Alzheimer Agent Simufilam Fails to Meet Primary End Point in Phase 3 Study

Rick Barry

New topline data from the phase 3 ReThink-ALZ study (NCT04994483) showed that treatment with investigational simufilam (Cassava Sciences), a small molecule agent targeting an altered form of filamen A (FLNA), did not meet each of its pre-specified co-primary, secondary, and exploratory biomarker end points in patients with mild-to-moderate Alzheimer disease (AD). As a result of these findings, the company has decided to discontinue its second phase 3 study of simufilam, ReFocus-ALZ (NCT05026177).

ReThink-ALZ was a double-blinded study that randomly assigned 804 patients with confirmed mild or moderate AD to either simufilam 100 mg (n = 403) or a matched placebo (n = 401), dosed orally twice daily (BID) for 52 weeks. After 52 weeks of treatment, simufilam failed to distinguish itself from placebo on the primary end points of Alzheimer’s Disease Assessment Scale-Cognitive Subscale 12 (ADAS-Cog12; simufilam least square [LS] mean change: 2.8 [SE. 0.36]; placebo: 3.2 [SE, 0.36]; P = .43) and Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; simufilam: –3.3 [SE, 0.44]; placebo: –3.8 [SE, 0.44]; P = .40).

"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. We took careful measures to enroll patients with mild-to-moderate AD. Despite that, the loss of cognition in the placebo group was less pronounced than was previously reported in other placebo-controlled studies in AD. We are working to understand this better," Rick Barry, president and chief executive officer at Cassava, said in a statement.¹

He added, "A result like this has implications on our second Phase 3 trial, ReFocus-ALZ. We have made the difficult decision to discontinue ReFocus-ALZ, given the nature of today’s reported results. The complete 52-week dataset will be available from the study along with a large portion of 76-week data. We intend to report detailed analyses of both studies in the future. We will also be discontinuing the Open Label Extension study."

Conducted under a Special Protocol Assessment with the FDA, ReThink-ALZ included patients with confirmed mild or moderate AD, defined by several well validated parameters including a mini-mental state examination (MMSE) score between 16 and 27, stratified as mild or moderate. Overall, simufilam was considered safe and well tolerated, with serious adverse events (AEs) occurring in 13.0% (n = 52) of patients. For reference, 9% (n = 36) of those on placebo experienced serious AEs.

READ MORE: Redesigning Clinical Trials in Alzheimer Disease to Promote Diversity and Accessibility

The most frequent AEs in the study for simufilam were COVID-19 (8.0%; n = 32), urinary tract infection (7.8%; n = 31), fall (7.5%; n = 30), dizziness (5.3%; n = 21), and headache (4.5%; n = 18). Notably, there was a higher rate of AEs leading to discontinuation in the simufilam group (6.5%; n = 26) than for those on placebo (4.3%; n = 17), as well as a slightly higher rate of any AEs in the study (71.2% vs 67.6%).

At the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, investigators presented interim data from ReFocus-ALZ, with results showing that treatment with simufilam did not result in amyloid-related imaging abnormalities (ARIA). The analysis comprised of 181 patients with mild to moderate AD who were randomly assigned to either twice-daily simufilam 50 mg and 100 mg or placebo and had week-40 safety reports available.²

In the MRI substudy, 1.5T and 3T scanners were used with 3DT1, FLAIR, T2, and DWI sequences. By week 40, 88% of participants (n = 160) had no clinically significant findings, while 7% (n = 13) had abnormalities such as infarcts and cortical superficial siderosis (CSS) identified at screening that persisted. New findings at week 40 emerged in 4% (n = 7) of participants, including cortical or lacunar infarcts (n = 3), CSS in patients with pre-existing CSS or at least 4 baseline microhemorrhages (n = 3), and 1 unifocal CSS case in an apolipoprotein e4/e4 patient. Additionally, 20 patients with baseline microhemorrhages showed new ones by week 40, with most exhibiting 1–4 and 6 patients showing 5 or more.

Simufilam was also previously assessed in a phase 2 randomized withdrawal study, with results presented at CTAD 2023. In the study, 157 patients who completed 12 months of open-label simufilam were randomly assigned to either active treatment or switched to matching placebo for a 6-month period. Over the 6-month time, treatment with 100 mg BID of simufilam slowed cognitive decline by 38% (95% CI, –2.1 to 1.0) in treated patients vs placebo, demonstrated by changes in ADAS-Cog11. Notably, those with mild AD randomized to simufilam (n = 40) improved –0.6 points over 6 months, a 205% difference in favor of the drug (95% CI, –2.6 to 0.4).³

REFERENCES
1. Cassava Sciences Topline Phase 3 Data Did Not Meet Co-Primary Endpoints. News release. Cassava Sciences. November 25, 2024. Accessed November 25, 2024. https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-topline-phase-3-data-did-not-meet-co-primary
2. Kupiec J, Bracoud L, Suhy J, Rodriguez L, Burns L. Interim MRI safety analysis from a 76-week phase 3 clinical trial of simufilam in Alzheimer’s disease. Presented at Clinical Trials on Alzheimer’s Disease conference; October 24-27, 2023; POSTER LP036
3. Malhotra S, Patel P, Hendrix S, et al. Results of a phase 2 randomized withdrawal study of simufilam in mild-to-moderate Alzheimer disease. Presented at Clinical Trials on Alzheimer’s Disease conference; October 24-27, 2023; POSTEER LB23