Data on Cassava Sciences’ Alzheimer’s drug candidate, simufilam, indicates that it was not only safe, but that it modified Alzheimer's biomarkers at six months, and improved cognition at nine months. Experts say it’s too soon to celebrate.
Cassava Sciences revealed positive clinical data from their simufilam trial, a potentially disease-modifying therapy for treating Alzheimer’s. Their preliminary study showed that simufilam significantly improved cognition and reduced psychiatric symptoms after nine months. Cassava Sciences is advancing this drug candidate — administered in oral tablets — to Phase 3 clinical trials.
Simufilam’s mechanism of function is different from other approved drugs already on the market, in that it doesn’t target the acetylcholine neurotransmitter system as ACh inhibitors like galantamine (Reminyl) do, nor does it target the deposition of beta-amyloid like the newly approved Aduhelm and donanemab which is currently being tested in clinical trials, do. Instead, simufilam is a small molecule that enters the brain and helps a certain protein — filamin A (FLNA), which, when it isn’t working right, might lead to beta-amyloid build-up and cause inflammation — fold and function properly.
Representatives from the company presented data from a nine-month open-label study, funded by the National Institutes of Health at the Alzheimer’s Association International Conference (AAIC) 2021, sharing results from 50 of the 150 people with mild-to-moderate Alzheimer’s being treated with simufilam. The data indicates that so far, the drug is not associated with any adverse events. The approach has yielded what appears to be some very promising results in addressing Alzheimer’s both from a pathology standpoint and a symptomatic one.
“Simufilam improved cognition, biomarkers and behavior, a triple-win for study participants,” said Remi Barbier, president and CEO of Cassava Sciences. “These clinical data combined with a clean safety profile and easy oral administration suggest highly encouraging and durable treatment effects for people living with Alzheimer’s disease.”
Barbier told Being Patient he believes this is “the first report of significant cognitive improvement at nine months that also tracks with profound improvements in biomarkers in patients with Alzheimer’s.”
Reduced Alzheimer’s biomarkers
Researchers analyzed the cerebrospinal fluid (CSF) for certain brain protein remnants that are biomarkers for Alzheimer’s. The outcome: Fewer biomarkers appeared in the CSF of participants who had been administered the experimental drug.
In the study, the total amount of tau was reduced 38 percent while a specific type of beta-amyloid increased 84 percent. Two other proteins, called neurogranin and neurofilament light chain, are normally increased as a result of neurodegeneration. After six months of simufilam, the study found a reduction of these proteins in CSF by 72 and 55 percent respectively. Similarly, neuroinflammatory markers YKL-40, sTREM2, and HMGB1 decreased 44, 55, and 63 percent respectively.
From previous studies, it was expected that people with mild-to-moderate Alzheimer’s who receive treatment experience a cognitive decline equivalent to a decrease in more than four points on the ADAS-Cog11 scale. However, the changes in biomarkers appeared to be accompanied by cognitive and behavioral improvements after nine months of treatment.
The study found an 18 percent improvement, equivalent to an increase of three points on the ADAS-Cog11 scale in cognitive scores at the end of the trial. Approximately two out of three people in the trial showed cognitive improvements. Another 22 percent of patients in this trial showed slower cognitive decline than expected, according to the literature. The improvements in cognition seen in the trial suggest that the cognitive decline in Alzheimer’s was slowed or even reversed in most participants.
Improved behavioral symptoms
In addition to cognitive decline, people with Alzheimer’s experience an array of behavioral and psychiatric symptoms, which may include anxiety and depression. At the start of the study, approximately 66 percent of participants experienced psychiatric symptoms such as anxiety, or delusions. At the end of the study, this number was reduced to 50 percent, suggesting that simufilam improved these symptoms as well.
A new disease-modifying drug?
While there are several approved drugs on the market that target the symptoms of Alzheimer’s, such as memantine and galantamine, they do not slow the progression or pathogenesis of the disease. Aduhelm, the recently approved controversial treatment for Alzheimer’s, is thus far the only treatment with disease-modifying potential as it has been shown to clear amyloid plaques in the brain.
“Today’s data with simufilam suggests disease modification,” Dr. Nadav Friedmann, Cassava Sciences’ chief medical officer, said at AAIC. “It appears the drug’s unique mechanism of action has potential to provide transformative treatment benefits following nine months of dosing.”
He affirmed the drug’s next steps, adding: “More testing in larger trials is needed to confirm these findings.”
Too Soon to Celebrate
According to an article published in STAT, several scientists agree with Friedmann that larger trials will be essential in confirming the drug’s potential. The company presented data on just a third of the 150 total trial participants, as it is still ongoing; some scientists expressed reservations as the study has an open-label design and was not placebo-controlled. Since participants are aware they are receiving treatment, experts say it’s possible their improvements over nine months may be attributed to the placebo effect.
“As we know with clinical measures, the numbers the company presents could easily reverse after the next 50 or 100 patients are added,” Dr. Lon Schneider, a professor at the Keck School of Medicine of the University of Southern California and previously a site investigator in one of Aduhelm’s clinical trials, told STAT.
Another expert, Dr. Robert Howard of University College London cautioned against making any therapeutic claims without a placebo-controlled trial.
What’s Next for Simufilam
Barbier and his team, however, are encouraged.
“In my opinion, what is truly impressive about simufilam is the continued improvement on the same dose, in a disease with inevitable decline,” Barbier wrote to Being Patient in an email following the conference. “This is unprecedented in Alzheimer’s. Even if just half of our open-label data replicate in Phase 3 clinical testing, we think simufilam can become an important drug for people with Alzheimer’s disease.”
Cassava Sciences will proceed with Phase 3 clinical trials, including 1,500 people with mild-to-moderate Alzheimer’s disease, beginning in fall 2021.