Have we Finally Found a Good Treatment for Alzheimer’s Disease?

Simufilam is an experimental drug developed for the treatment of Alzheimer’s disease. It works by targeting altered Filamin A (FLNA), whose dysfunction causes inflammation in the brain through signaling of Aß42. Simufilam binds altered FLNA, restores its proper shape and function, reducing neurodegeneration and neuroinflammation and preventing abnormal protein accumulation in the brain, which are associated with the progression of Alzheimer’s. Clinical trials are ongoing to assess its effectiveness and safety in treating this neurodegenerative condition, and it represents a potential hope for Alzheimer’s patients.

Recent Results Promising?

At the recent presentation at CTAD (Clin. Trials on Alz. Disease) of Cassava Sciences’ Cognition Maintenance Study (CMS), the results appeared lackluster, and for good reason. In this trial, patients with mild and moderate Alzheimer’s were given simufilam in a open label trial for 12 months. On the recommendation of the FDA, a randomized withdrawal trial with placebo vs. simufilam for 6 months was added. Basically, the FDA said, “Wow, these open label (without a placebo) trials look good, let’s try and turn this into a randomized trial by extending it with a placebo arm.”

As in the graph above, there is a definite difference between moderate and mild AD groups. There seems to be an improvement in the simufilam groups vs. placebo, but these differences were not statistically significant. This is where the lackluster results should have been anticipated. If simufilam does indeed have a disease-modifying effect, we would expect some lasting benefits from the drug after taking it for one year, even if the drug is stopped for 6 months.

Another Look at Simufilam

To look at this another way, I compared the CMS results with data from the ADNI (AD neuroimaging) database, to create some “placebo groups” from 0–18 months, for a better comparison of the CMS patients to those who had never received simufilam. Patients from the ADNI database were categorized based on the mini mental exam (MMSE) scores used in the CMS, for categories of mild (21–30) and moderate (10–20) Alzheimer’s Disease. ADNI also includes patients with mild cognitive impairment (MCI), which is even more mild, so if any effect is seen in those receiving simufilam compared to the ADNI, that should be significant.

Mild Alzheimer’s Disease

Based on my limited time, I did not run statistical comparisons, but plotted the means just to get a visual representation of what is happening. In the mild group, the baseline ADAS-Cog (a test for AD that gives points for each error) for the ADNI group was lower than the CMS patients, which was helpful to see if any effect exists. Over 18 months, the ADNI group increased in its ADAS-Cog scores, which is expected in AD. The more severe AD patients with increase even more quickly. In the open-label simufilam patients with mild AD, ADAS-Cog scores decreased, which is generally unheard of in Alzheimer’s trials. The recently approved AD drugs slowed the decline of mild patients, but there was no improvement. In the CMS, at 12 months the patients were randomized to either simufilam or placebo. From 12–18 months, the simufilam patients continued to improve, while those receiving placebo began to worsen. It is interested to note, just visually, that the slope of the placebo patients is similar to the ADNI group.

Moderate Alzheimer’s Disease

The moderate groups for the ADNI was similarly lower than the simufilam moderate patients, which was good as a starting point to get a rough idea of any change. It appears that those receiving simufilam had less worsening compared to those receiving placebo. As stated in the CTAD presentation, these were not statistically significant. It is nice however, to have a visual comparison to get a feel for the changes. When comparing the results to the ADNI, it is interesting to see how the less severe “placebo” ADNI patients have worsening that catches up to the simufilam group (see the gray and blue lines above). This pattern usually doesn’t happen in real life. Usually more severe AD patients worsen more quickly than those with milder disease. The same change in slope of the placebo lines is also notable here, where those receiving placebo seem to have their slope of decline start to match the ADNI. While this is not a rigorous scientific study, I believe it signals that something important is happening here.

Hope for Alzheimer’s Disease Sufferers

While the statistical analysis here is lacking, and the analysis that was performed showed no difference, I believe we can see the difference in those treated with simufilam when compared to historical placebo groups. Just the visual impact comparing these groups is striking. With simufilam currently in phase 3 clinical trials, we will no doubt see a difference in AD patients (especially mild patients, who represent 60–70% of these trials) treated with simufilam vs. placebo. This is an exciting time for those struggling with AD and their family members. I have referred patients to these clinical trials, but they are currently fully enrolled, so we will have to wait for this medicine to become available. Simufilam will probably be a preventive medicine for AD, so if I could, I would take it myself. Only time will tell whether the clinical trials show these expected results and whether the FDA will approve the drug.

For full transparency, I do own shares in Cassava Sciences (SAVA), the developer of simufilam.