Cassava Sciences, Inc. (Nasdaq: SAVA), a biotechnology company,
today announced positive top-line Phase 2 results for simufilam,
its oral drug candidate for Alzheimer’s disease dementia. This was
an open-label safety study with exploratory efficacy endpoints. The
study enrolled over 200 patients with mild-to-moderate Alzheimer’s
disease (MMSE 16-26). Study participants were administered
open-label simufilam tablets 100mg twice daily for 1 year or more.
Endpoints were measured at baseline (study entry) and month 12.
Top-line Results – mean scores, baseline
to month 12 (lower is better, except for MMSE):
- ADAS-Cog11
scores changed from 19.1 (±9.2) to 19.6 (±13.3)
- MMSE scores
changed from 21.5 (±3.6) to 20.2 (±6.4)
- NPI10 scores
changed from 3.2 (±4.6) to 2.9 (±4.6)
- GDS scores
changed from 1.8 (±1.8) to 1.4 (±1.9)
Alzheimer’s is a degenerative disease of the
brain. Over time, cognition progressively worsens in the
mild-to-moderate stages of Alzheimer’s as the disease takes its
toll. ADAS-Cog scores that change minimally (or improve) over 1
year is a highly desirable outcome in a clinical study of
mild-to-moderate Alzheimer’s disease.
Figure 1 presents a model of historical declines
on ADAS-Cog in patients with mild-to-moderate Alzheimer’s
disease.
Figure 1: Statistical model of
historical 1-year declines on ADAS-Cog, placebo vs simufilam
treatment, mild-to-moderate disease.1
Response Analysis – baseline to month
12
- ADAS-Cog scores
improved in 47% of patients; this group had a mean change of -4.7
(±3.8) points (lower is better).
- In an additional
23% of patients, ADAS-Cog declined less than 5 points; this group
had a mean change of 2.5 (±1.4) points.
- Patients with
an NPI10 score of zero increased from 42% to 54%, indicating
reduced dementia-related neuropsychiatric symptoms.
“I’m very excited about these 1-year data,” said
Remi Barbier, President & CEO. “They add strength and
determination to our goal of helping people fight Alzheimer’s
disease. Simufilam is an innovative drug candidate that we are
developing methodically, one study at a time, and this open-label
safety study served its purpose. Next up in 2023 are top-line
clinical results of our Cognition Maintenance Study, which is a
randomized, controlled trial.”
Analysis of Efficacy
EndpointsEfficacy outcomes were analyzed by an
independent, outside biostatistical consulting firm led by Suzanne
Hendrix, PhD. The pre-specified primary efficacy endpoint was
change in baseline on ADAS-Cog, a cognitive scale widely used in
Alzheimer’s clinical research. Exploratory endpoints included the
Mini-Mental State Examination (MMSE) to assess disease stage by
cognitive impairment; the Neuropsychiatric Inventory (NPI10) to
assess dementia related behavior; and the Geriatric Depression
Scale (GDS). The Full Analysis Set (FAS) population (N=216) was
used for the statistical analysis of efficacy endpoints.
Alzheimer’s is a progressive disease. Severity
of disease is typically assessed by MMSE score. In this study, mild
patients are MMSE 21-26; moderate patients are MMSE 16-20. Mild and
moderate sub-groups showed notable differences on changes in
ADAS-Cog mean scores, baseline to month 12 (lower is better):
- In the mild sub-group, ADAS-Cog
scores improved, from 15.0 (±6.3) to 12.6 (±7.8)
- In the moderate sub-group, ADAS-Cog
scores worsened, from 25.7 (±9.2) to 30.1 (±13.1)
“The data for simufilam are noteworthy,” said
Suzanne Hendrix, PhD. “The improvement in ADAS-Cog over 1 year in
mild patients taking simufilam is well outside the expected range
of historic placebo decline rates from numerous other studies.”
Figure 2 presents a model of historical declines
on ADAS-Cog in early disease and mild disease.
Figure 2: Statistical model of historical
1-year declines on ADAS-Cog, placebo vs simufilam treatment, in
early disease and mild disease.2
Safety DataSimufilam 100 mg
twice daily was safe and well tolerated. There were no drug-related
serious adverse events. Three treatment-emergent adverse events
(TEAEs) occurred in 7% or more of study patients: COVID-19 (12%),
urinary tract infection (10%) and headache (9%). Reported TEAEs are
based on all study patients who received at least one dose of drug.
The top three reasons for patient discontinuations were withdrawal
of informed consent (N=14), adverse events (N=13) and patient
non-compliance (N=7).
Biomarker Data‘Research use
only’, non-safety, exploratory biomarkers were analyzed from
cerebrospinal fluid (CSF) collected from 25 patients in the
open-label study who agreed to undergo a lumbar puncture at
baseline and again after 6 months of treatment. CSF samples were
analyzed blind by our academic collaborator at City University of
New York (CUNY). We previously announced results of this
bioanalysis in a press release dated July 29, 20213 (p-values shown
below are baseline vs. 6-month levels by paired t-test):
- CSF biomarkers
of disease pathology, t-tau and p-tau181, decreased 38% and 18%,
respectively (both p<0.00001).
- CSF biomarkers
of neurodegeneration, neurogranin and neurofilament light chain
(NfL), decreased 72% and 55%, respectively (both
p<0.00001).
- CSF biomarkers
of neuroinflammation, sTREM2 and YKL-40, decreased 65% and 44%
(both p<0.00001).
Of the 25 patients who provided 6-month CSF
samples, 24 subsequently completed 1 year of treatment with
open-label simufilam. This sub-set of patients improved -4.96 mean
points on ADAS-Cog from baseline to month 12 (ad hoc analysis
conducted internally; lower is better). We have not conducted
further CSF sample analyses in the open-label study.
Chain of Custody for Clinical
DataInvestigator sites collected clinical data from study
patients. Sites entered their clinical data directly into an
electronic data capture system managed by an independent, outside
data management vendor. The data management vendor also maintains
the clinical database. The data management vendor transmitted the
clinical database directly to Pentara Corporation, an independent,
outside consulting firm that specializes in complex statistical
analysis of clinical trial results. Suzanne Hendrix, PhD, CEO of
Pentara, has >150 peer-reviewed publications of clinical trial
results and statistical approaches for clinical trials, many
focusing on statistical methodology for Alzheimer’s disease.
Study LimitationsData results
from our open-label safety study do not constitute, and should not
be interpreted as, regulatory evidence of safety or efficacy for
simufilam in Alzheimer’s disease. Rigorous evidence for drug safety
and efficacy is derived from one or more large, randomized,
placebo-controlled studies. The open-label design and size of this
study may introduce clinical or statistical bias or may generate
results that may not fully distinguish between drug effects and
random variation. Different methods of statistical analysis on
clinical data from the same study may lead to objectively different
numerical results. These and other statistical and clinical
features of our open-label study add complexity or limitations to
the scope of data interpretation.
‘Top-line data’ is a summary of the clinical
data prior to the completion of a full and final audit or
quality-control of the clinical database. We are communicating
top-line data so that stakeholders may have timely access to a
summary of the study’s findings prior to us receiving the final
dataset. Final data may change from today’s top-line data. We
expect to disclose the final dataset in a future medical conference
or science publication.
On-going Phase 3 Studies with
SimufilamCassava Sciences is currently evaluating
simufilam tablets for Alzheimer’s disease dementia in two Phase 3
clinical studies. These are randomized, double-blind,
placebo-controlled trials. The Phase 3 program is recruiting a
total of approximately 1,750 patients with mild-to-moderate
Alzheimer’s disease who also meet other study eligibility criteria.
Both Phase 3 studies have received a Special Protocol Assessment
(SPA) from the U.S. Food and Drug Administration. The Phase 3
studies are actively recruiting Alzheimer's patients in over 100
clinical sites in the United States, Canada, Puerto Rico, South
Korea and Australia.
About SimufilamSimufilam is
Cassava Sciences’ proprietary, small molecule (oral) drug candidate
that restores the normal shape and function of altered filamin A
(FLNA) protein in the brain. Cassava Sciences owns worldwide
development and commercial rights to its research programs in
Alzheimer’s disease, and related technologies, without royalty
obligations to any third party.
About Cassava Sciences,
Inc.Cassava Sciences is a clinical-stage biotechnology
company based in Austin, Texas. Our mission is to detect and treat
neurodegenerative diseases, such as Alzheimer’s disease. Our novel
science is based on stabilizing—but not removing—a critical protein
in the brain. Our product candidates have not been approved by any
regulatory authority, and their safety, efficacy or other desirable
attributes have not been established.
For more information, please visit:
https://www.CassavaSciences.com
For More Information Contact: Eric Schoen,
Chief Financial Officer(512) 501-2450, or
eschoen@CassavaSciences.com
Cautionary Note Regarding
Forward-Looking Statements:This news release contains
forward-looking statements, including statements made pursuant to
the safe harbor provisions of the Private Securities Litigation
Reform Act of 1995, relating to: our current expectations regarding
the target patient enrollment numbers for our Phase 3 studies; our
goals regarding timing for releasing top-line data for the
Cognition Maintenance Study; comments made by our employees
regarding simufilam and the treatment of Alzheimer’s disease; and
potential benefits, if any, of our product candidates. These
statements may be identified by words such as “may,” “anticipate,”
“believe,” “could,” “expect,” “would”, “forecast,” “intend,”
“plan,” “possible,” “potential,” and other words and terms of
similar meaning.
Drug development involves a high degree of risk,
and only a small number of research and development programs result
in regulatory approval and commercialization of a product. Our
interim data and analyses should not be relied upon as predictive
of full study results for any of our studies. Our clinical results
from earlier-stage clinical trials may not be indicative of full
study results, or results from later-stage, or larger scale
clinical trials, and do not ensure regulatory approval. You should
not place undue reliance on these statements or any scientific data
we present or publish.
Such statements are based largely on our current
expectations and projections about future events. Such statements
speak only as of the date of this news release and are subject to a
number of risks, uncertainties and assumptions, including, but not
limited to, those risks relating to the ability to conduct or
complete clinical studies on expected timelines, to demonstrate the
specificity, safety, efficacy or potential health benefits of our
product candidates, the severity and duration of health care
precautions given the COVID-19 pandemic, any unanticipated impacts
of the pandemic on our business operations, and including those
described in the section entitled “Risk Factors” in our Annual
Report on Form 10-K for the year ended December 31, 2021, and
future reports to be filed with the SEC. The foregoing sets forth
many, but not all, of the factors that could cause actual results
to differ from expectations in any forward-looking statement. In
light of these risks, uncertainties and assumptions, the
forward-looking statements and events discussed in this news
release are inherently uncertain and may not occur, and actual
results could differ materially and adversely from those
anticipated or implied in the forward-looking statements.
Accordingly, you should not rely upon forward-looking statements as
predictions of future events. Except as required by law, we
disclaim any intention or responsibility for updating or revising
any forward-looking statements contained in this news release. For
further information regarding these and other risks related to our
business, investors should consult our filings with the SEC, which
are available on the SEC's website at www.sec.gov.
1 Figure 1: Forest plot meta-analysis model by
Pentara Corporation. Data was sourced from randomized, controlled
trials conducted by other sponsors in patients with
mild-to-moderate Alzheimer’s disease.
2 Figure 2: Forest plot meta-analysis model by
Pentara Corporation. Data was sourced from non-randomized studies
(i.e., ADNI) and randomized, controlled trials conducted by other
sponsors in patients with early (i.e., MCI + mild) and mild
Alzheimer’s disease.
3 Statistical analysis on changes in CSF biomarkers was
conducted internally; press release is available on-line:
https://www.cassavasciences.com/node/15486/pdf.
Photos accompanying this announcement are available
athttps://www.globenewswire.com/NewsRoom/AttachmentNg/eff72f31-4f4c-4fae-94ca-50d517abcdb6
https://www.globenewswire.com/NewsRoom/AttachmentNg/595f0219-0f9e-43c6-b7a0-4b26dbcbd147
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