Cassava Sciences recently reported results from this second of two phase 3 studies known as REFOCUS-ALZ. This was a huge study, as it recruited a total of 1,125 patients. It was noted that the co-primary endpoints of this late-stage trial were not met with statistical significance, in that the drug was no better than placebo in terms of allowing patients to see an improvement in two cognitive measures known as ADAS-COG12 and ADCS-ADL.
This was not a huge surprise, though, because back on November 25th of 2024, the company ended up discontinuing another phase 3 study, known as RETHINK-ALZ. This 52-week late-stage trial also reported that the co-primary endpoints were not met with statistical significance. At that time, the company terminated the trial on the basis of it not achieving its intended goals.
It was a long battle for this biotech to prove that simufilam could be able to help treat patients with Alzheimer’s disease. They laid out a lot of groundwork about seeing success in prior early-stage studies in terms of biomarkers being keen, but unfortunately this didn’t translate to success in the clinic in terms of the co-primary endpoints.
Alzheimer’s disease is a progressive type of neurodegenerative disorder whereby thinking and memory skills are affected. The reason for these items being affected in a patient is because there is a buildup of abnormal protein deposits that build up on the brain. In turn, such deposits kill off brain cells and shrink the brain at the same time, leading to the symptoms that these patients then eventually experience. Speaking of symptoms, they can range from bad to worse. It can start off in a mild nature, just having forgetfulness or not recognizing particular places. After which, the nature of the disease can become so severe that the person can no longer even take care of themselves or perform daily tasks on their own.
In terms of the science here, the goal of simufilam was to bind to filamin A (FLNA), which is altered in patients with Alzheimer’s disease. Upon binding to this, the drug is intended to restore function of it and block interactions with other proteins, which are the alpha-7 nicotinic acetylcholine receptor (a7nAChR) and inflammatory receptors, respectively. Ultimately, the blocking of interactions of these proteins results in the mitigation of neuroinflammation present in this disorder.
Before the phase 3 trial failures, things were looking somewhat good for this biotech, which reported positive data from several studies. One study in particular was a Cognition Maintenance Study (CMS), in which the drug simufilam was compared with a placebo over a 6-month period in terms of a measurement used in Alzheimer’s studies known as ADAS-Cog11. This specific score measures tasks and determines disease severity. The higher the score that it is in place after evaluation, the worse the patient is in terms of disease. More importantly, any score that ends up being 18 or higher indicates cognitive impairment.
Unfortunately, investors are now left holding the bag as this small-cap biotech shifts its focus to preclinical studies evaluating simufilam’s potential in being able to treat Tuberous Sclerosis Complex-related epilepsies. While a shift in focus is the right thing to do, it remains to be seen if it can get this program into the clinic rapidly. With that being said, it could potentially be a few years before this enters the clinic, depending upon how much animal testing or preclinical work is needed to file an IND to begin phase 1 testing and beyond.
It would have been ideal if this drug worked in treating these Alzheimer’s disease patients, because treatment options are limited. Plus, the trial failure rate for developing a drug of this caliber targeting this patient population remains high. With no other pipeline in place at the moment, other than preclinical work on advancing simufilam for TSC-related epilepsies, its future is looking bleak at the moment.
TSC-related epilepsy is also known as tuberous sclerosis complex (TSC), which occurs when patients not only have seizures but are marked with cognitive disability as well. This can be broken down into other types of categories of epilepsies like focal epilepsy (seizures is in one portion of the brain) and status epilepticus (SE), where seizures just continue on without any type of recovery period. If that isn’t bad enough, such epilepsies also become what is known as treatment-resistant. Despite many anti-seizure medications being attempted to treat these patients, they don’t respond at all to them.
Surgery might be a possible option for these patients, although that’s only if the disorder is caught early enough. There has been some promise in using cannabis-derived medications in clinical testing, but it remains to be seen how effective they will truly be. The hope is that Cassava can at least pivot to this indication, since the Alzheimer’s disease drug development program has been scrapped entirely.