Improvements with simufilam
A scheduled interim safety review in late 2023 didn’t raise any noteworthy issues with the two trials and interim data from REFOCUS-ALZ hinted that simufilam may not carry the safety risks seen with other recently Alzheimer’s medications.
Antibody-based treatments targeting amyloid-beta can cause swelling in the brain, known as ARIA-E (amyloid-related imaging abnormalities edema). An interim analysis of MRI data from 180 patients in REFOCUS-ALZ showed none had ARIA-E after 40 weeks, about 10 months.
The analysis noted some instances of bleeding in the brain, known as ARIA-H, but the rates were low; about 5% of patients who didn’t have bleeding when they entered the trial had new bleeding at week 40. That’s consistent with rates of brain bleeding in patients who aren’t on treatment, so it’s unlikely these bleeds are from simufilam, according to Cassava.
Alzheimer’s disease is characterized by toxic clumps of proteins in the brain, such as amyloid-beta and tau, which may contribute to its progression. Simufilam is designed to target filamin A, a protein that forms abnormal clumps in Alzheimer’s and that’s also involved in amyloid-beta and tau clumping. By targeting filamin A, simufilam seeks to reduce brain damage and slow disease progression. It’s also thought to have anti-inflammatory effects.
Simufilam was tested in a Phase 2 clinical trial (NCT04388254) that enrolled 216 people with mild to moderate Alzheimer’s disease. For the first part, all participants were treated with simufilam (100 mg twice daily) for a year. Topline results from the first part involving 157 patients showed nearly half saw improvements in cognition, based on the ADAS-Cog11 , which is similar to ADAS-Cog12.
In the next part, the participants were randomly assigned to continue taking simufilam or switch to a placebo for six months. Results showed that average ADAS-Cog11 scores worsened by 0.9 points with simufilam and by 1.5 points with a placebo.
That works out to a 38% difference favoring simufilam, though it wasn’t statistically significant, meaning it’s plausible the difference could be due to chance. Phase 2 studies, which primarily assess safety, often don’t have a large enough sample size to detect statistically meaningful results, which is why the Phase 3 trials include nearly 2,000 patients.