Early, Sustained and Statistically Significant
Reduction in Plasma P-tau181 Reaching 31% at 24 Months Observed in
Carriers of One or Two Copies of APOE4 Gene, who Represent Two
Thirds of Alzheimer’s Patients
Preservation of Hippocampal Volume Compared to
External Control of Matched Subjects from Alzheimer’s Disease
Neuroimaging Initiative Suggests Neuroprotective Effects on Brain
Structures
Improvement on Cognitive Tests at 6 Months and
Sustained Stabilization of Cognition Above Baseline for 24 Months
Consistent with Biomarker & Brain Imaging Effects on Core
Alzheimer’s Pathologies
Quantitative Systems Pharmacology Analysis of
Amyloid Fluid Biomarkers and Cognitive Benefits Supports
ALZ-801/Valiltramiprosate Target Engagement, and Potential for
Disease Modification and Clinical Efficacy
Topline Data from Pivotal APOLLOE4 Phase 3
Trial and Initiation of Regulatory Filings for Valiltramiprosate
Expected in 2H 2024
Alzheon, Inc., a clinical-stage biopharmaceutical company
developing a broad portfolio of product candidates and diagnostic
assays for patients suffering from Alzheimer’s disease (AD) and
other neurodegenerative disorders, today announced two scientific
publications of results from the Phase 2 biomarker trial showing
statistically significant and clinically relevant reduction in
plasma biomarkers of neurodegeneration, preservation of brain
volume, and positive cognitive effects in Early AD patients who are
carriers of apolipoprotein ε4 allele (APOE4) following 24 months of
treatment with investigational oral agent
ALZ-801/valiltramiprosate.
The research papers, “Effects of Oral ALZ-801/Valiltramiprosate
on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition:
Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4
Carriers with Early Alzheimer’s Disease” and “Analysis of
Cerebrospinal Fluid, Plasma β-Amyloid Biomarkers, and Cognition
from a 2-Year Phase 2 Trial Evaluating Oral
ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s
Disease Using Quantitative Systems Pharmacology Model” were
published in the scientific journal Drugs, and are available
through open access at: https://doi.org/10.1007/s40265-024-02067-8
and https://doi.org/10.1007/s40265-024-02068-7, respectively.
“The two new seminal papers showcase Alzheon’s scientific
leadership in understanding of the pathogenesis of Alzheimer’s
disease and provide support for the single toxin theory of brain
neurodegeneration, our thesis that the aggregation of misfolded
native proteins initiates and drives the pathogenic cascade that
leads to Alzheimer’s disease and other age-related
neurodegenerative disorders. In addition, our new analyses further
strengthen the growing body of evidence for ALZ-801’s potential as
the first oral disease-modifying therapy,” said Martin Tolar, MD,
PhD, Founder, President, and CEO of Alzheon, and the senior author
of both publications. “Valiltramiprosate is the most advanced of
the next generation of highly selective anti-oligomer agents in
development and these efficacy data, combined with a favorable
safety profile showing no increased risk of vasogenic edema,
underscore the differentiated clinical profile of our lead agent.
We look forward to further validation of these findings from the
ongoing pivotal APOLLOE4 Phase 3 trial in APOE4/4 homozygotes that
is expected to report in the third quarter of 2024.”
ALZ-801/valiltramiprosate is an investigational oral
disease-modifying therapy in Phase 3 development for the treatment
of Early AD. In mechanism of action studies, ALZ-801 fully blocked
the formation of neurotoxic soluble beta amyloid (Aβ) oligomers at
the Phase 3 clinical dose. ALZ-801 has shown both potential for
clinical efficacy in the highest-risk and most fragile Alzheimer’s
population – patients with two copies of the apolipoprotein ε4
allele (APOE4/4 homozygotes) and favorable safety with no increased
risk of vasogenic brain edema. This population is the focus of the
pivotal 78-week APOLLOE4 Phase 3 trial, which is fully enrolled
with topline data expected in the third quarter of 2024.
The Phase 2 biomarker study was designed to inform the
development of ALZ-801 in the broader population of APOE4 carriers,
which represents ~65% of all patients with AD. The open-label,
multicenter, single-arm Phase 2 trial evaluated the effects of
ALZ-801 265 mg administered orally twice daily on plasma AD
biomarkers, hippocampal volume (HV) as measured by magnetic
resonance imaging (MRI), and clinical tests of learning and memory,
as well as safety and tolerability, over 104 weeks. The trial
enrolled 84 patients ages 50 to 80 years with early AD (MMSE
22-30), who carry either one or two copies of the ε4 allele of the
apolipoprotein E gene (APOE3/4 heterozygotes and APOE4/4
homozygotes, respectively), and showed positivity for amyloid and
tau biomarkers in cerebrospinal fluid (CSF). APOE4 genotype, the
leading risk factor for AD after aging, is associated with a
several-fold higher risk of symptomatic AD and higher brain burden
of neurotoxic amyloid oligomers and of aggregated amyloid in
cerebral microvasculature (cerebral amyloid angiopathy, CAA). The
study was designed to provide evidence of target engagement to
support initiation of a pivotal Phase 3 trial in APOE4
carriers.
“The published data from our Phase 2 study
reinforce the potential benefits of ALZ-801 in patients with early
symptomatic Alzheimer’s disease who are APOE4 carriers. Study
participants experienced a significant positive impact on core
biomarkers of AD pathology, hippocampal brain atrophy and cognitive
decline over two years of treatment with ALZ-801,” said John Hey,
PhD, Chief Scientific Officer of Alzheon and the lead author of
both publications. “In addition, the quantitative systems
pharmacology biomarker analysis supports ALZ-801 target engagement
and suggests potential for disease modification and meaningful
clinical efficacy in Alzheimer’s patients with APOE4 genotype.
These are encouraging results, given that this high-risk AD patient
population typically experiences rapid cognitive decline and
disease progression. Our goal is to bring valiltramiprosate to
these patients as the first potential oral disease-modifying
therapy, and we look forward to sharing the topline data from our
pivotal APOLLOE4 Phase 3 trial and initiating a New Drug
Application to the FDA later this year.”
This positive Phase 2 study evaluating oral ALZ-801 in APOE4
patients with early AD achieved its primary efficacy endpoint of
reduction in plasma p-tau181 over two years, suggesting a robust
decrease in amyloid-induced brain neurodegeneration and target
engagement. A significant 31% reduction (p=0.045) in plasma
p-tau181 from baseline to 104 weeks started at 13 weeks and was
sustained at every visit through 104 weeks. HV atrophy was
significantly reduced by 25% (p=0.0014) compared to a matched
external control from ADNI-1, an observational AD study. Memory
scores showed improvement from baseline at 26 weeks and thereafter
showed minimal decline from baseline at 104 weeks. These cognitive
effects correlated significantly with decreased HV atrophy
(p=0.002). The most common treatment-emergent adverse events were
nausea and urinary tract infections, and no drug-related serious
adverse events were reported. Of 14 early withdrawals, six were due
to non-serious treatment-emergent adverse events and there was one
death due to COVID-19 (not related to study drug). No vasogenic
brain edema (amyloid-related imaging abnormalities with brain
edema, ARIA-E) was observed on MRI over 104 weeks. After completion
of the core study, a long-term extension of an additional 104 weeks
was initiated and is in progress to allow long-term assessment of
plasma biomarkers, hippocampal volume, cognitive tests, and safety
over four years of treatment.
“Well-tolerated disease-modifying treatments are needed for
patients with Alzheimer’s disease, particularly those who are APOE4
carriers, since these patients are at increased risk of vascular
complications known as amyloid-related imaging abnormalities. The
Phase 2 biomarker trial generated compelling data demonstrating
that treatment with oral ALZ-801 leads to a sustained reduction in
p-tau181, a key measure of brain neurodegeneration, as well as
slowing of hippocampal atrophy compared to a matched external
control arm, and stabilization of cognition for two years,” said
Susan Abushakra, MD, Chief Medical Officer at Alzheon. “A
well-tolerated oral agent with a simple dosing regimen would be
optimal for presymptomatic individuals who may require life-long
treatment. This study adds to the body of data for ALZ-801, a
well-differentiated investigational oral therapeutic with a
favorable safety profile with no increased risk of vasogenic brain
edema that has the potential to transform the treatment of
Alzheimer’s disease and reduce its burden on patients, their loved
ones and society as a whole."
In the Phase 2 trial, oral ALZ-801 showed early and sustained
significant reduction of plasma p-tau181 and plasma Aβ42 levels
over 2 years, suggesting alleviation of neurodegeneration due to
toxic effects of soluble amyloid oligomers. The quantitative
systems pharmacology (QSP) biomarker analysis supports the positive
therapeutic effect of ALZ-801, with evidence of arresting the
natural decline of monomeric CSF and plasma amyloid biomarkers,
consistent with the target engagement to prevent aggregation of
amyloid monomers into soluble neurotoxic oligomers. Accompanying
the amyloid biomarker changes, ALZ-801 also stabilized the natural
trajectory of memory decline, suggesting that the clinical benefits
are consistent with its mechanism of action. The QSP analysis
provides supportive amyloid fluid biomarker and clinical evidence
for ALZ-801 as a potential first-in-class, oral small-molecule
anti-Aβ oligomer agent with disease modification potential in
AD.
About ALZ-801/Valiltramiprosate
ALZ-801/valiltramiprosate is a potential first-in-class,
investigational oral agent in Phase 3 development as a potentially
disease modifying treatment for AD.1-4,6,9 ALZ‑801 is designed to
block the formation of neurotoxic soluble beta amyloid oligomers
implicated in cognitive decline in Alzheimer’s patients.1-4,6,11 In
mechanism of action studies, ALZ-801 has fully inhibited the
formation of neurotoxic soluble beta amyloid oligomers at the Phase
3 clinical dose.6,9,11 ALZ‑801 acts through a novel enveloping
molecular mechanism of action to block formation of neurotoxic
soluble amyloid oligomers in the human brain11 associated with the
onset and progression of cognitive decline in AD patients.1,4,6,7
ALZ-801 received Fast Track designation from the U.S. Food and Drug
Administration in 2017 for Alzheimer’s disease. In clinical trials,
ALZ-801 has shown potential for robust clinical efficacy and
favorable safety results with no increased risk of brain vasogenic
edema.2-7,10,12 The initial Phase 3 program for ALZ-801 is focusing
on Early AD patients with two copies of the apolipoprotein ε4
allele (APOE4/4 homozygotes), with potential future program
expansion to AD treatment and prevention in patients carrying one
copy of the APOE4 gene and noncarriers.1–7
ALZ-801 Phase 2 Biomarker Trial
Biomarker Effects of ALZ-801 in APOE4 Carriers With Early
Alzheimer's Disease (NCT04693520): This ongoing trial was designed
to evaluate the effects of 265 mg twice daily oral dose of ALZ-801
on biomarkers of AD pathology in subjects with Early AD, who have
either the APOE4/4 or APOE3/4 genotype and constitute 65-70% of
Alzheimer's patients. The trial also included evaluation of
clinical efficacy, safety, tolerability, and pharmacokinetic
profile of ALZ-801 over 104 weeks of treatment (primary endpoint).
An ongoing long-term extension of the trial evaluates ALZ-801 for
an additional 104 weeks of treatment for a total of 208 weeks.
ALZ-801 APOLLOE4 Phase 3 Trial
An Efficacy and Safety Study of ALZ-801 in APOE4/4 Early
Alzheimer's Disease Subjects (NCT04770220): This ongoing trial is
designed to evaluate the efficacy, safety, biomarker and imaging
effects of 265 mg twice daily oral dose of ALZ-801 in Early AD
subjects with two copies of the apolipoprotein ε4 allele (APOE4/4
homozygotes), who constitute approximately 15% of Alzheimer's
patients. This is a double-blind, randomized trial comparing oral
ALZ-801 to placebo treatment over 78 weeks. The APOLLOE4 trial is
supported by a $51 million grant from the National Institute on
Aging.
ALZ-801 APOLLOE4 Long Term Extension Trial
An ongoing long-term extension of the trial, APOLLOE4-LTE,
evaluates ALZ-801 in subjects who complete the core APOLLOE4 study
for an additional 52 weeks of treatment for a total of 130 weeks or
2.5 years (NCT06304883).
About Alzheon
Alzheon, Inc. is a clinical-stage biopharmaceutical company
developing a broad portfolio of product candidates and diagnostic
assays for patients suffering from Alzheimer’s disease and other
neurodegenerative disorders. We are committed to developing
innovative medicines by directly addressing the underlying
pathology of neurodegeneration. Our lead Alzheimer’s clinical
candidate, ALZ-801/valiltramiprosate, is a first-in-class oral
agent in Phase 3 development as a potentially disease modifying
treatment for AD. ALZ-801 is an oral small molecule that has been
observed to fully block the formation of neurotoxic soluble amyloid
oligomers in preclinical tests. Our clinical expertise and
technology platform are focused on developing drug candidates and
diagnostic assays using a precision medicine approach based on
individual genetic and biomarker information to advance therapies
with the greatest impact for patients.
Alzheon Scientific Publications
1 Tolar M, et al: The Single Toxin Origin of Alzheimer’s Disease
and Other Neurodegenerative Disorders Enables Targeted Approach to
Treatment and Prevention, International Journal of Molecular
Sciences, 2024; 25, 2727. 2 Hey J, et al: Analysis of
Cerebrospinal Fluid, Plasma β‑Amyloid Biomarkers, and Cognition
from a 2‑Year Phase 2 Trial Evaluating Oral
ALZ‑801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer’s
Disease Using Quantitative Systems Pharmacology Model, Drugs
2024. 3 Hey J, et al: Effects of Oral ALZ‑801/Valiltramiprosate on
Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results
of 2‑Year Single‑Arm, Open‑Label, Phase 2 Trial in APOE4 Carriers
with Early Alzheimer’s Disease, Drugs 2024. 4 Tolar M, et
al: Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer’s
Pathogenesis and Represent a Clinically Validated Target for
Slowing Disease Progression, International Journal of Molecular
Sciences, 2021; 22, 6355. 5 Abushakra S, et al: APOE ε4/ε4
Homozygotes with Early Alzheimer’s Disease Show Accelerated
Hippocampal Atrophy and Cortical Thinning that Correlates with
Cognitive Decline, Alzheimer’s & Dementia, 2020; 6:
e12117. 6 Tolar M, et al: Aducanumab, Gantenerumab, BAN2401, and
ALZ-801—the First Wave of Amyloid-Targeting Drugs for Alzheimer’s
Disease with Potential for Near Term Approval, Alzheimer’s
Research & Therapy, 2020; 12: 95. 7 Tolar M, et al: The
Path Forward in Alzheimer’s Disease Therapeutics: Reevaluating the
Amyloid Cascade Hypothesis, Alzheimer’s & Dementia,
2019; 1-8. 8 Hey JA, et al: Discovery and Identification of an
Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that
Inhibits Beta Amyloid Oligomer Formation in the Human Brain, CNS
Drugs, 2018; 32(9): 849-861. 9 Hey JA, et al: Clinical
Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of
Tramiprosate in Development for the Treatment of Alzheimer’s
Disease, Clinical Pharmacokinetics, 2018; 57(3): 315–333. 10
Abushakra S, et al: Clinical Effects of Tramiprosate in APOE4/4
Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease
Modification Potential, Journal of Prevention of Alzheimer’s
Disease, 2017; 4(3): 149-156. 11 Kocis P, et al: Elucidating
the Aβ42 Anti-Aggregation Mechanism of Action of Tramiprosate in
Alzheimer’s Disease: Integrating Molecular Analytical Methods,
Pharmacokinetic and Clinical Data, CNS Drugs, 2017; 31(6):
495-509. 12 Abushakra S, et al: Clinical Benefits of Tramiprosate
in Alzheimer’s Disease Are Associated with Higher Number of APOE4
Alleles: The “APOE4 Gene-Dose Effect,” Journal of Prevention of
Alzheimer’s Disease, 2016; 3(4): 219-228.
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version on businesswire.com: https://www.businesswire.com/news/home/20240625752393/en/
Media Nate Greene, Alzheon, Inc. 401.487.4390
nate.greene@alzheon.com
Investor Erwan de Naurois, Alzheon, Inc. 802.735.8789
erwan.denaurois@alzheon.com