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Shares of Cassava Sciences SAVA plunged 32.1% on Tuesday after the company announced that its lead pipeline candidate, simufilam, failed to meet the prespecified co-primary endpoints in the second late-stage study for Alzheimer’s disease (AD). Simufilam is SAVA’s proprietary, investigational oral small molecule that targets the filamin A protein.
Cassava released top-line results from the phase III REFOCUS-ALZ study, which evaluated simufilam in patients with mild-to-moderate AD. Treatment with the drug failed to achieve a significant reduction in cognitive and functional decline in AD patients when compared to placebo over 76 weeks, as assessed by the ADAS-COG12 and ADCS-ADL scales. The study also failed to meet any pre-specified secondary and exploratory biomarker endpoints.
The REFOCUS-ALZ study had enrolled 1,125 AD patients who were randomized equally to receive either a twice-daily, oral dose of simufilam (50 mg or 100 mg tablets) or placebo for 76 weeks. The candidate, however, demonstrated an acceptable safety profile in the study.
Year to date, Cassava shares have plunged 19.5% against the industry’s 0.5% growth.
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SAVA’s AD Drug Failure in First Late-Stage Study
Under its AD program, Cassava evaluated simufilam in another late-stage study. In November 2024, the company faced a massive setback after it reported that the candidate failed to meet the primary endpoints in the late-stage RETHINK-ALZ study, which evaluated simufilam in patients with mild-to-moderate AD. Treatment with the drug failed to achieve a significant reduction in cognitive or functional decline in AD patients when compared to placebo over 52 weeks, as assessed by the ADAS-COG12 and ADCS-ADL scales. The study failed to meet any pre-specified secondary and exploratory biomarker endpoints as well.
Based on the above study results, SAVA had discontinued the 76-week phase III REFOCUS-ALZ study and the open-label extension study on the drug.
SAVA’s Next Steps
Following simufilam’s failure to demonstrate therapeutic benefit in AD patients in two late-stage studies, Cassava expects to phase out the AD program by the end of the second quarter of 2025. Despite the setbacks, SAVA has reportedly initiated preclinical studies to evaluate simufilam’s potential as a treatment for tuberous sclerosis complex-related epilepsy.
In early January, Cassava announced plans to reduce its workforce by 33% in first-quarter 2025 as part of ongoing cost management efforts. Additionally, it will discontinue the planned biomarker analysis of plasma samples from past mid-stage studies. The workforce reduction is expected to result in a one-time cost of approximately $0.4 million in first-quarter 2025.