Topline results from Phase 3 trial of simufilam due this year

Two ongoing trials have collectively enrolled 1,929 people with disease

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Two Phase 3 clinical trials are testing the effectiveness of simufilam, an experimental oral therapy that’s designed to improve cognition in people with Alzheimer’s disease.

Top-line results from the RETHINK-ALZ trial (NCT04994483) are expected by the end of this year, according to simufilam’s developer Cassava Sciences. Results from the second study, REFOCUS-ALZ study (NCT05026177), are due in 2025. The two studies collectively enrolled 1,929 people with mild to moderate Alzheimer’s and the U.S. Food and Drug Administration (FDA) has confirmed they could support an application for simufilam’s approval if the results are positive.

“Cassava Sciences is a small company doing cutting-edge research in neurosciences. If you have Alzheimer’s disease, we work for you. I’m hopeful that our experimental pill may potentially become another treatment option for people living with Alzheimer’s disease,” Remi Barbier, president and CEO of Cassava, wrote in an email to Alzheimer’s News Today.

RETHINK-ALZ is testing simufilam (100 mg twice daily) against a placebo for a year in people with mild to moderate Alzheimer’s. It finished recruiting last October, with 804 patients enrolled. REFOCUS-ALZ is testing two doses of simufilam — 50 or 100 mg twice daily — against a placebo for 76 weeks (about a year and a half). It finished enrollment in November, with 1,125 people with mild to moderate Alzheimer’s.

The main goal in both is to evaluate simufilam’s effects on two standardized measures: the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12), which assesses cognitive function, and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), which assesses a person’s ability to function independently in daily life.

“A lot of people, us included, look forward to seeing clinical results of our Phase 3 tests, which should happen over the next 12 to 18 months,” Barbier said.

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 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.