Simufilam Fails to Meet Key End Points in Phase 3 Alzheimer Disease Trial

Rick Barry

In a new company update, Cassava Sciences has announced that its phase 3 REFOCUS-ALZ trial (NCT05026177) testing simufilam, a proprietary, investigational oral small molecule that targets the filamin A protein, in mild-to-moderate Alzheimer disease (AD) failed to meet its co-primary, secondary, and exploratory biomarker end points. The trial enrolled 1125 patients and was thus officially discontinued on November 25, 2024.¹

The co-primary end points evaluated cognitive and functional changes from baseline to week 76, using the Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-COG12) and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale. Overall, results indicated no statistically significant improvement in simufilam-treated patients compared with those on placebo. Despite maintaining a favorable safety profile, the negative outcomes prompted Cassava to terminate the program by the end of the second quarter in 2025.

For cognitive function measured by ADAS-COG12, the least squares (LS) mean change from baseline was 4.97 (±0.46) in the 100 mg group and 5.26 (±0.46) in the 50 mg group, compared with 4.70 (±0.46) in the placebo group. The differences, indicated by deltas of 0.27 (P = 0.67) and 0.56 (P = 0.37) for the 100 mg and 50 mg groups, respectively, were not statistically significant.

Functional outcomes assessed by ADCS-ADL also showed no meaningful improvement, with LS mean changes of -6.27 (±0.57) and -6.43 (±0.57) in the 100 mg and 50 mg groups, respectively, compared with -5.32 (±0.57) in the placebo group. Delta values of -0.95 (P = 0.23) and -1.10 (P = 0.16) further highlighted the lack of significant functional benefits.

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“We are disappointed that the results of REFOCUS-ALZ and RETHINK-ALZ showed no treatment benefit for patients with mild-to-moderate Alzheimer’s disease. These results were unambiguous. Working with patients, their families and their caregivers has brought a special dignity to our Phase 3 Alzheimer’s disease clinical trial program and to each of us at Cassava. We are deeply grateful for the dedication and committed efforts of study investigators and site teams, who enabled us to conduct these trials with integrity and scientific rigor and whose efforts provided a clear data read out,” Rick Barry, president and chief executive officer at Cassava, said in a statement.¹

The REFOCUS-ALZ study was a multi-center, double-blind, placebo-controlled trial conducted at over 75 clinical sites in the U.S., Canada, Puerto Rico, and South Korea. Patients were randomized 1:1:1 to receive either 50 mg or 100 mg doses of simufilam or placebo twice daily for 76 weeks. The study aimed to replicate findings from the earlier RETHINK-ALZ trial (NCT04994483), which also failed to meet its co-primary end points.²

Despite the lack of efficacy, simufilam demonstrated a favorable safety profile. Adverse events (AEs) were consistent across all groups, with incidences of 76.5% to 76.6%. Serious AEs were slightly higher in the 50 mg group (16.2%) compared with the 100 mg (11.5%) and placebo (12.1%) groups. COVID-19 was the most reported AE, along with urinary tract infections, falls, dizziness, and diarrhea. Deaths were rare, with occurrences in 0.5%, 1.6%, and 0.8% of participants in the 100 mg, 50 mg, and placebo groups, respectively.

Cassava Sciences’ decision to terminate the simufilam program may reflect the unambiguous negative results of both the REFOCUS-ALZ and RETHINK-ALZ trials. “Cassava will discontinue all efforts to develop simufilam for Alzheimer’s disease and we expect to phase out the program by the end of Q2 2025,” Barry, said in a statement.¹ “We remain dedicated to our mission of developing novel medicines for central nervous system disorders. While we have initiated preclinical studies to evaluate simufilam’s potential as a treatment for TSC-related epilepsy, we maintain ongoing strategic expense management efforts.”

REFERENCES
1. Cassava Sciences Reports Topline Phase 3 REFOCUS-ALZ Data. News Release. Cassava Sciences. Published March 25, 2025. Accessed March 25, 2025. https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-reports-topline-phase-3-refocus-alz-data
2. Cassava Sciences Topline Phase 3 Data Did Not Meet Co-Primary Endpoints. News release. Cassava Sciences. November 25, 2024. Accessed March 25, 2025. https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-topline-phase-3-data-did-not-meet-co-primary