The results point to the potential for sumifilam to become a transformative treatment for patients with Alzheimer disease.
Cassava Sciences announced that its lead drug candidate, sumifilam, significantly improved a panel of validated Alzheimer disease (AD) biomarkers in patients with a clinical diagnosis of AD in a phase 2b study, something that no drug has shown the ability to do to date.1
Patients with AD administered sumifilam in the randomized, placebo-controlled, double-blind, multicenter clinical study (NCT04079803) showed improvements in tests of episodic and spatial working memory compared with patients on placebo. Additionally, improvements in cognition correlated most strongly with decreases in phosphorylated tau (P-tau181), of which an 8% to 11% reduction was recorded versus placebo.
“Filamin-binding molecules are new to Alzheimer research and may represent an important advance if these data can be replicated in larger studies,” Jeffrey Cummings, MD, ScD, founding director, Cleveland Clinic Lou Ruvo Center for Brain Health, and Chambers Professor of Brain Science, University of Nevada–Las Vegas, said in a statement.1 “I am pleased to see early evidence of disease-modifying effects in patients with this investigational drug. The data appear to represent a step forward toward urgently needed treatments for Alzheimer disease.”
The phase 2b study funded by the National Institutes of Health (NIH) included 64 patients with mild to moderate AD, age 50 to 85, who were randomized 1:1:1 to 50- or 100-mg oral sumifilam or matching placebo twice daily for 28 days.
Sumifilam is a small molecule drug that restores the normal shape and function of altered filamin A (FLNA), a scaffolding protein. Upon conclusion of the trial, both active treatment doses showed statistically significant (P <.05) improvements in biomarkers of disease pathology, neurodegeneration, and neuroinflammation compared with placebo.
Core markers of AD pathology including total-tau decreased by 15% and 18% for patients in the 50- and 100-mg groups, respectively (all P <.01). P-tau decreased by 8% for patients in the 50-mg group and 11% in the 100-mg group (all P <.01), while amyloid beta-42 (Aβ42) increased by 17% and 14% in the 50- and 100-mg groups, respectively (all P <.01).
Elevated cerebrospinal fluid (CSF) levels of neurogranin (ng) and neurofilament light chain (NfL), which indicate neurodegeneration, decreased by 36% and 28% in the 50-mg group, respectively, and by 43% and 34% in patients in the 100-mg group, respectively.
Proinflammatory IL-6 (interleukin 6), produced in response to tissue stress and injury, decreased by 10% in the 50-mg group and 11% in the 100-mg group (all P <.01).
Investigators also noted that patients in the 50-mg group had decreased levels of YKL-40 by 10% (P <.01). Those in the 100-mg group saw similar results, with decreases of 12% (P <.01). sTREM2, a neuroinflammation biomarker, decreased by 43% and 46% in the 50- and 100-mg groups, respectively (all P <.01).
Cognition, which was assessed via the Cambridge Neuropsychological Test Automated Battery (CANTAB) at baseline and day 28, showed directional improvements on tests of episodic memory and spatial memory in patients treated with sumifilam compared with placebo, with an effect size of 46% to 17%.
Furthermore, episodic memory improved by –5.7 and –4.3 for patients with AD in the 50- and 100-mg groups, respectively, compared to –1.5 for patients in the placebo group. Spatial memory also improved by –1.6 for patients with AD in the 50-mg group and –3.3 for patients in the 100-mg group compared with –0.4 in the placebo group.
The investigators noted that improvements in cognition correlated most strongly (statistical R2 = 0.5) with decreases in cerebrospinal fluid P-tau181, with decreases of 8% to 11% recorded in the treatment groups compared with placebo.
Overall, findings observed in this study are consistent with prior clinical and preclinical results (NCT03784300; NCT03748706). The drug was deemed both safe and tolerable, with no treatment-related discontinuations recorded.
There is currently an ongoing long-term, open-label study of sumifilam 100-mg twice-daily for 12 months. The study is currently at 50% enrollment, with a target enrollment of approximately 100 patients with mild to moderate AD.
"Other than a few drugs to help ease the decline, there’s really nothing out there to treat people with Alzheimer," Remi Barbier, chairman, president and chief executive officer, Cassava Sciences, said in a statement.1 "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 disease."
Notably, Cassava initially reported disappointing topline results from the phase 2b study in May of this year2 after an initial bioanalysis showed highly "anomalous data" that included major swings in levels of biomarkers observed in patients in the placebo group. Deemed invalid, a new bioanalysis of the full results was undertaken and is reported herein.