Cassava's Mixed Alzheimer's Data Underwhelms Investors (Updated)

Alzheimers concept

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The saga of Cassava Sciences' Alzheimer’s candidate simufilam continued Tuesday as the South San Francisco-based company reported results from a Phase II study that underwhelmed investors.

While Cassava touted “positive” top-line results from the study of more than 200 patients with mild-to-moderate Alzheimer’s disease, changes in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores were minimal. The company’s stock dropped 17% following the reveal.

Over the course of one year, 47% of patients saw a 4.7-point improvement on the ADAS-Cog. Another 23% experienced a decline of 2.5 points.

Simufilam had a greater effect on patients with mild AD than on those with moderate disease. Participants with mild disease saw their scores improve from 15.0 to 12.6, while their moderately-afflicted counterparts experienced a decline from 25.7 to 30.1.

In Tuesday’s press release, Cassava claimed ADAS-Cog scores that change minimally (or improve) over 1 year is a “highly desirable outcome.” Not all of the numbers were positive, however.

The study’s primary endpoint was a change from baseline on the ADAS-Cog, while exploratory endpoints included the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI10) and Geriatric Depression Scale (GDS).

From baseline to 12 months, mean scores changed from:

  • 19.1 to 19.6 on the ADAS-Cog11
  • 21.5 to 20.2 on the MMSE
  • 3.2 to 2.9 on the NPI10 (indicating reduced dementia-related neuropsychiatric symptoms)
  • 1.8 to 1.4 on the GDS

Simufilam was safe and well-tolerated, Cassava reported.

Remi Barbier, president and CEO of Cassava, expressed excitement with the results, saying in a prepared statement that they “add strength and determination” to the company’s goal of helping people fight AD.

Suzanne Hendrix, Ph.D., president and CEO of Pentara Corp., a healthcare data management organization, called the data “noteworthy”.

“The improvement in ADAS-Cog over one year in mild patients taking simufilam is well outside the expected range of historic placebo decline rates from numerous other studies,” she said in a prepared statement.

Pentara assisted in analyzing the Phase II results.

Laura Nisenbaum, Ph.D., executive director of drug development at the Alzheimer's Drug Discovery Foundation, agreed that an improvement or minimal change in ADAS-Cog scores is a desirable outcome. 

"However, it’s important to keep in mind that the current results come from an open-label safety study, which means that all patients, caregivers and doctors know that the patients were receiving [the] drug," she told BioSpace in an e-mailed statement. 

"Thus, while the results are potentially promising, they need to be interpreted with caution."

Nisenbaum said placebo-treated patients show worsening of about 4 points in 12 months and that preventing this worsening would be viewed as a good result.

"However, it is difficult to assess improvement in this study due to the lack of placebo-controlled group," she said.  

Cassava anticipates topline results from a Cognition Maintenance Study of simufilam in 2023. Beyond this, Eric Schoen, CFO, told BioSpace the company's next steps are the completion of ongoing Phase III studies of simufilam. 

These include the REFOCUS-ALZ and RETHINK-ALZ studies, both of which are currently recruiting, according to ClinicalTrials.gov

A Challenging 18 Months

The mixed mid-stage results follow a challenging 18-month period in which Cassava was hit with allegations of data manipulation in relation to research conducted on simufilam. The company was later cleared by the Journal of Prevention of Alzheimer's Disease and subsequently filed a lawsuit against the accusers.

The allegations were brought in a Citizen’s Petition by two neuroscientists who claimed simufilam research included images of experiments that appeared to have been manipulated.

In its lawsuit, Cassava countered that the defendants, short sellers, were trying to profit off the resulting stock declines.

More recently, Cassava mourned the loss of company officer and board member Nadav Friedmann, Ph.D., M.D., who died from cancer in December. 

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