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 reported positive top-line results from the
Phase 3 randomized, double-blind, placebo-controlled AVATAR trial
of ANAVEX®2-73 (blarcamesine) in adult female patients with Rett
syndrome and demonstrated a statistically significant improvement
over placebo for the primary efficacy endpoint as well as for all
the secondary efficacy endpoints. Convenient once daily oral liquid
doses of up to 30mg ANAVEX®2-73 was well tolerated with very good
medication compliance. Rett syndrome is a chronic CNS disease
caused by a spontaneous mutation of one gene, MECP2.
ANAVEX®2-73 activates the sigma-1 receptor
(SIGMAR1). Data suggests that activation of SIGMAR1 results in the
restoration of homeostatic function within the body and is pivotal
to restoring neural cell balance and the promotion of
neuroplasticity.1 Recent independent findings strengthen the
understanding of the beneficial effects of SIGMAR1 activation as a
compensatory mechanism to chronic CNS diseases.2
In the primary endpoint, RSBQ AUC, ANAVEX®2-73
induced a statistically significant and clinical meaningful
improvement in 72.2% of patients as compared to 38.5% on placebo;
(p = 0.037) with a Cohen’s d effect size of 1.91 (very large). The
secondary efficacy endpoints also demonstrated statistically
significant and clinical meaningful improvements. For the ADAMS, a
measure of emotional behavior symptoms, a significantly higher
proportion of ANAVEX®2-73 treated adult patients with Rett syndrome
(52.9%) than placebo-treated patients (8.3%) showed improvement (p
= 0.010), which corresponded to a Cohen’s d effect size of 0.609
(large). For the CGI-I, more patients achieved clinically
meaningful CGI-I response over the treatment duration in the
ANAVEX®2-73-treated group (72.2%) than in the placebo group
(38.5%); (p = 0.037) with a Cohen’s d effect size of 1.91 (very
large).
Professor Terence O’Brien, MD, FRACP, Chair of
Medicine and Head, The Central Clinical School, Monash University,
Program Director of Alfred Brain & Deputy Director of Research
at Alfred Health and Principal Investigator of the study commented:
“The outcome of this trial has confirmed the promising results of
the early lower-dose study in adults with Rett syndrome.
ANAVEX®2-73 was not only safe but it also demonstrated clinically
meaningful improvements in multiple common areas of impairment,
which are known to impair the quality of life of girls and women
affected by the disorder.”
Professor Paramala J Santosh, MBBS, Dip NB
(Psych), MD, PhD, FRCPsych, Developmental Neuropsychiatry &
Psychopharmacology, Department of Child and Adolescent Psychiatry
at King's College London added: ”These exciting results indicate a
high likelihood of marked improvements in younger, usually more
drug-responsive, patients with Rett syndrome, such as those
participating in the ongoing pediatric EXCELLENCE study.”
“The consistent efficacy across primary and
secondary endpoints in the Phase 3 AVATAR study confirms the
potential of ANAVEX®2-73 for treating Rett syndrome, which has been
suggested by a prior Phase 2 study,” commented Walter E Kaufmann,
MD, Chief Scientific Officer of Anavex. He also said, “Moreover,
the convergent clinical evidence is supported by parallel changes
in blood-based biomarkers of disease, including the key
neurotransmitter GABA. This strong body of data opens the
possibility of successful treatment for both adults and children
with Rett syndrome and early interventions for modifying the course
of the disease.”
Based on the results in this Phase 3 study
(ANAVEX®2-73-RS-002)3 and the prior successful U.S. Phase 2
(ANAVEX®2-73-RS-001)4 study in adult patients with Rett syndrome,
Anavex is planning to meet with FDA to discuss the approval
pathway. There are no FDA-approved drugs for Rett syndrome.
ANAVEX®2-73 has Fast Track designation, Rare Pediatric Disease
designation and Orphan Drug designation from the FDA for the
treatment of Rett syndrome and may be considered for accelerated
approval.
The placebo-controlled EXCELLENCE Phase 2/3
pediatric Rett syndrome study (ANAVEX®2-73-RS-003)5 is currently
ongoing and is evaluating ANAVEX®2-73 for Rett syndrome patients
ages 5 to 17.
“This is now the second successful
placebo-controlled study of ANAVEX®2-73 in adult patients with Rett
syndrome, and this Phase 3 study builds on the platform potential
of ANAVEX®2-73 and its ability to demonstrate clinically meaningful
improvements in Rett syndrome symptoms in the ANAVEX®2-73 treatment
group compared to placebo,” said Christopher U Missling, PhD,
President & Chief Executive Officer of Anavex. "I would like to
thank the patients and caregivers who participated in this trial,
the Anavex team, trial clinics, and doctors who have worked
tirelessly on this program. Special thanks go to the supportive
Rett Syndrome advocacy groups in the countries where our program
has been implemented. We look forward to continuing the journey
together."
Summary of Top-line ANAVEX®2-73
(blarcamesine) Placebo-Controlled Phase 3 AVATAR Rett Syndrome
Trial Results
The study evaluated the efficacy and safety of
ANAVEX®2-73 in 33 adult female patients diagnosed with Rett
syndrome (positive MECP2 gene mutation).
Effect on Rett Syndrome Symptoms:
- Primary (RSBQ AUC; p = 0.037) and secondary (ADAMS; p = 0.010);
(CGI-I; p = 0.037) efficacy endpoints met.
- ANAVEX®2-73 induces a statistically
significant and clinical meaningful improvement of RSBQ AUC in
72.2% of patients as compared to 38.5% on placebo; (p = 0.037).
Cohen’s d effect size 1.91 (very large).
- Clinically meaningful and
statistically significant reduction of emotional behavior symptoms
(ADAMS) in ANAVEX®2-73 treated adult patients with Rett syndrome
(52.9%) vs placebo (8.3%); (p = 0.010). Cohen’s d effect size 0.609
(large).
- Significantly more patients achieve
clinically meaningful CGI-I response over the treatment duration in
ANAVEX®2-73-treated group (72.2%) as compared with placebo (38.5%);
(p = 0.037). Cohen’s d effect size 1.91 (very large).
- Efficacy endpoints demonstrated statistically significant and
clinically meaningful reductions in Rett syndrome symptoms with
related changes in potential biomarkers of disease pathology:
- GABA was significantly increased (p = 0.0205).
- L-Alpha-aminoadipic acid (L-AAA) was significantly decreased (p
= 0.0392).
- Confirmed dose-response:
- RS-001 study 5mg ANAVEX®2-73 dose RSBQ AUC Cohen’s d (effect
size) of 0.517.
- RS-002 study 30mg ANAVEX®2-73 dose RSBQ AUC Cohen’s d (effect
size) of 1.91.
- ANAVEX®2-73 demonstrated dose-related significant improvement
in overall Quality of Life (QoL) measured with CHQ-PF50 (p =
0.030).
Safety and Tolerability:
- Convenient once daily orally liquid
doses of up to 30mg ANAVEX®2-73 was well tolerated with very good
medication compliance of 95%.
- Similar TEAE rates observed in
ANAVEX®2-73 and placebo arms.
- AEs ≥10% were predominantly mild or
moderate.
- There were no clinically
significant differences in vital signs, lab values and EKG
parameters between the active drug and placebo groups.
- There was no signal for increased
risk for common disorder-related manifestations.
- Collectively, the study results are
consistent with the known safety profile of ANAVEX®2-73.
Conference Call Information
Anavex Life Sciences will host a webcast today
at 8:30 a.m. ET to discuss the top-line results from the Phase 3
AVATAR clinical trial of ANAVEX®2-73 in adult patients with Rett
syndrome. The live webcast can be accessed on the investor page of
Anavex’s website at www.anavex.com. A replay of the webcast will be
available and will be archived for up to 30 days.
About Rett Syndrome
Rett syndrome is a devastating, non-inherited
genetic post-natal 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 easily breathe. The hallmark of Rett syndrome
is near constant repetitive hand movements while awake. The disease
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.Rett syndrome is caused by mutations in the MECP2 gene
and affects all racial and ethnic groups. The disease occurs
worldwide in approximately one in every 10,000 to 15,000 live
births. The population of patients with Rett syndrome is estimated
to be approximately 11,000 patients in the U.S. There is currently
no cure for Rett syndrome.
About the Phase 3
ANAVEX®2-73-RS-002 AVATAR Clinical Study
(NCT03941444)
The Phase 3 trial was a randomized double-blind,
placebo-controlled safety, tolerability, pharmacokinetic and
efficacy study of oral liquid ANAVEX®2-73 to treat Rett syndrome in
a total of 36 adult patients with Rett syndrome over a 7-weeks
treatment period incorporating precision medicine biomarkers.
Preceding the placebo-controlled randomization of 33 patients (Part
B), a 3-patient cohort (Part A) underwent a pharmacokinetic (PK)
assessment with safety, tolerability, pharmacokinetic and efficacy
evaluation of ANAVEX®2-73. All patients who completed the study are
eligible to continue to receive ANAVEX®2-73 for additional 48 weeks
within the open label extension protocol.
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),
successfully completed a Phase 2a clinical trial for Alzheimer’s
disease and recently a Phase 2 proof-of-concept study in
Parkinson’s disease dementia and a Phase 2 study in adult patients
with Rett syndrome. ANAVEX®2-73 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 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 for the treatment
of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and
muscarinic M1 receptors, is a promising clinical stage 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
mitochondrial dysfunction and neuroinflammation. Further
information is available at www.anavex.com. You can also connect
with the company on Twitter, Facebook, Instagram 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:Andrew J.
BarwickiInvestor RelationsTel: 516-662-9461Email:
andrew@barwicki.com
1 Advances in Experimental Medicine and Biology Volume 964
(2017) Sigma Receptors: Their Role in Disease and as Therapeutic
Targets.2 Prasanth MI, Malar DS, Tencomnao T, Brimson JM. The
emerging role of the sigma-1 receptor in autophagy: Hand-in-hand
targets for the treatment of Alzheimer's. Expert Opin Ther Targets.
2021 Jun 10. doi: 10.1080/14728222.2021.1939681. Epub ahead of
print. PMID: 34110944.3 ClinicalTrials.gov Identifier: NCT039414444
ClinicalTrials.gov Identifier: NCT037589245 ClinicalTrials.gov
Identifier: NCT04304482
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