Simufilam fails to meet Phase 3 trial goals; development discontinued
REFOCUS-ALZ study was testing drug as treatment for Alzheimer's
Cassava Sciences will discontinue developing simufilam for mild to moderate Alzheimer’s disease by the end of the second quarter of this year after the experimental treatment failed to meet key Phase 3 trial goals for improving cognition and daily function.
In REFOCUS-ALZ (NCT05026177), patients treated with simufilam showed no significant improvements in cognitive functioning, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12), after about a year and a half over a placebo.
Simufilam remained safe and well tolerated, but it also failed to significantly improve daily functioning, as measured by the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), a questionnaire that covers both basic and more complex activities of daily living.
The study enrolled 1,125 patients, but was terminated last year after an earlier Phase 3 clinical trial called RETHINK-ALZ (NCT04994483)Â also failed to meet its main goals after about a year. By the time REFOCUS-ALZ was discontinued, many participants had already completed their final visits.
“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,” Rick Barry, Cassava’s president and CEO, said in a company press release. “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.”
What was simufilam designed to do in Alzheimer’s?
Simufilam is an oral small molecule designed to restore the normal shape of an altered version of filamin A that occurs in Alzheimer’s. Filamin A is a scaffolding protein that helps organize other proteins within cells to work together in signaling pathways, but its altered version appears to be involved in forming toxic beta-amyloid plaques and tau tangles, which interfere with how brain cells communicate and contribute to Alzheimer’s. The aim of simufilam was to restore filamin A to its normal shape and help prevent toxic proteins from building up, easing cognitive decline and other disease symptoms.
REFOCUS-ALZ tested the safety and efficacy of simufilam in patients diagnosed with mild to moderate Alzheimer’s, ages 50-87, at more than 75 clinical trial sites across the U.S., Canada, Puerto Rico, and South Korea.
The patients were randomly assigned to either 50 or 100 mg of simufilam as oral tablets or a placebo twice daily for about a year and a half. The main goals included watching for changes in both ADAS-Cog12 and ADCS-ADL scores from the trial’s start until its end.
Top-line results showed no significant differences in ADAS-Cog12 scores, which increased by an average of 5.26, 4.97, and 4.7 points in the simufilam 50 mg, 100 mg, and placebo groups, respectively. Higher ADAS-COG12 scores indicate worse cognitive functioning.
Similarly, there were no significant differences in ADCS-ADL scores, which fell by an average of 6.43, 6.27, and 5.32 points in the simufilam 50 mg, 100 mg, and placebo groups, respectively. In ADCS-ADL, lower scores indicate more functional impairment.
Secondary and exploratory biomarker goals, such as measures of neuropsychiatric symptoms in dementia, stress and burden among caregivers, changes in brain volume, and levels of amyloid-beta and tau proteins, among other biomarkers, also weren’t met.
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