Cassava Sciences, Inc. (Nasdaq: SAVA) today announced final results
of a Phase 2b study with its lead drug candidate, sumifilam, in
Alzheimer’s disease. In a clinical study funded by the National
Institutes of Health (NIH), sumifilam significantly improved an
entire panel of validated biomarkers of disease in patients with
Alzheimer’s disease. The ability to improve multiple biomarkers
from distinct biological pathways with one drug has never been
shown before in patients with Alzheimer’s disease. Study results
are expected to be published in a peer-reviewed publication.
Sumifilam is the first of a new class of drug compounds that bind
to a protein called Filamin A.
“Filamin-binding molecules are new to
Alzheimer’s research and may represent an important advance if
these data can be replicated in larger studies,” said Jeffrey
Cummings, M.D., Sc.D., Founding Director of the Cleveland Clinic
Lou Ruvo Center for Brain Health, and Chambers Professor of Brain
Science at the University of Nevada, Las Vegas. “I am pleased to
see early evidence of disease-modifying effects in patients with
this investigational drug. The data appear to represent a step
forward toward urgently needed treatments for Alzheimer’s
disease.”
In addition, Alzheimer’s patients treated with
sumifilam showed directional improvements in tests of remembering
new information, versus patients on placebo. Improvements in
cognition correlated most strongly with decreases in P-tau181, a
biomarker that, when elevated, leads to tangles in the brain.
Sumifilam decreased brain levels of Ptau-181 by 8-11%, versus
placebo.
In this study, Alzheimer’s patients treated with
50 mg or 100 mg of sumifilam twice-daily for 28 days showed
statistically significant (p<0.05) improvements in biomarkers of
disease pathology, neurodegeneration and neuroinflammation, versus
Alzheimer’s patients who took placebo. In addition, Alzheimer’s
patients treated with sumifilam showed directional improvements in
validated tests of episodic memory and spatial working memory,
versus patients on placebo (Effect Sizes 46-17%). Cognitive
improvements correlated most strongly (R2=0.5) with decreases in
P-tau181. The study achieved a 98% response rate, defined as the
proportion of study participants taking sumifilam who showed
improvements in biomarkers.
“The clinical data suggest sumifilam may be
slowing disease progression in Alzheimer’s patients,” said Nadav
Friedmann, PhD/MD, Chief Medical Officer, Cassava Sciences. “This
exciting possibility will need to be evaluated in future
collaborations with patients, physicians, advisors and others.”
“Other than a few drugs to help ease the
decline, there’s really nothing out there to treat people with
Alzheimer’s,” said Remi Barbier, Chairman, President & CEO,
Cassava Sciences. “The improvement on multiple biomarkers in this
clinical study is a first and offers hope that sumifilam has
potential to become a transformative treatment for people with
Alzheimer’s disease.”
Phase 2b Study DesignPhase 2b
was a randomized, placebo-controlled, double-blind, multi-center
clinical study of sumifilam (formerly, PTI-125). Sixty-four
patients with mild-to-moderate Alzheimer’s disease, age 50-85, were
randomized (1:1:1) to 100 mg or 50 mg oral sumifilam or matching
placebo. Treatment was administered twice daily for 28 days. Nine
U.S. study sites enrolled patients. A clinical diagnosis of
Alzheimer’s disease was confirmed with the Mini-Mental State
Examination (MMSE) ≥16 to ≤26 and a CSF T-tau/Aβ42 ratio ≥0.28.
Safety was assessed by ECGs, clinical labs, adverse event
monitoring and physical examinations.
Phase 2b Study ResultsIn this
study, drug was safe and well-tolerated, with no drug-related
patient discontinuations. The study used biomarkers to measure drug
effects. Biomarkers are objective biological endpoints used to
track the progression of Alzheimer’s disease. Molecular aberrations
in the brain are reflected in biomarkers found in cerebrospinal
fluid (CSF), a fluid that surrounds the brain. A key objective of
this study was to measure changes in levels of CSF biomarkers in
study participants before and after 28 days of treatment (i.e.,
percent change from baseline).
Key biomarker results include the following (all
p-values versus placebo):
- Core markers of Alzheimer’s
pathology are total tau (T-tau), phosphorylated tau (P-tau181), and
amyloid beta42 (Aβ42). In Alzheimer’s, tau and P-tau levels are
elevated and Aβ42 is low. - T-tau decreased 15%
(p<0.01) for patients in the 50 mg drug group.- T-tau
decreased 18% (p<0.01) for patients in the 100 mg drug
group.- P-tau decreased 8% (p<0.01) for patients in the 50
mg drug group.- P-tau decreased 11% (p<0.01) for patients
in the 100 mg drug group.- Aβ42 increased 17% (p<0.01) for
patients in the 50 mg drug group.- Aβ42 increased 14%
(p<0.01) for patients in the 100 mg drug group.
- Elevated CSF levels of two
proteins, Neurogranin (Ng) and Neurofilament Light Chain (NfL)
indicate neurodegeneration. - Ng decreased 36%
(p<0.01) for patients in the 50 mg drug group.- Ng
decreased 43% (p<0.01) for patients in the 100 mg drug
group.- NfL decreased 28% (p<0.05) for patients in the 50
mg drug group.- NfL decreased 34% (p<0.01) for patients in
the 100 mg drug group.
- Proinflammatory IL-6 (Interleukin
6) is produced in response to tissue stress and injury.- IL-6
decreased 10% (p<0.01) for patients in the 50 mg drug
group.- IL-6 decreased 11% (p<0.01) for patients in the
100 mg drug group.
- Elevated levels of
neuroinflammatory marker YKL-40 indicate microglial
activation.- YKL-40 decreased 10% (p<0.01) for patients in
the 50 mg drug group.- YKL-40 decreased 12% (p<0.01) for
patients in the 100 mg drug group.
- sTREM2 is a neuroinflammation
biomarker that has commanded substantial recent attention from
researchers for its role in Alzheimer’s disease and frontotemporal
dementia. - sTREM2 decreased 43% (p<0.01) for patients in
the 50 mg drug group.- sTREM2 decreased 46% (P<0.01) for
patients in the 100 mg drug group.
A further objective of this study was to measure
drug effects on cognition. Patients were tested at baseline and
again on Day 28. Changes in episodic memory and spatial working
memory were assessed on CANTAB, a validated, computer-based battery
of tests. CANTAB is designed to measure cognitive skills regardless
of the subject’s language skills, speed, gender or education. Only
directional trends are observed, due to limitations around study
size (N=64).
Key cognition results include:
- Alzheimer’s patients in both drug
groups showed directional improvements on tests of episodic memory
and spatial memory after 28 days of treatment, versus patients on
placebo. Effect Sizes were 46-17% versus placebo.
- Episodic memory improved by -5.7 (lower score is better) for
Alzheimer’s patients in the 50 mg drug group, versus -1.5 for
patients on placebo.
- Episodic memory improved by -4.3 (lower score is better) for
Alzheimer’s patients in the 100 mg drug group, versus -1.5 for
patients on placebo.
- Spatial memory improved by -1.6 (lower score is better) for
Alzheimer’s patients in the 50 mg drug group, versus -0.4 for
patients on placebo.
- Spatial memory improved by -3.3 (lower score is better) for
Alzheimer’s patients in the 100 mg drug group, versus -0.4 for
patients on placebo.
- Improvements in cognition correlated most strongly (statistical
R2=0.5) with decreases in CSF P-tau181, a biomarker that, when
elevated, leads to tangles in the brain. Sumifilam decreased brain
levels of Ptau-181 by 8-11%, versus placebo.
Study Methods for Cerebrospinal Fluid
(CSF) BioanalysisCSF was drawn from all study participants
by lumbar puncture, an outpatient procedure used to remove a small
sample of CSF from the lower spine. Study participants underwent
two CSF draws: before treatment started and again after 28
continuous days of treatment. All CSF samples were sent to outside
labs for bioanalysis. Bioanalysis refers to a set of laboratory
tests that detect and measure very small amounts (pg/mL) of
biomarkers in CSF. Bioanalyses were conducted under blinded
conditions to eliminate any possibility of bias. An academic lab
generated final results. The validity of final results is evidenced
by robust correlations (R2=0.96, on average) between biomarker
movements over 28 days in the dataset for placebo samples, and only
small changes in biomarkers in the placebo group, as expected.
As previously disclosed, an initial bioanalysis
by a different lab showed highly anomalous data, e.g., huge swings
(in both directions) in levels of biomarkers, as well as biomarkers
moving in opposite directions in the same patients, all in the
group who took placebo for 28 days. With its validity in question,
the initial bioanalysis serves no useful purpose.
Phase 2b Study ConclusionsA
small, well-controlled study of sumifilam showed promising
treatment effects in patients with mild-to-moderate Alzheimer’s
disease. In this study, sumifilam treatment over 28 days improved
an entire panel of validated biomarkers of Alzheimer’s disease,
decreased measurements of neuroinflammation, showed a 98% responder
rate, appears safe and well-tolerated, and appears to benefit
cognition. Importantly, the data are consistent with prior clinical
and preclinical results, the drug’s mechanism of action and over 10
years of basic research.
Ongoing Open Label StudyCassava
Sciences is conducting an ongoing, long-term, open-label,
multi-center, extension study of sumifilam 100 mg twice-daily for
12 months. The study’s target enrollment is approximately 100
patients with mild-to-moderate Alzheimer’s disease, including
patients from prior studies of sumifilam. The open-label study is
currently over 50% enrolled.
About Alzheimer's Disease
Alzheimer’s disease is a progressive brain disorder that destroys
memory and thinking skills. Currently, there are no drug therapies
to halt Alzheimer’s disease, much less reverse its course. In the
U.S. alone, approximately 5.8 million people are currently living
with Alzheimer’s disease, and approximately 487,000 people age 65
or older developed Alzheimer’s in 2019.1 The number of people
living with Alzheimer’s disease is expected to grow dramatically in
the years ahead, resulting in a growing social and economic
burden.2
About SumifilamSumifilam is a
proprietary, small molecule (oral) drug that restores the normal
shape and function of altered filamin A (FLNA), a scaffolding
protein, in the brain. Altered FLNA in the brain disrupts the
normal function of neurons, leading to Alzheimer’s pathology,
neurodegeneration and neuroinflammation. The underlying science for
sumifilam is published in peer-reviewed journals, including Journal
of Neuroscience, Neurobiology of Aging, Journal of Biological
Chemistry, Neuroimmunology and Neuroinflammation and Journal of
Prevention of Alzheimer’s Disease. The Company is also developing
an investigational diagnostic, called SavaDx, to detect Alzheimer’s
disease with a simple blood test.
Sumifilam and SavaDx were both developed
in-house. Both product candidates are substantially funded by
peer-review research grant awards from the National Institutes of
Health. 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.
Patent protection in this area currently runs beyond 2037, plus
extensions, and includes seven issued patents and related patent
filings and applications.
About Cassava Sciences,
Inc.Cassava Sciences’ mission is to discover and develop
innovations for chronic, neurodegenerative conditions. Over the
past 10 years, Cassava Sciences has combined state-of-the-art
technology with new insights in neurobiology to develop novel
solutions for Alzheimer’s disease. For more information, please
visit: https://www.CassavaSciences.com
For More Information
Contact:Eric Schoen, Chief Financial OfficerCassava
Sciences, Inc.eschoen@CassavaSciences.com(512) 501-2450
Cassava Sciences’ Phase 2b study of sumifilam in
Alzheimer’s disease was funded by clinical research grant #AG060878
from the National Institutes of Health (NIH/NIA).
The content of this press release is solely the
responsibility of Cassava Sciences and does not necessarily
represent the official views of the NIH/NIA.
Cautionary Note Regarding
Forward-Looking Statements: This press release contains
“forward-looking statements” for purposes of the Private Securities
Litigation Reform Act of 1995 (the Act). Cassava Sciences claims
the protection of the Safe Harbor for forward-looking statements
contained in the Act. All statements other than statements of
historical fact contained in this press release including, but not
limited to, statements regarding the status of current and
future clinical studies with sumifilam; the interpretation of
results of our Phase 2 clinical studies including cognition data
and plans to publish results in a peer-reviewed journal; potential
health benefits, if any, of changes in levels of biomarkers; verbal
commentaries made by Cassava Sciences’ employees and scientific
advisors; and potential benefits, if any, of the Company’s product
candidates for Alzheimer’s disease are forward-looking
statements. Such statements are based largely on the Company’s
current expectations and projections about future events. Such
statements speak only as of the date of this press 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 Cassava Sciences’ Annual Report on Form 10-K for the
year ended December 31, 2019 and future reports to be filed with
the SEC. In light of these risks, uncertainties and assumptions,
the forward-looking statements and events discussed in this press
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, the
Company disclaims any intention or responsibility for updating or
revising any forward-looking statements contained in this press
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.
1,2 Source: Alzheimer’s Association. 2019 Alzheimer’s Disease
Facts and Figures. Available online at:
https://www.alz.org/media/documents/alzheimers-facts-and-figures-2019-r.pdf
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