Positive top-line clinical results in phase II study evaluating simufilam in Alzheimer’s disease

This was an open-label safety study with exploratory efficacy endpoints. The study enrolled over 200 patients with mild-to-moderate Alzheimer’s disease (MMSE 16-26). Study participants were administered open-label simufilam tablets 100mg twice daily for 1 year or more. Endpoints were measured at baseline (study entry) and month 12.

Top-line Results – mean scores, baseline to month 12 (lower is better, except for MMSE): i. ADAS-Cog11 scores changed from 19.1 (±9.2) to 19.6 (±13.3) . ii. MMSE scores changed from 21.5 (±3.6) to 20.2 (±6.4). iii. NPI10 scores changed from 3.2 (±4.6) to 2.9 (±4.6) . iv. GDS scores changed from 1.8 (±1.8) to 1.4 (±1.9).

Alzheimer’s is a degenerative disease of the brain. Over time, cognition progressively worsens in the mild-to-moderate stages of Alzheimer’s as the disease takes its toll. ADAS-Cog scores that change minimally (or improve) over 1 year is a highly desirable outcome in a clinical study of mild-to-moderate Alzheimer’s disease.

Response Analysis – baseline to month 12: ADAS-Cog scores improved in 47% of patients; this group had a mean change of -4.7 (±3.8) points (lower is better). In an additional 23% of patients, ADAS-Cog declined less than 5 points; this group had a mean change of 2.5 (±1.4) points. Patients with an NPI10 score of zero increased from 42% to 54%, indicating reduced dementia-related neuropsychiatric symptoms.

Analysis of Efficacy Endpoints: Efficacy outcomes were analyzed by an independent, outside biostatistical consulting firm led by Suzanne Hendrix, PhD. The pre-specified primary efficacy endpoint was change in baseline on ADAS-Cog, a cognitive scale widely used in Alzheimer’s clinical research. Exploratory endpoints included the Mini-Mental State Examination (MMSE) to assess disease stage by cognitive impairment; the Neuropsychiatric Inventory (NPI10) to assess dementia related behavior; and the Geriatric Depression Scale (GDS). The Full Analysis Set (FAS) population (N=216) was used for the statistical analysis of efficacy endpoints.

Alzheimer’s is a progressive disease. Severity of disease is typically assessed by MMSE score. In this study, mild patients are MMSE 21-26; moderate patients are MMSE 16-20. Mild and moderate sub-groups showed notable differences on changes in ADAS-Cog mean scores, baseline to month 12 (lower is better) ;: i. In the mild sub-group, ADAS-Cog scores improved, from 15.0 (±6.3) to 12.6 (±7.8). In the moderate sub-group, ADAS-Cog scores worsened, from 25.7 (±9.2) to 30.1 (±13.1).

“The data for simufilam are noteworthy,” said Suzanne Hendrix, PhD. “The improvement in ADAS-Cog over 1 year in mild patients taking simufilam is well outside the expected range of historic placebo decline rates from numerous other studies.”

Safety Data: Simufilam 100 mg twice daily was safe and well tolerated. There were no drug-related serious adverse events. Three treatment-emergent adverse events (TEAEs) occurred in 7% or more of study patients: COVID-19 (12%), urinary tract infection (10%) and headache (9%). Reported TEAEs are based on all study patients who received at least one dose of drug. The top three reasons for patient discontinuations were withdrawal of informed consent (N=14), adverse events (N=13) and patient non-compliance (N=7).

Biomarker Data: ‘Research use only’, non-safety, exploratory biomarkers were analyzed from cerebrospinal fluid (CSF) collected from 25 patients in the open-label study who agreed to undergo a lumbar puncture at baseline and again after 6 months of treatment. CSF samples were analyzed blind by our academic collaborator at City University of New York (CUNY). We previously announced results of this bioanalysis in a press release dated July 29, 2021 (p-values shown below are baseline vs. 6-month levels by paired t-test): i. CSF biomarkers of disease pathology, t-tau and p-tau181, decreased 38% and 18%, respectively (both p<0.00001). ii. csf biomarkers of neurodegeneration, neurogranin and neurofilament light chain (nfl), decreased 72% and 55%, respectively (both p><0.00001). iii. csf biomarkers of neuroinflammation, strem2 and ykl-40, decreased 65% and 44% (both p><0.00001).

Of the 25 patients who provided 6-month CSF samples, 24 subsequently completed 1 year of treatment with open-label simufilam. This sub-set of patients improved -4.96 mean points on ADAS-Cog from baseline to month 12 (ad hoc analysis conducted internally; lower is better). We have not conducted further CSF sample analyses in the open-label study.

Chain of Custody for Clinical Data: Investigator sites collected clinical data from study patients. Sites entered their clinical data directly into an electronic data capture system managed by an independent, outside data management vendor. The data management vendor also maintains the clinical database. The data management vendor transmitted the clinical database directly to Pentara Corporation, an independent, outside consulting firm that specializes in complex statistical analysis of clinical trial results. Suzanne Hendrix, PhD, CEO of Pentara, has >150 peer-reviewed publications of clinical trial results and statistical approaches for clinical trials, many focusing on statistical methodology for Alzheimer’s disease.

Study Limitations: Data results from our open-label safety study do not constitute, and should not be interpreted as, regulatory evidence of safety or efficacy for simufilam in Alzheimer’s disease. Rigorous evidence for drug safety and efficacy is derived from one or more large, randomized, placebo-controlled studies. The open-label design and size of this study may introduce clinical or statistical bias or may generate results that may not fully distinguish between drug effects and random variation. Different methods of statistical analysis on clinical data from the same study may lead to objectively different numerical results. These and other statistical and clinical features of our open-label study add complexity or limitations to the scope of data interpretation.

On-going Phase III Studies with Simufilam: Cassava Sciences is currently evaluating simufilam tablets for Alzheimer’s disease dementia in two Phase III clinical studies. These are randomized, double-blind, placebo-controlled trials. The Phase III program is recruiting a total of approximately 1,750 patients with mild-to-moderate Alzheimer’s disease who also meet other study eligibility criteria. Both Phase III studies have received a Special Protocol Assessment (SPA) from the FDA. The Phase III studies are actively recruiting Alzheimer's patients in over 100 clinical sites in the United States, Canada, Puerto Rico, South Korea and Australia.