Cassava Sciences' Phase 3 ReThink-ALZ study evaluating simufilam for mild-to-moderate Alzheimer's disease has failed to meet its co-primary endpoints. The trial, which assessed changes in cognition and function over 52 weeks using the ADAS-COG12 and ADCS-ADL scales, did not demonstrate a significant reduction in cognitive or functional decline compared to placebo. This outcome has led to the discontinuation of the second Phase 3 trial, ReFocus-ALZ, and the Open Label Extension study.
Trial Results and Endpoints
The ReThink-ALZ trial (NCT04994483) was a multi-center, double-blinded, placebo-controlled, randomized parallel group study involving over 75 clinical trial sites in the U.S., Canada, and Australia. It randomized 804 patients with confirmed mild or moderate Alzheimer's disease, defined by a Mini-Mental State Examination (MMSE) score between 16 and 27. Patients were randomized 1:1 to receive simufilam 100 mg (n=403) or a matched placebo (n=401), dosed orally twice daily (BID) for 52 weeks.
The co-primary endpoints were the change in cognition and function from baseline to the end of the double-blind treatment period at week 52, assessed by the ADAS-COG12 and ADCS-ADL scales, comparing simufilam to placebo. Topline analysis of the mild and moderate sub-groups, likewise, did not demonstrate statistical significance at week 52.
| Co-Primary Endpoint | Data | Simufilam 100 mg BID (N=403) | Placebo BID (N=401) | Delta | P-value |
|---|---|---|---|---|---|
| ADAS-COG12 (SE) | LS means change from baseline to the end of the double-blind treatment period | 2.8 (0.36) | 3.2 (0.36) | -0.39 (0.50) | P=0.43 |
| ADCS-ADL (SE) | LS means change from baseline to the end of the double-blind treatment period | -3.3 (0.44) | -3.8 (0.44) | 0.51 (0.61) | P=0.40 |
Secondary endpoints also included measures of neuropsychiatric symptoms and caregiver burden. Safety was evaluated through adverse event monitoring.
Safety Profile and Adverse Events
Simufilam maintained a favorable safety profile throughout the trial. The most frequent adverse events reported were COVID-19, urinary tract infection, falls, dizziness, and headache.
| Metrics for Simufilam and Placebo | Simufilam 100 mg BID | Placebo BID |
|---|---|---|
| Any Adverse Event (AE) | 284 (71.2%) | 269 (67.6%) |
| Serious AEs | 52 (13.0%) | 36 (9.0%) |
| Death | 1 (0.3%) | 3 (0.8%) |
| AEs leading to discontinuation from the study | 26 (6.5%) | 17 (4.3%) |
Company's Response and Future Plans
"The results are disappointing for patients and their families who are living with this disease and physicians who have been looking for novel treatment options," said Rick Barry, President and Chief Executive Officer of Cassava Sciences. The company has decided to discontinue the ReFocus-ALZ trial and the Open Label Extension study. Cassava Sciences intends to present detailed analyses of both studies at a future medical meeting.
Financial Position
As of the end of the third quarter of 2024, Cassava Sciences reported approximately $149.0 million in cash and cash equivalents. Eric Schoen, Chief Financial Officer, stated that the company remains focused on enhancing shareholder value.
