Cassava Sciences, Inc. (Nasdaq: SAVA), a biotechnology company,
today announced top-line clinical results from its Cognition
Maintenance Study (CMS). The CMS is a small proof-of-concept study
designed to demonstrate the effects of drug versus placebo in a
randomized withdrawal trial design. The study enrolled 157 patients
with mild-to-moderate Alzheimer’s disease, a more advanced and
difficult-to-treat stage of disease.
In this double-blind, placebo-controlled,
randomized study, all patients first received open-label simufilam
100 mg for 12 months; patients were then randomized (1:1) to
receive either simufilam 100 mg or placebo for 6 months. 16 U.S.
clinical sites participated. The CMS had one pre-specified
cognitive endpoint: mean change in ADAS-Cog11 scores over 6 months,
drug versus placebo.
Simufilam treatment for 6 months slowed
cognitive decline by 38% compared to placebo in mild-to-moderate
Alzheimer’s disease (MMSE 16-26). The placebo arm declined
1.5 points on ADAS-Cog, and this arm declined at all measured
timepoints. The simufilam arm declined 0.9 points on ADAS-Cog, a
38% difference in favor of drug at month 6 (95% CI, – 2.1 to 1.0;
not significant for sample sizes). See Table 1 and Chart 1.
Table 1: Results of Randomized Withdrawal Study –
cognitive change, full analysis set (FAS)
Full Analysis Set |
Simufilam 100 mg(N = 78) |
Placebo(N = 77) |
Numerical Difference |
Percent Difference |
6-month Change inADAS-Cog |
0.9 pointDecline |
1.5 pointDecline |
– 0.6 |
38% in favor of drug |
Upon randomization into the CMS, mean baseline
MMSE scores were 18.6 and 18.1 for the simufilam and placebo arms,
respectively. Mean baseline ADAS-Cog scores were 19.3 and 21.9 for
the simufilam and placebo arms, respectively.
“Monoclonal antibody drugs have slowed cognitive
decline by 35% or less in early Alzheimer’s patients in large Phase
3 trials over 18 months,” said James Kupiec, MD, Chief Medical
Officer. “In this context, we believe results of our 6-month study
are encouraging, despite vast differences in patient selection and
the design and results of our randomized withdrawal study compared
to large Phase 3 trials.”
Simufilam Drug Effects Favored Patients
with Mild Alzheimer’s Disease.
Simufilam treatment for 6 months slowed
cognitive decline > 200% compared to placebo in
mild Alzheimer’s disease. CMS
patients with mild Alzheimer’s (MMSE 21-26) on placebo declined 0.6
points on ADAS-Cog over 6 months as a group. CMS patients with mild
Alzheimer’s on simufilam improved 0.6 points over 6 months as a
group, a 205% difference in favor of drug (95% CI, – 2.6 to 0.4;
not significant for sample sizes). See Table 2 and Chart 2.
Table 2: Results of Randomized
Withdrawal Study – cognitive change, mild patients
Mild Patients |
Simufilam 100 mg(N= 40) |
Placebo(N= 36) |
Numerical Difference |
Percent Difference |
6-month Change in ADAS-Cog |
0.6 pointImprovement |
0.6 pointDecline |
– 1.1 |
205% in favor of drug |
“Patients started out taking open-label
simufilam for 12 months prior to enrolling in the CMS,” said Remi
Barbier, President & CEO. “CMS patients on placebo were, in
effect, withdrawn from simufilam for 6 months. This placebo arm
declined while the CMS arm randomized to simufilam improved. We
believe the emerging separation of cognitive scores between these
two arms represents a drug effect.”
Suzanne Hendrix, PhD, CEO of Pentara
Corporation, added: “Results for simufilam continue to be
noteworthy. The lack of disease progression in cognition, as
measured by the ADAS-Cog over 18 months of treatment in mild
patients, is well outside the range in historic placebo decline
rates from numerous other studies. The placebo group in the CMS has
started to decline again but continues to maintain benefit over
historical placebo groups.”
Upon randomization into the CMS, mean baseline
MMSE scores for mild patients were MMSE 24.0 and MMSE 24.1 for the
simufilam and placebo arms, respectively. Mean baseline ADAS-Cog
scores for mild patients were 11.0 and 11.2 for the simufilam and
placebo arms, respectively.
Simufilam for 18 months stabilized
cognition in mild Alzheimer’s
disease.After taking open-label simufilam for 12 months,
76 patients with mild Alzheimer’s disease (MMSE 21-26) enrolled in
the CMS and were randomized to receive either simufilam (N=40) or
placebo (N=36) for 6 months. Mild patients randomized to simufilam
in the CMS showed no material decline in ADAS-Cog scores over 18
months as a group, indicating stable cognition. Mild patients
randomized to placebo in the CMS (and therefore withdrawn from
simufilam treatment for 6 months) declined by 0.8 points in
ADAS-Cog as a group. See Figure 1.
Figure 1. Historical declines on
ADAS-Cog over 18 months in Alzheimer's disease (MMSE 20-30),
placebo arms vs simufilam treatment.1
Notes: results shown for CLARITY P3 trial of lecanemab; EMERGE and
ENGAGE P3 studies of aducanumab; and TRAILBLAZER P3 trial of
donanemab; in this figure, the CMS is referred to as the
‘PTI-125-04’ study; ‘Simufilam100mg-Simufilam100mg’ refers to
patients who received simufilam in both the open-label phase and
the CMS; ‘Simufilam100mg-Placebo’ refers to patients who received
simufilam in the open-label phase and placebo in the CMS.
Safety DataSimufilam 100 mg
twice daily was safe and well tolerated in this study. There were
no drug-related serious adverse events. No treatment-emergent
adverse events (TEAEs) occurred in 5% or more of study participants
in the CMS.
DiscussionThe CMS was a
randomized withdrawal study. Patients who completed 12 months of
open-label simufilam treatment were all invited to participate in
the CMS. It is not known how long a washout period may be needed to
remove lingering drug effects, if any, from prior treatment with
open-label simufilam for 12 months.
In this small study of oral simufilam in
patients with mild-to-moderate Alzheimer’s disease, the
pre-specified cognitive endpoint showed a 38% decline in ADAS-Cog
over six months in favor of simufilam, with good drug safety.
Effects were pronounced in mild patients. Mean baseline MMSE and
ADAS-Cog scores were approximately balanced given the small size of
each arm.
Analysis of Efficacy
EndpointsThe pre-specified cognition endpoints were
analyzed by Pentara Corporation, an independent consulting firm
that specializes in complex statistical analysis of clinical trial
results. Suzanne Hendrix, PhD, CEO of Pentara, has over 150
peer-reviewed publications of clinical trial results and
statistical approaches for clinical trials, many focusing on
statistical methodology for Alzheimer’s disease.
Chain of Custody for Clinical
DataInvestigator sites collected clinical data from study
participants. 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 for analysis.
Study LimitationsThe CMS is a
proof-of-concept study involving a small number of patients and
limited data. Top-line clinical CMS results 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 Phase 3 studies. The limited size of
the CMS 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 CMS study add complexity or limitations to the
scope of data interpretation. In addition, ‘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 CMS findings prior to us receiving the
final dataset. Final data may change from today’s top-line
data.
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 large, 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.
Patient enrollment is expected to be completed
for both Phase 3 studies by yearend 2023.
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)
501-2450ESchoen@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: the design, scope, conduct or
intended purpose of our randomized withdrawal study or Phase 3
program of simufilam in patients with Alzheimer's disease; the
ability of simufilam to provide patients with drug effects; the
apparent ability of simufilam to favor patients with mild
Alzheimer’s disease; the safety or tolerance of simufilam in the
CMS clinical trial; our current expectations regarding timing of
and the target patient enrollment numbers for our Phase 3 studies;
any expected clinical results of Phase 3 studies; the treatment of
people with Alzheimer’s disease dementia; the safety or efficacy of
simufilam in people with Alzheimer’s disease dementia; comments
made by our employees regarding simufilam, drug effect, 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.
Simufilam is our investigational product
candidate. It is not approved by any regulatory authority in any
jurisdiction and its safety, efficacy or other desirable attributes
have not been established in patients.
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. Clinical
results from our prior studies may not be indicative of results of
future 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, any unanticipated impacts of inflation 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, 2022, 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.
This news release may also contain statistical
data and drug information based on independent industry
publications or other publicly available information. We have not
independently verified the accuracy or completeness of the data
contained in these publicly available sources of data and
information. Accordingly, we make no representations as to the
accuracy or completeness of such data or information. You are
cautioned not to give undue weight to such data.
The content of this presentation is solely our
responsibility and does not represent the official views of the
National Institutes of Health or any other government agency.
___________________________________
1 Figure 1: Forest plot by Pentara Corporation.
Data was sourced from the placebo groups in randomized, controlled
trials of monoclonal antibodies conducted by other sponsors in
Alzheimer’s disease (MMSE 20-30).
Photos accompanying this announcement are available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/c920d107-3c33-450a-b801-48b008614378
https://www.globenewswire.com/NewsRoom/AttachmentNg/35197b1c-ad89-4067-b692-2163afc22158
https://www.globenewswire.com/NewsRoom/AttachmentNg/bb23047a-5f15-4047-b402-c3cce6d70290
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