Sumifilam Lowers Levels of Multiple Biomarkers of Disease Activity, Trial Shows

Sumifilam Lowers Levels of Multiple Biomarkers of Disease Activity, Trial Shows
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Treatment with sumifilam significantly lowered the levels of multiple biomarkers of disease activity, neurodegeneration, and inflammation in people with mild-to-moderate Alzheimer’s after 28 days of treatment, according to final data from a Phase 2b trial.

Sumifilam, Cassava Sciences’ lead investigational candidate for Alzheimer’s disease, also was found to be safe and well-tolerated, and to improve patients’ cognitive function, compared with a placebo.

“Other than a few drugs to help ease the decline, there’s really nothing out there to treat people with Alzheimer’s,” Remi Barbier, chairman, president and CEO of Cassava Sciences, said in a press release.

“The improvement on multiple biomarkers in this clinical study is a first and offers hope that sumifilam has potential to become a transformative treatment for people with Alzheimer’s disease,” Barbier said.

Sumifilam, formerly known as PTI-125, is a proprietary small oral molecule that has been designed to bind and restore the normal shape and function of filamin A (FLNA), a protein that is misfolded in patients with Alzheimer’s and is thought to contribute to the accumulation of toxic protein clumps (aggregates) inside nerve cells.

Data from a previous open-label Phase 2a study (NCT03748706) had shown that, when given at a dose of 100 mg twice per day, sumifilam was able to lower the levels of several disease biomarkers in 13 patients with mild-to-moderate Alzheimer’s within a period of 28 days.

These promising findings led the company to launch a larger, double-blind, placebo-controlled Phase 2b trial (NCT04079803) to confirm the positive effects of sumifilam on Alzheimer’s disease biomarkers.

Funded by the National Institutes of Health (NIH), the study enrolled 64 patients with mild-to-moderate Alzheimer’s who were randomly assigned to receive one of two doses (50 or 100 mg, twice daily) of sumifilam or a placebo, for a period of 28 days.

The study’s main goal was to assess if sumifilam would be superior to the placebo at lowering the levels of several biomarkers of disease activity, neurodegeneration, and inflammation in the cerebrospinal fluid (CSF). Of note, the CSF is the liquid that circulates around the brain and spinal cord.

Among the disease activity biomarkers assessed were total and phosphorylated tau and beta-amyloid protein. Neurogranin and neurofilament light chain were two neurodegeneration biomarkers evaluated, while YKL-40, sTREM2, and interleukin 6 were inflammation biomarkers that were assessed. The levels were examined over the 28-day period.

Although top-line data from the trial failed to show sumifilam was superior to a placebo at lowering the levels of certain disease biomarkers, including total and phosphorylated tau protein, full data from the study — including a new analysis — now show the opposite. 

Updated study findings now showed that, compared with a placebo, both doses of sumifilam were able to significantly lower the CSF levels of all biomarkers within a period of 28 days. In general, reductions tended to be stronger in patients receiving the highest dose of the therapy. These responses were seen in 98% of the study participants who were given sumifilam during the trial.

From all biomarkers assessed, the ones whose levels dropped the most, in the higher dose group, were sTREM2 (up to 46%), neurogranin (up to 43%), and neurofilament light chain (up to 34%). The ones that dropped the least, in the higher dose group, were phosphorylated tau protein (up to 11%), interleukin-6 (up to 11%), and YKL-40 (up to 12%).

Sumifilam also improved patients’ cognitive abilities, particularly their episodic and spatial working memory, compared with the placebo (effect size of 46% vs. 17%). These improvements in cognition also were found to be correlated with reductions in the CSF levels of phosphorylated tau 181 (p-tau181), which can promote the formation of toxic protein clumps in the brain when elevated.

Treatment with sumifilam also was found to be safe and well-tolerated.

“The clinical data suggest sumifilam may be slowing disease progression in Alzheimer’s patients,” said Nadav Friedmann, PhD, MD, chief medical officer of Cassava Sciences.

“This exciting possibility will need to be evaluated in future collaborations with patients, physicians, advisors and others,” Friedmann added.

A Phase 2 open-label extension study (NCT04388254) is currently ongoing. It has enrolled patients who completed one of the two previous Phase 2 trials of sumifilam as well as new participants with mild-to-moderate Alzheimer’s.

This long-term extension study aims to enroll approximately 100 participants to evaluate the long-term safety and efficacy of sumifilam, when given at a dose of 100 mg twice per day, for one year. According to Cassava, about 50% of the patients have already enrolled in the study.

Recruitment is still underway at several sites in the U.S. More information can be found here.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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