included the change in cognition and function from baseline to the end of the double-blind treatment period, as assessed by the ADAS-Cog12 and ADCS-ADL scales, comparing simufilam with placebo. Secondary endpoints included validated measures of neuropsychiatric symptoms and caregiver burden. Safety was evaluated by adverse event monitoring, as well as standard laboratory and ECG assessments. REFOCUS-ALZ also included an evaluation of changes in plasma and cerebrospinal fluid biomarkers as well as an evaluation of MRI and PET scans.

Topline results of RETHINK-ALZ (NCT04994483), which randomly assigned 804 participants with mild to moderate Alzheimer disease, were originally reported in November 2024, and topline results from REFOCUS-ALZ (NCT05026177), which randomly assigned 1125 participants, were reported in March 2025. Based on these results, Cassava has discontinued development of, and plans no further investment in, the Alzheimer disease program.

Again, although the trials failed to meet their coprimary, secondary, and exploratory biomarker endpoints, some prespecified secondary endpoints and post hoc hypothesis-generating analyses showed potential treatment differences between the higher dose of simufilam and placebo in the predefined mild subgroup (mini-mental state exam (MMSE) score 21-27) on the 12-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-Cog12).

“In keeping with our commitment to report the detailed results, we are pleased to make the data from the RETHINK-ALZ and REFOCUS-ALZ studies available to the Alzheimer disease scientific community through publication in the highly respected Journal of Prevention of Alzheimer’s Disease. We hope the paper can serve as a foundation for further research in the field,” said Rick Barry, the president and chief executive officer of Cassava. “The detailed safety observations reported in the article provide heartening encouragement for our ongoing development program in TSC-related epilepsy, as we work to initiate a proof-of-concept study in collaboration with leading investigators.”

Additionally, in the REFOCUS-ALZ trial, simufilam (100 mg) was associated with slower cognitive decline than placebo in the prespecified mild subgroup, with differences at week 4 and weeks 28, 40, 52, and 64 (nominally significant at P = 0.01, 0.01, 0.02, 0.02, and 0.02, respectively). This potential treatment difference was not replicated in RETHINK-ALZ and was no longer evident at week 76 of REFOCUS-ALZ, which had 45% missing data due to early study termination.

A prespecified pooled analysis of mild patients administered simufilam (100 mg) or placebo in both trials through week 52 showed potential treatment group differences at weeks 4 and 28 (nominally significant at P < 0.01). An exploratory post hoc analysis of the pooled mild subgroups using a plasma p-tau181 cutoff of ≥ 67 (the highest half of all patients) showed a difference in the slowing of decline at weeks 4, 28, and 40 (nominally significant at P = 0.03, 0.001, 0.006, respectively), with a trend at week 52 (P = 0.066).

Importantly, these clinical trials were the first phase 3 Alzheimer disease studies to rely primarily on a plasma biomarker (p-tau181) for biological confirmation of disease. The authors of the paper observed that an amyloid PET (positron emission tomography) sub-study in REFOCUS-ALZ showed that 21% of participants (33 of 160) were unexpectedly amyloid negative at baseline, indicating an absence of Alzheimer disease pathology. This suggests that the plasma p-tau181 assay cut-off used as an entry criterion in both trials was insufficient to screen effectively for Alzheimer disease pathology in trial participants.

James Kupiec, MD, the retired chief medical officer of Cassava and primary publication author, commented, “Exploratory and post hoc analyses identified specific subgroups of patients with an observed treatment difference between the higher dose of simufilam and placebo. While Cassava does not intend to conduct further studies in this indication, we believe these observations are informative. We have made our data and analyses accessible through JPAD with the hope that this paper can serve as a valuable resource for the Alzheimer’s community’s mission to improve patient care.”¹

“I am very pleased that the results of the REFOCUS-ALZ and RETHINK-ALZ studies have been meticulously written and peer reviewed. Publication of the results from these large, rigorously designed and conducted phase 3 studies plays an essential role in shaping future studies and ensuring a complete scientific record for the betterment of drug development and public health,” concluded Anton P. Porsteinsson, MD, the director of the University of Rochester’s Alzheimer’s Disease Research, Care and Education Program.¹

These data will be published in an upcoming issue of the Journal of Prevention of Alzheimer’s Disease.²

References

1. Cassava announces publication of peer-reviewed phase 3 results for simufilam in Alzheimer’s disease in the Journal of Prevention of Alzheimer’s Disease. News release. January 13, 2026. Accessed January 13, 2026. https://www.cassavasciences.com/news-releases/news-release-details/cassava-announces-publication-peer-reviewed-phase-3-results

2. Kupiec JW, Porsteinsson AP, Turner RS, et al. Phase 3 randomized clinical trials of simufilam in mild-to-moderate Alzheimer’s disease. J Prev Alzheimers Dis. 2026:100469. Online ahead of print.