Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq:
AVXL), a clinical-stage biopharmaceutical company developing
differentiated therapeutics for the treatment of neurodegenerative
and neurodevelopmental disorders including Alzheimer’s disease,
Parkinson’s disease, Rett syndrome and other central nervous system
(CNS) disorders, today announced preliminary clinical data of the
U.S. Phase 2 Rett syndrome clinical trial.
Preliminary Clinical Data is derived from the
ANAVEX®2-73-RS-001 study on the first 6-patient cohort ranging in
age from 18 to 36 years who completed the pharmacokinetic (PK) part
of the study and who received a low dose of approx. 5 mg daily oral
liquid dose of ANAVEX®2-73 (blarcamesine) for 7 weeks. Patients are
continuing participation in the ANAVEX®2-73-RS-001 open label
extension study.
Both efficacy endpoints, the Rett Syndrome
Behaviour Questionnaire (RSBQ) and the Clinical Global Impression –
Improvement (CGI-I) showed significant improvement with respect to
baseline after 7 weeks of treatment. The RSBQ Total average scores
improved from 50 to 34 points (2-tailed Wilcoxon signed rank test,
p = 0.027) and the CGI-I scores were positively correlated with
RSBQ Total scores at 7 weeks (2-tailed Spearman’s rho = 0.956, p =
0.003).
Supporting the clinical assessments, plasma
levels of the biomarker Glutamate also decreased significantly
(Week 0 vs. Week 7; 2-tailed Wilcoxon signed rank test, p = 0.046)
and levels of Glutamate at Week 7 were directly correlated with
CGI-I scores at Week 7 (2-tailed Spearman’s rho = 0.837, p = 0.038)
with greater decreases in Glutamate associated with greater
improvement in these efficacy scores. Glutamate is the main
excitatory neurotransmitter in the brain and is known to be higher
in patients with Rett syndrome compared to healthy subjects in the
brain, as measured by magnetic resonance imaging spectroscopy
(MRS), as well as in cerebrospinal fluid (CSF) and blood
plasma.
Additionally, the magnitude of GABA change was
inversely correlated with the magnitude of decrease in RSBQ Total
scores (2-tailed Spearman’s rho = -0.812, p = 0.050) and GABA
changes demonstrated an inverse correlation of the magnitude of
Glutamate changes (2-tailed Spearman’s rho = -0.829, p =
0.042).GABA is the main inhibitory neurotransmitter in the brain,
known to be deficient in animal models of Rett syndrome.
Excitatory-inhibitory imbalances postulated in many neurologic
disorders, including Rett syndrome, have been linked to imbalances
between Glutamate and GABA1,2.
An independent DSMB review determined that
ANAVEX®2-73 (blarcamesine) was well tolerated, with no SAEs
reported and with all patients completing the study. Therefore, the
DSMB issued a positive recommendation for the continuation of the
Phase 2 Rett syndrome study without any modifications.
“This is a remarkable first strong signal for
patients with Rett syndrome especially given that the strong
effects were seen in adult patients, and we look forward to
discussing these results with the FDA and the European regulatory
agency as we continue our Rett Syndrome Program including pediatric
patients,” said Walter E Kaufmann, MD, Principal Investigator of
the study and Chief Medical Officer of Anavex. “Importantly, we've
now observed that the ANAVEX®2-73 (blarcamesine) effect is
correlated with changes of Glutamate and GABA levels, objective
measures and biomarkers in several neurodevelopmental
disorders.”
Detailed results will be presented at the 6th
European Rett Syndrome Conference in Tampere, Finland, September
27-28, 2019 and submitted for publication in a peer-reviewed
journal.
Neurobehavioral effects of ANAVEX®2-73
(blarcamesine) previously observed in preclinical studies were also
detected in patients with Rett syndrome, pointing to the ability of
translation of preclinical to clinical data. ANAVEX®2-73
(blarcamesine) has received orphan drug designation from the FDA
and EMA for the treatment of Rett syndrome.
Christopher U Missling, PhD, President and Chief
Executive Officer of Anavex, stated, “We are encouraged by the
insights gleaned from these first clinical data for ANAVEX®2-73
(blarcamesine) in patients with Rett syndrome and we look forward
to both confirm this clinical data and continue the Rett syndrome
program with determination. In addition to Rett syndrome3, Anavex
has ongoing clinical development programs for ANAVEX®2-73
(blarcamesine) for the treatment of Alzheimer’s disease4 and
Parkinson’s disease dementia5.”
About Rett Syndrome
Rett syndrome is a devastating, non-inherited
genetic postnatal progressive neurodevelopmental disorder that
occurs almost exclusively in girls and leads to severe impairments,
affecting nearly every aspect of the child’s life: their ability to
speak, walk, eat and even breathe easily. The hallmark of Rett
syndrome is near constant repetitive hand movements while awake. It
is characterized by normal early growth and development (6 to 18
months) followed by a slowing of development, loss of purposeful
use of the hands, distinctive hand movements, autistic features,
slowed brain and head growth, ataxia, seizures and intellectual
disability. There is currently no cure for Rett syndrome. Rett
syndrome is caused by mutations in the MECP2 gene and strikes all
racial and ethnic groups and occurs worldwide in approximately one
in every 10,000 to 15,000 live female births.
About ANAVEX®2-73-RS-001 Clinical Study
The Phase 2 trial is a randomized double-blind,
placebo-controlled safety, tolerability, pharmacokinetic and
efficacy study of oral liquid ANAVEX®2-73 (blarcamesine) to treat
Rett syndrome. Pharmacokinetic and dose-finding elements in a total
of 21 patients over a 7-week treatment period will be evaluated
incorporating precision medicine biomarkers. Preceding the
placebo-controlled randomization of 15 patients, a 6 patient cohort
underwent a 7-week pharmacokinetic (PK) assessment with safety,
tolerability, pharmacokinetic and efficacy evaluation of
ANAVEX®2-73 (blarcamesine). All patients who participate in the
study will be eligible to receive ANAVEX®2-73 (blarcamesine) under
an open label extension protocol.
About ANAVEX®2-73
ANAVEX®2-73 (blarcamesine) activates the Sigma-1
receptor (S1R) protein, which serves as a molecular chaperone and
functional modulator involved in restoring homeostasis. In a Phase
2a Alzheimer’s disease (AD) study, ANAVEX®2-73 (blarcamesine) has
shown dose dependent improvement in exploratory endpoints of
cognition (MMSE) and activities of daily living (ADCS-ADL). Full
genomic analysis of ANAVEX®2-73 (blarcamesine) Phase 2a AD patients
was performed. The ANAVEX®2-73 (blarcamesine) Phase 2 Rett syndrome
study design includes genomic biomarkers identified in the
ANAVEX®2-73 (blarcamesine) Phase 2a AD study. Studies of
ANAVEX®2-73 (blarcamesine) in a mouse model with a heterozygous
Mecp2-null mutation (HET) that causes neurological symptoms that
mimic Rett syndrome, ANAXEX®2-73 (blarcamesine) was evaluated in
automatic visual responses and breathing tests in 7-month old mice,
an age at which advanced pathology is evident. Vehicle-treated HET
mice demonstrated fewer automatic visual responses and more
frequent expiratory apneas than wild-type mice. Treatment with
ANAVEX®2-73 (blarcamesine) for four weeks significantly increased
these visual responses in the HET mice (p<0.05). Additionally,
chronic oral dosing daily for 3-6.5 weeks of ANAVEX®2-73
(blarcamesine) starting at ~5 weeks of age was also conducted in
the HET mouse model of Rett syndrome, and dose-dependent
improvements in a variety of sensory and motor deficits, including
those involving motor coordination, balance, and learning, were
also observed. Notably, one of the strongest effects was on
hindlimb clasping, a postural response that resembles the
characteristic hand stereotypes present in Rett syndrome. These
experiments were sponsored by Rettsyndrome.org.
About Anavex Life Sciences Corp.
Anavex Life Sciences Corp. (Nasdaq: AVXL) is a
publicly traded biopharmaceutical company dedicated to the
development of differentiated therapeutics for the treatment of
neurodegenerative and neurodevelopmental disorders including
Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other
central nervous system (CNS) diseases, pain and various types of
cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine),
recently completed a successful Phase 2a clinical trial for
Alzheimer’s disease. ANAVEX®2-73 (blarcamesine) is an orally
available drug candidate that restores cellular homeostasis by
targeting sigma-1 and muscarinic receptors. Preclinical studies
demonstrated its potential to halt and/or reverse the course of
Alzheimer’s disease. ANAVEX®2-73 (blarcamesine) also exhibited
anticonvulsant, anti-amnesic, neuroprotective and anti-depressant
properties in animal models, indicating its potential to treat
additional CNS disorders, including epilepsy. The Michael J. Fox
Foundation for Parkinson’s Research previously awarded Anavex a
research grant, which fully funded a preclinical study to develop
ANAVEX®2-73 (blarcamesine) for the treatment of Parkinson’s
disease. ANAVEX®3-71, which targets sigma-1 and M1 muscarinic
receptors, is a promising preclinical drug candidate demonstrating
disease-modifying activity against the major hallmarks of
Alzheimer’s disease in transgenic (3xTg-AD) mice, including
cognitive deficits, amyloid and tau pathologies. In preclinical
trials, ANAVEX®3-71 has shown beneficial effects on
neuroinflammation and mitochondrial dysfunction. Further
information is available at www.anavex.com. You can also connect
with the company
on Twitter, Facebook and LinkedIn.
Forward-Looking Statements
Statements in this press release that are not
strictly historical in nature are forward-looking statements. These
statements are only predictions based on current information and
expectations and involve a number of risks and uncertainties.
Actual events or results may differ materially from those projected
in any of such statements due to various factors, including the
risks set forth in the Company’s most recent Annual Report on Form
10-K filed with the SEC. Readers are cautioned not to place undue
reliance on these forward-looking statements, which speak only as
of the date hereof. All forward-looking statements are qualified in
their entirety by this cautionary statement and Anavex Life
Sciences Corp. undertakes no obligation to revise or update this
press release to reflect events or circumstances after the date
hereof.
For Further Information:
Anavex Life Sciences Corp.Research &
Business DevelopmentToll-free: 1-844-689-3939Email:
info@anavex.com
Investors & Media:Email:
ir@anavex.com
1 Kaufmann et al. Expert Opin Orphan Drugs 4:1043-1055, 2016
2 Banerjee et al. Brain 142:239-248, 2019
3 ClinicalTrials.gov Identifier: NCT03758924; NCT03941444
4 ClinicalTrials.gov Identifier: NCT03790709
5 ClinicalTrials.gov Identifier: NCT03774459
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