Simufilam, an investigational oral drug for Alzheimer’s Disease, improved cognition in 47% of treated patients in a Phase 2 study

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I’m very excited about these 1-year data. They add strength and determination to our goal of helping people fight Alzheimer’s disease. Simufilam is an innovative drug candidate that we are developing methodically, one study at a time, and this open-label safety study served its purpose.

Remi Barbier, President and CEO, Cassava Sciences

On Jan 24, 2023, Cassava Sciences announced the top-line results of a phase 2 clinical trial of Simufilam, an investigational oral drug for Alzheimer’s disease. In this single-arm, open-label safety study, Simufilam demonstrated good safety and tolerability. In terms of the exploratory efficacy endpoint, 47% of treated patients had a 4.7-point improvement from baseline on the ADAS-Cog score, which assesses cognitive decline, after 1 year of treatment. The company has initiated Phase 3 clinical trials to evaluate the effect of Simufilam in patients with mild to moderate Alzheimer’s disease.

Alzheimer’s disease is the most common neurodegenerative disease in the elderly and has become an important threat to the health of the elderly and an important economic burden on human society. For Alzheimer’s disease, in addition to directly targeting the traditional target β-amyloid or Tau protein, more companies are exploring other disease-related mechanisms of action. Simufilam targets filamin A (FLNA), a scaffold protein highly expressed in the brain. In the patient’s brain, the conformation of FLNA changes, which allows amyloid beta fragment (Aβ42) to trigger the production of hyperphosphorylated tau protein and the release of inflammatory cytokines by binding to the receptor.

The mechanism of action of Simufilam (Source: Cassava Sciences website)

Simufilam is an oral small-molecule compound. Its target is not amyloid, however, it binds to FLNA and restores its normal conformation and function, and prevents signal transduction via Aβ42. Therefore, it has the ability to specifically target a scaffold protein while reducing and preventing neurodegeneration and neuroinflammation.

The study enrolled 216 patients with mild-to-moderate Alzheimer’s disease who had scores between 16 and 26 on the Mini-Mental State Examination Examination (MMSE). Patients received Simufilam oral therapy for more than 1 year, and the primary efficacy endpoint was the change from baseline in the ADAS-Cog score at 12 months. ADAS-Cog is a comprehensive score for evaluating the cognitive function of patients with Alzheimer’s disease. The score ranges from 0 to 70, and the higher the score, the lower the cognitive ability.

The results of the trial showed that after 12 months of treatment, the ADAS-Cog score of the subgroup of patients with mild Alzheimer’s disease (defined as MMSE score 21-26) improved from 15.0 (± 6.3) to 12.6 (± 7.8). However, ADAS-Cog scores increased from 25.7 (± 9.2) to 30.1 (± 13.1) in the subgroup of patients with moderate Alzheimer’s disease (MMSE score 16-20). According to the press release, ADAS-Cog scores improved in 47 percent of the overall patient population, with a mean score reduction of 4.7 (± 3.8) points for these patients.

The improvement in ADAS-Cog scores is a potentially positive outcome, Dr. Laura Nisenbaum, executive director of drug development at the Alzheimer’s Disease Drug Discovery Foundation (ADFF), told industry media BioSpace. However, it should be noted that this result comes from an open-label safety study, which means that all patients, nurses, and doctors are aware that patients are receiving drug treatment, so the data need to be interpreted with caution. Because the trial did not have a placebo control, it was difficult to accurately assess cognitive improvement as she emphasized.

In terms of safety, Simufilam at a dose of 100 mg showed good safety and tolerability, and no drug-related serious adverse events were observed. Treatment-emergent adverse events (TEAEs) occurring in more than 7% of patients included COVID-19 (12%), urinary tract infection (10%), and headache (9%).

While the final Phase 2 trial data are awaited, recruitment for two comprehensive Phase 3 studies of Simufilam, namely RETHINK-ALZ (NCT04994483) and REFOCUS-ALZ (NCT05026177), is underway at dozens of sites across the U.S., Canada, Puerto Rico, Australia, and South Korea.

More than 950 people with mild-to-moderate Alzheimer’s are already enrolled across the two placebo-controlled phase 3 trials, which plan to recruit a total of 1,750 patients, as announced by the company in a separate press release.

If you or your loved ones are willing to participate in one of these trials, contact and enrollment information for RETHINK-ALZ and REFOCUS-ALZ trials are available.

[1] Cassava Sciences Announces Positive Top-Line Clinical Results in Phase 2 Study Evaluating Simufilam in Alzheimer’s Disease (Press Release)
[2] Cassava Sciences Announces Patient Enrollment Update for Phase 3 Studies of Simufilam for the Treatment of Alzheimer’s Disease (Press Release)

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