UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
FORM
10-K
(Mark One)
☒
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the fiscal year ended September 30, 2022
☐ TRANSITION
REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For
the transition period from ______________ to________________
Commission
file number: 001-37606
ANAVEX LIFE SCIENCES CORP.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
Registrant’s
telephone number, including area code 1-844-689-3939
Securities
registered under Section 12(b) of the Act:
Common Stock, $0.001 par value AVXL NASDAQ Stock Market LLC
Title of each class Trading Symbol Name of each exchange on which registered
Securities
registered pursuant to Section 12(g) of the Act:
None
(Title
of class)
Yes ☒ No ☐
Yes ☐ No ☒
Yes ☒ No ☐
Yes ☒ No ☐
Large accelerated filer ☒ Accelerated filer ☐
Smaller reporting company ☐
Non-accelerated filer ☐
Emerging growth company ☐
☐
Yes ☒ No ☐
Yes ☐ No ☒
State
the aggregate market value of the voting and non-voting common equity held by non-affiliates computed by reference to the price at which
the common equity was last sold, or the average bid and asked price of such common equity, as of the last business day of the registrant’s
most recently completed second fiscal quarter: $921 million based on a price of $12.31 per share, being the closing price of the registrant’s
common stock on March 31, 2022.
Indicate
the number of shares outstanding of each of the registrant’s classes of common stock, as of the latest practicable date: 77,961,815
issued and outstanding as of November 28, 2022.
DOCUMENTS
INCORPORATED BY REFERENCE
None.
ii
TABLE OF CONTENTS
PART I 6
ITEM 1. BUSINESS 6
ITEM 1A. RISK FACTORS 30
ITEM 1B. UNRESOLVED STAFF COMMENTS 51
ITEM 2. PROPERTIES 51
ITEM 3. LEGAL PROCEEDINGS 51
ITEM 4. MINE SAFETY DISCLOSURES 51
ITEM 6 [Reserved] 52
ITEM 7A QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 57
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA 58
ITEM 9A. CONTROLS AND PROCEDURES 82
ITEM 9B OTHER INFORMATION 82
PART III 83
ITEM 10 DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 83
ITEM 11. EXECUTIVE COMPENSATION 83
ITEM 14. PRINCIPAL ACCOUNTING FEES AND SERVICES 83
ITEM 15. EXHIBITS, FINANCIAL STATEMENT SCHEDULES 84
iii
Forward Looking Statements.
This Annual Report on Form 10-K includes forward-looking
statements. All statements other than statements of historical facts contained in this Annual Report on Form 10-K, including statements
regarding our anticipated future clinical and regulatory milestone events, future financial position, business strategy and plans
and objectives of management for future operations, are forward-looking statements. The words “believe,” “may,”
“estimate,” “continue,” “anticipate,” “intend,” “expect,” “should,”
“forecast,” “potential,” “predict,” “could,” “would,” “will,”
“suggest,” “plan” and similar expressions, as they relate to us, are intended to identify forward-looking
statements. Such forward-looking statements include, without limitation, statements regarding:
● volatility in our stock price and in the markets in general;
● the impact of the COVID-19 outbreak and its effect on us;
● our ability to generate any revenue or to continue as a going concern;
● our ability to obtain the support of qualified scientific collaborators;
● our ability to identify and obtain additional product candidates;
● our reliance on third parties in non-clinical studies and clinical trials;
● our ability to defend against product liability claims;
● our ability to safeguard against security breaches;
● our ability to comply with our intellectual property licensing agreements;
● our ability to defend against claims of intellectual property infringement;
● our ability to protect our intellectual property rights throughout the world;
● competition;
● the anticipated designs of our future clinical trials;
● our ability to attract and retain qualified employees;
● the impact of Fast Track designation on receipt of actual FDA approval;
We have based these forward-looking
statements largely on our current expectations and projections about future events, including the responses we expect from the
U.S. Food and Drug Administration, (“FDA”), and other regulatory authorities and financial trends that we believe may
affect our financial condition, results of operations, business strategy, preclinical and clinical trials, and financial needs.
These forward-looking statements are subject to a number of risks, uncertainties and assumptions including, without limitation,
the risks described in “Risk Factors” in Part I, Item 1A of this Annual Report on Form 10-K. These risks are not exhaustive.
Other sections of this Annual Report on Form 10-K include additional factors which could adversely impact our business and financial
performance. Moreover, we operate in a very competitive and rapidly changing environment. New risk factors emerge from time to
time and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our
business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those
contained in any forward-looking statements. You should not rely upon forward-looking statements as predictions of future events.
We cannot assure you that the events and circumstances reflected in the forward-looking statements will be achieved or occur and
actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable
laws including the securities laws of the United States, we assume no obligation to update or supplement forward-looking statements.
As used in this Annual Report on Form
10-K, the terms “we,” “us,” “our,”, “Company” and “Anavex” mean Anavex
Life Sciences Corp., unless the context clearly requires otherwise.
iv
PART I
ITEM 1. BUSINESS
Overview and Strategy
Anavex Life Sciences Corp. is a clinical stage
biopharmaceutical company engaged in the development of differentiated therapeutics by applying precision medicine to central nervous
system (“CNS”) diseases with high unmet need. We analyze genomic data from clinical trials to identify biomarkers,
which we use in the analysis of our clinical trials.
Our lead product candidate, ANAVEX®2-73,
is being developed to treat Alzheimer’s disease, Parkinson’s disease and potentially other central nervous system diseases,
including rare diseases, such as Rett syndrome, a rare severe neurological monogenic disorder caused by mutations in the X-linked
gene, methyl-CpG-binding protein 2 (“MECP2”).
We currently have two core programs and two
seed programs. Our core programs are at various stages of clinical and preclinical development, in neurodegenerative and neurodevelopmental
diseases.
The following table summarizes key information about our programs:
* = Orphan Drug Designation by the FDA;
Dashed lines indicate planned clinical trials to-date
Anavex has a portfolio of compounds varying
in sigma-1 receptor (SIGMAR1) binding activities. The SIGMAR1 gene encodes the SIGMAR1 protein, which is an intracellular chaperone
protein with important roles in cellular communication. SIGMAR1 is also involved in transcriptional regulation at the nuclear envelope
and restores homeostasis and stimulates recovery of cell function when activated. In order to validate the ability of our compounds
to activate quantitatively the SIGMAR1, we performed, in collaboration with Stanford University, a quantitative Positron Emission
Tomography (PET) imaging scan in mice, which demonstrated a dose-dependent ANAVEX®2-73 target engagement or receptor
occupancy with SIGMAR1 in the brain.
Source: Reyes S et al., Sci Rep. 2021 Aug 25;11(1):17150
Cellular Homeostasis
Many diseases are possibly directly caused
by chronic homeostatic imbalances or cellular stress of brain cells. In pediatric diseases, such as Rett syndrome or infantile
spasms, the chronic cellular stress is possibly caused by the presence of a constant genetic mutation. In neurodegenerative diseases,
such as Alzheimer’s and Parkinson’s diseases, chronic cellular stress is possibly caused by age-correlated buildup
of cellular insult and hence chronic cellular stress. Specifically, defects in homeostasis of protein or ribonucleic acid (“RNA”)
lead to the death of neurons and dysfunction of the nervous system. The spreading of protein aggregates resulting in a proteinopathy,
a characteristic found in Alzheimer’s and Parkinson’s diseases that results from disorders of protein synthesis, trafficking,
folding, processing or degradation in cells. The clearance of macromolecules in the brain is particularly susceptible to imbalances
that result in aggregation and degeneration in nerve cells. For example, Alzheimer’s disease pathology is characterized by
the presence of amyloid plaques, and neurofibrillary tangles, which are aggregates of hyperphosphorylated Tau protein that are
a marker of other diseases known as tauopathies as well as inflammation of microglia. With the SIGMAR1 activation through SIGMAR1
agonists like ANAVEX®2-73, our approach is to restore cellular balance (i.e. homeostasis). Therapies that correct
defects in cellular homeostasis might have the potential to halt or delay neurodevelopmental and neurodegenerative disease progression.
ANAVEX®2-73-specific Biomarkers
As part of some of our clinical trials, we
have incorporated a genomic analysis to better understand potential populations for whom our clinical programs might benefit. In
our clinical trials, a full genomic analysis of Alzheimer’s disease patients treated with ANAVEX®2-73 has
helped us identify actionable genetic variants. A significant impact of the genomic biomarkers SIGMAR1, the direct target of ANAVEX®2-73
and COMT, a gene involved in memory function, on the drug response level was identified, leading to an early ANAVEX®2-73-specific
biomarker hypothesis. We believe that excluding patients with SIGMAR1 identified biomarker variant (approximately 10%-20%
of the population) in prospective studies would identify approximately 80%-90% patients that would display clinically significant
improved functional and cognitive scores. The consistency between the identified DNA and RNA data related to ANAVEX®2-73,
which are considered independent of Alzheimer’s disease pathology, as well as multiple endpoints and time-points, provides
support for the potential precision medicine clinical development of ANAVEX®2-73 by using genetic biomarkers identified
within the trial population itself to target patients who are most likely to respond to ANAVEX®2-73 treatment. We
may in the future utilize such an approach in Alzheimer’s disease as well as indications like Parkinson’s disease dementia
or Rett syndrome in which ANAVEX®2-73 is currently being studied.
Clinical Trials Overview
Alzheimer’s Disease
In November 2016, we completed a Phase 2a clinical
trial, consisting of Part A and Part B, which lasted a total of 57 weeks, for ANAVEX®2-73 in mild-to-moderate Alzheimer’s
patients. This open-label, randomized trial in Australia met both primary and secondary endpoints and was designed to assess the
safety and exploratory efficacy of ANAVEX®2-73 in 32 patients. ANAVEX®2-73 targets sigma-1 and muscarinic
receptors, which have been shown in preclinical studies to reduce stress levels in the brain believed to restore cellular homeostasis
and to reverse the pathological hallmarks observed in Alzheimer’s disease. In October 2017, we presented positive pharmacokinetic
(“PK”) and pharmacodynamic (“PD”) data from the Phase 2a clinical trial, which established a concentration-effect
relationship between ANAVEX®2-73 and trial measurements. These measures obtained from all patients who participated
in the entire 57 weeks include exploratory cognitive and functional scores as well as biomarker signals of brain activity. Additionally,
the clinical trial appeared to show that ANAVEX®2-73 activity was enhanced by its active metabolite (ANAVEX19-144),
which also targets the SIGMAR1 receptor and has a half-life approximately twice as long as the parent molecule.
Two consecutive trial extensions for the Phase
2a trial have allowed participants who completed the 52-week Part B of the trial to continue taking ANAVEX®2-73,
providing us an opportunity to gather extended safety data for a cumulative time period of five years. In August 2020, patients
completing these Phase 2a trial extensions were granted continued access to treatment with ANAVEX®2-73 through the
Australian Government Department of Health – Therapeutic Goods Administration’s compassionate use Special Access Scheme.
A larger Phase 2b/3 double-blind, placebo-controlled
trial of ANAVEX®2-73 in Alzheimer’s disease commenced in August 2018. The Phase 2b/3 trial enrolled 509 patients
for 48 weeks, randomized 1:1:1 to two different ANAVEX®2-73 doses or placebo. The trial commenced in Australia;
and during fiscal 2020 additional regions were added in the United Kingdom, The Netherlands, Germany and Canada. Primary and secondary
endpoints will assess safety and both cognitive and functional efficacy, measured through Alzheimer’s Disease Assessment
Scale – Cognition (ADAS-Cog), ADCS-ADL and Clinical Dementia Rating – Sum of Boxes for cognition and function (CDR-SB).
In addition to the primary endpoints, the ANAVEX®2-73 Phase 2b/3 trial design incorporated pre-specified statistical
analyses related to potential genomic precision medicine biomarkers identified in the ANAVEX®2-73 Phase 2a clinical
trial. The trial completed enrollment in June 2021, exceeding the 450 patient enrollment target at 52 sites across Canada, Europe
and Australia.
In October 2019, we initiated a long-term
open label extension study of ANAVEX®2-73, entitled the ATTENTION-AD trial, for patients who have completed the
48-week Phase 2b/3 placebo-controlled trial referenced above. This trial extension for an additional two years gives patients
the opportunity to continue their treatment. Upon request by patients, caretakers and investigators, this extension trial was
extended by one additional year.
Rett Syndrome
In February 2016, we presented positive preclinical
data for ANAVEX®2-73 in Rett syndrome, a rare neurodevelopmental disease. The data demonstrated dose related and
significant improvements in an array of behavioral and gait paradigms in a mouse model with a MECP2-null mutation that causes neurological
symptoms that mimic Rett syndrome. The study was funded by the International Rett Syndrome Foundation (“Rettsyndrome.org”). In January 2017, we were awarded a financial grant
from Rettsyndrome.org of a minimum of $0.6 million to cover some of the costs of a multicenter Phase 2 clinical trial of ANAVEX®2-73
for the treatment of Rett syndrome. This award was received in quarterly instalments which commenced during fiscal 2018.
In March 2019, we commenced the first Phase
2 clinical trial in a planned Rett syndrome program of ANAVEX®2-73 for the treatment of Rett syndrome. The clinical
trials are being conducted in a range of patient age demographics and geographic regions, utilizing an oral liquid once-daily formulation
of ANAVEX®2-73.
The first Phase 2 trial, (ANAVEX®2-73-RS-001), which took place in the
United States, was completed in December 2020. This trial was a randomized double-blind, placebo-controlled safety, tolerability, PK and
efficacy trial of oral liquid ANAVEX®2-73 formulation in 25 adult female patients with Rett syndrome over a 7-week treatment
period including ANAVEX®2-73-specific genomic precision medicine biomarkers. The primary endpoint of the trial was safety.
The dosing of 5 mg ANAVEX®2-73 was well-tolerated and demonstrated dose-proportional PK. All secondary efficacy endpoints
of the trial showed statistically significant and clinically meaningful response in the Rett Syndrome Behaviour Questionnaire (“RSBQ”)
response, when compared to placebo, in the intent to treat (“ITT”) cohort (all participants, p = 0.011). 66.7% of ANAVEX®2-73
treated subjects showed a statistically significant improvement in RSBQ response as compared to 10% of the subjects on placebo in the
ITT cohort (all participants, p = 0.011). ANAVEX®2-73 treatment resulted in a sustained improvement in Clinical Global
Impression Improvement (“CGI-I”) response throughout the 7-week clinical trial, when compared to placebo in the ITT cohort
(all participants, p = 0.014). Consistent with previous ANAVEX®2-73 clinical trials, patients carrying the common form
of the SIGMAR1 gene treated with ANAVEX®2-73 experienced stronger improvements in the prespecified efficacy endpoints.
The second, international
trial of ANAVEX®2-73 for the treatment of Rett syndrome, called the AVATAR trial, commenced in June 2019. This
trial took place in Australia and the United Kingdom using a higher dose than the U.S. based Phase 2 trial for Rett syndrome.
The trial was a Phase 3 randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of ANAVEX®2-73
in 33 adult patients over a 7-week treatment period including ANAVEX®2-73 specific precision medicine biomarkers.
Based upon the input from the successful U.S. Phase 2 Rett syndrome trial (ANAVEX®2-73-RS-001), we updated the endpoints for
the AVATAR trial (ANAVEX®2-73-RS-002) to appropriately assess the clinically meaningful outcome following International Conference
on Harmonization (ICH) guidelines. These updates were approved by the respective regulatory authorities in the U.K. and in Australia,
respectively, where the AVATAR trial was conducted.
The data from the AVATAR trial was released in February 2022. The clinical
trial met all primary and secondary efficacy and safety endpoints, with consistent improvements in primary efficacy endpoint, RSBQ response
(p = 0.037), and secondary efficacy endpoints, ADAMS (p = 0.010) and CGI-I (p = 0.037) response. Efficacy endpoints demonstrated statistically
significant and clinically meaningful reductions in Rett syndrome symptoms. Convenient once daily oral liquid doses of up to 30 mg of
ANAVEX®2-73 were also well tolerated with good medication compliance. All patients who participated in the trial were
eligible to receive ANAVEX®2-73 under a voluntary open label extension protocol.
In July 2020, we commenced the third trial
of ANAVEX®2-73 for the treatment of Rett syndrome, called the EXCELLENCE trial. This Phase 2/3 trial in pediatric
patients with Rett syndrome includes trial sites in Australia, the United Kingdom, and Canada, and will evaluate the safety and
efficacy of ANAVEX®2-73 in approximately 84 pediatric patients, aged 5 to 18, over a 12-week treatment period incorporating
ANAVEX®2-73 specific precision medicine biomarkers. All patients who participate in the trial will be eligible
to receive ANAVEX®2-73 under a voluntary open label extension protocol, which is currently ongoing.
Parkinson’s Disease
In September 2016, we presented positive preclinical
data for ANAVEX®2-73 in an animal model of Parkinson’s disease, which demonstrated significant improvements
on behavioral, histopathological, and neuroinflammatory endpoints. The study was funded by the Michael J. Fox Foundation. Additional
data announced in October 2017 indicated that ANAVEX®2-73 induced robust neurorestoration in experimental Parkinsonism.
We believe that the encouraging results we have gathered in this preclinical model, coupled with the favorable profile of this
product candidate in the Alzheimer’s disease trial, support the notion that ANAVEX®2-73 has the potential
to treat Parkinson’s disease dementia.
In October 2020, we completed a double-blind,
randomized, placebo-controlled proof-of-concept Phase 2 trial with ANAVEX®2-73 in Parkinson’s disease dementia
in Spain and Australia, to study the effect of the compound on both the cognitive and motor impairment of Parkinson’s disease.
The Phase 2 trial enrolled approximately 132 patients for 14 weeks, randomized 1:1:1 to two different ANAVEX®2-73
doses, 30 mg and 50 mg, or placebo. The ANAVEX®2-73 Phase 2 Parkinson’s disease dementia trial design incorporated
genomic precision medicine biomarkers identified in the ANAVEX®2-73 Phase 2a Alzheimer’s disease trial.
The trial demonstrated that ANAVEX®2-73
was safe and well tolerated in oral doses up to 50 mg once daily. The results showed clinically meaningful, dose-dependent, and
statistically significant improvements in the Cognitive Drug Research (“CDR”) computerized assessment system analysis.
Treatment with ANAVEX®2-73 also resulted in clinically meaningful improvements as measured by the global composite
score of Parkinson’s disease symptom severity, MDS-Unified Parkinson’s Disease Rating Scale total score on top of standard
of care including dopaminergic therapy, levodopa and other anti-PD medications after 14 weeks of treatment, suggesting ANAVEX®2-73’s
potential capability of slowing and reversing symptoms that progress in Parkinson’s disease. In addition, the trial confirmed
the precision medicine approach of targeting SIGMAR1 as a genetic biomarker in response to ANAVEX®2-73 may result
in improved clinical outcomes.
In January 2021, we were awarded a research
grant of $1.0 million from The Michael J. Fox Foundation for Parkinson’s Research to develop ANAVEX®2-73
for the treatment of Parkinson’s disease. The award will explore utilization of PET imaging biomarkers to enable measurement
of target engagement and pathway activation of the SIGMAR1 with clinically relevant doses in people with Parkinson’s disease.
Frontotemporal Dementia
In July 2020, we commenced the First-in-Human
Phase 1 clinical trial of ANAVEX®3-71. ANAVEX®3-71 was previously granted orphan drug designation
for the treatment of Frontotemporal Dementia (“FTD”) by the FDA. ANAVEX®3-71 is an orally administered small molecule
targeting sigma-1 and M1 muscarinic receptors that is designed to be beneficial for neurodegenerative diseases. In preclinical
studies, ANAVEX®3-71 demonstrated disease-modifying activity against the major hallmarks of Alzheimer’s disease
in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, as well as beneficial effects on mitochondrial
dysfunction and neuroinflammation.
The Phase 1 clinical trial was a prospective
double-blind, randomized, placebo-controlled trial in Australia. A total of 36 healthy male and female subjects were included.
Single escalating doses of ANAVEX®3-71 were administered in order to evaluate the safety, tolerability, and PK of
ANAVEX®3-71 and the effects of food and gender on its PK in healthy volunteers.
The trial met its primary and secondary endpoints
of safety, with no serious adverse events (“SAEs”) or dose-limiting toxicities observed. ANAVEX®3-71
was well tolerated in all cohorts receiving ANAVEX®3-71 in single doses ranging from 5 mg to 200 mg daily with no
SAEs and no significant lab abnormalities in any subject. In the trial, ANAVEX®3-71 exhibited linear PK. Its pharmacokinetics
was also dose proportional for doses up to 160 mg. Gender had no effect on the PK of the drug and food had no effect on the bioavailability
of ANAVEX®3-71. The trial also met the secondary objective of characterizing the effect of ANAVEX®3-71
on electrocardiogram (“ECG”) parameters. There were no clinically significant ECG parameters throughout the trial.
Participant QTcF measures were normal across all dose groups with no difference between ANAVEX®3-71 and placebo.
Based on these results, and ANAVEX®3-71’s
pre-clinical profile, we intend to advance ANAVEX®3-71 into a biomarker-driven clinical development dementia program
for the treatment of schizophrenia, FTD and Alzheimer’s disease, evaluating longitudinal effect of treatment with ANAVEX®3-71.
We believe the results of these clinical trials and preclinical study could serve as the basis for advancing into respective registration
studies in the U.S.
Our Pipeline
Our research and development pipeline includes
ANAVEX®2-73 currently in three different clinical trial indications, and several other compounds in different stages
of clinical and pre-clinical development.
Our proprietary SIGMACEPTORTM Discovery
Platform produced small molecule drug candidates with unique modes of action, based on our understanding of sigma receptors. Sigma
receptors may be targets for therapeutics to combat many human diseases, both of neurodegenerative nature, including Alzheimer’s
disease, as well as of neurodevelopmental nature, like Rett syndrome. When bound by the appropriate ligands, sigma receptors influence
the functioning of multiple biochemical signals that are involved in the pathogenesis (origin or development) of disease. Multiple
viruses including SARS-CoV-2 (COVID-19) induce cellular stress by intrinsic mitochondrial apoptosis and other related cellular
processes, in order to ensure survival and replication. Hence, it is possible that SIGMAR1 could play a role in modulating the
cellular response to viral infection and ameliorate pathogenesis.
Compounds that have been subjects of our research
include the following:
ANAVEX®2-73 (blarcamesine)
We believe ANAVEX®2-73 may offer
a disease-modifying approach in neurodegenerative and neurodevelopmental diseases by activation of SIGMAR1. ANAVEX®2-73
is being developed in an oral liquid once-daily formulation for rare diseases such as Rett syndrome as well as an oral once-daily
capsule formulation for diseases such as Alzheimer’s disease.
In Rett syndrome, administration of ANAVEX®2-73
in liquid form resulted in both significant and dose related improvements in an array of behavioral paradigms in the MECP2 HET
Rett syndrome disease model. In addition, in a further experiment sponsored by Rettsyndrome.org, ANAVEX®2-73 was
evaluated in automatic visual response and respiration tests in 7-month old mice, an age at which advanced pathology is evident.
Vehicle-treated MECP2 mice demonstrated fewer automatic visual responses than wild-type mice. Treatment with ANAVEX®2-73
for four weeks significantly increased the automatic visual response in the MECP2 Rett syndrome disease mice. Additionally, chronic
oral dosing daily for 6.5 weeks of ANAVEX®2-73 starting at ~5.5 weeks of age was conducted in the MECP2 HET Rett
syndrome disease mouse model assessed the different aspects of muscular coordination, balance, motor learning and muscular strengths,
some of the core deficits observed in Rett syndrome. Administration of ANAVEX®2-73 resulted in both significant
and dose related improvements in an array of these behavioral paradigms in the MECP2 HET Rett syndrome disease model.
In May 2016 and June 2016, the FDA granted
Orphan Drug Designation to ANAVEX®2-73 for the treatment of Rett syndrome and infantile spasms, respectively. In
November 2019, the FDA granted to ANAVEX®2-73 the Rare Pediatric Disease (RPD) designation for the treatment of
Rett syndrome. The RPD designation is intended to encourage the development of treatments for rare pediatric diseases.
Further, in February 2020, the FDA granted
Fast Track designation for the ANAVEX®2-73 clinical development program for the treatment of Rett syndrome. The
FDA Fast Track program is designed to facilitate and expedite the development and review of new drugs to address unmet medical
needs in the treatment of serious and life-threatening conditions.
For Parkinson’s disease, data demonstrates
significant improvements and restoration of function in a disease modifying animal model of Parkinson’s disease. Significant
improvements were seen on all measures tested: behavioral, histopathological, and neuroinflammatory endpoints. In October 2020,
we completed a double-blind, randomized, placebo-controlled proof-of-concept Phase 2 trial with ANAVEX®2-73 in Parkinson’s
disease dementia, to study the effect of the compound on both the cognitive and motor impairment of Parkinson’s disease.
The Phase 2 trial enrolled approximately 132 patients for 14 weeks, randomized 1:1:1 to two different ANAVEX®2-73
doses, 30 mg and 50 mg, or placebo. The ANAVEX®2-73 Phase 2 Parkinson’s disease dementia trial design incorporated
genomic precision medicine biomarkers identified in the ANAVEX®2-73 Phase 2a Alzheimer’s disease trial.
The trial demonstrated that ANAVEX®2-73
was safe and well tolerated in oral doses up to 50 mg once daily. The results showed clinically meaningful, dose-dependent, and
statistically significant improvements in the CDR computerized assessment system analysis. We anticipate conducting further clinical
trials of ANAVEX®2-73 in Parkinson’s disease dementia after submitting the results of the trial to the FDA
to obtain regulatory guidance.
In Alzheimer’s disease animal models,
ANAVEX®2-73 has shown pharmacological, histological and behavioral evidence as a potential neuroprotective, anti-amnesic,
anti-convulsive and anti-depressive therapeutic agent, due to its potent affinity to SIGMAR1 and moderate affinities to M1-4 type
muscarinic receptors. In addition, ANAVEX®2-73 has shown a potential dual mechanism which may impact amyloid, tau
pathology and inflammation. In a transgenic Alzheimer’s disease animal model Tg2576, ANAVEX®2-73 induced a
statistically significant neuroprotective effect against the development of oxidative stress in the mouse brain, as well as significantly
increased the expression of functional and synaptic plasticity markers that is apparently amyloid-beta independent. It also statistically
alleviated the learning and memory deficits developed over time in the animals, regardless of sex, both in terms of spatial working
memory and long-term spatial reference memory.
Based on the results of pre-clinical testing,
we initiated and completed a Phase 1 single ascending dose (SAD) clinical trial of ANAVEX®2-73. In this Phase 1
SAD trial, the maximum tolerated single dose was defined per protocol as 55-60 mg. This dose is above the equivalent dose shown
to have positive effects in mouse models of Alzheimer’s disease. There were no significant changes in laboratory or ECG parameters.
ANAVEX®2-73 was well tolerated below the 55-60 mg dose with only mild adverse events in some subjects. Observed
adverse events at doses above the maximum tolerated single dose included headache and dizziness, which were moderate in severity
and reversible. These side effects are often seen with drugs that target CNS conditions, including Alzheimer’s disease.
In November 2016, we completed a Phase 2a clinical
trial for ANAVEX®2-73, for the treatment of Alzheimer’s disease. The open-label randomized trial was designed
to assess the safety and exploratory efficacy of ANAVEX®2-73 in 32 patients with mild-to-moderate Alzheimer’s
disease. The Phase 2a trial met both primary and secondary objectives of the trial.
In July 2018, we presented
the results of a genomic DNA and RNA evaluation of the participants in the Phase 2a clinical trial. More than 33,000 genes were
analyzed using unbiased, data driven, machine learning, artificial intelligence (AI) system for analyzing DNA and RNA data in patients
treated with ANAVEX®2-73. The analysis identified genetic variants that impacted response to ANAVEX®2-73,
among them variants related to the SIGMAR1, the target for ANAVEX®2-73. Results showed that trial participants with
the common SIGMAR1 wild type gene variant, which is estimated to be about 80% of the population worldwide, demonstrated improved
cognitive (MMSE) and the functional (ADCS-ADL) scores. The results from this evaluation supported the continued evaluation of genomic
information in subsequent clinical trials, since these signatures can now be applied to neurological indications tested in future
clinical trials with ANAVEX®2-73 including Alzheimer’s disease, Parkinson’s disease dementia and Rett
syndrome.
ANAVEX®2-73
data met prerequisite information in order to progress into a Phase 2b/3 placebo-controlled trial. On July 2, 2018, the Human Research
Ethics Committee in Australia approved the initiation of our Phase 2b/3, double-blind, randomized, placebo-controlled 48-week safety
and efficacy trial of ANAVEX®2-73 for the treatment of early Alzheimer’s disease. Clinical trial sites in
Canada, the United Kingdom, the Netherlands and Germany were also added. This Phase 2b/3 trial design incorporates inclusion of
genomic precision medicine biomarkers identified in the ANAVEX®2-73 Phase 2a trial. The Phase 2b/3 trial, which
has completed enrollment, randomized 1:1:1 to either two different ANAVEX®2-73 doses or placebo.
We believe preclinical data from our studies
also supports ANAVEX®2-73 as a potential platform drug for other neurodegenerative diseases beyond Alzheimer’s
disease, Parkinson’s disease or Rett syndrome, more specifically, epilepsy, infantile spasms, Fragile X syndrome, Angelman
syndrome, multiple sclerosis and, more recently, tuberous sclerosis complex (TSC). ANAVEX®2-73 demonstrated significant
improvements in all of these indications in the respective preclinical animal models.
In a preclinical study sponsored by the Foundation
for Angelman Syndrome, ANAVEX®2-73 was assessed in a mouse model for the development of audiogenic seizures. The
results indicated that ANAVEX®2-73 administration significantly reduced audiogenic-induced seizures. In a study
sponsored by FRAXA Research Foundation regarding Fragile X syndrome, data demonstrated that ANAVEX®2-73 restored
hippocampal brain-derived neurotrophic factor (BDNF) expression to normal levels. BDNF under-expression has been observed in many
neurodevelopmental and neurodegenerative pathologies. BDNF signaling promotes maturation of both excitatory and inhibitory synapses.
ANAVEX®2-73 normalization of BDNF expression could be a contributing factor for the positive data observed in both
neurodevelopmental and neurodegenerative disorders like Angelman and Fragile X syndromes.
In addition, preclinical data to-date also
indicates that ANAVEX®2-73 has the potential to demonstrate protective effects of mitochondrial enzyme complexes
during pathological conditions, which, if impaired, are believed to play a role in the pathogenesis of neurodegenerative and neurodevelopmental
diseases.
In addition, preclinical data on ANAVEX®2-73
related to multiple sclerosis indicates that ANAVEX®2-73 may promote remyelination in multiple sclerosis disease.
Further, our data also demonstrates that ANAVEX®2-73 has the potential to provide protection for oligodendrocytes
(“OL’s”) and oligodendrocyte precursor cells (“OPC’s”), as well as central nervous system neurons
in addition to helping repair by increasing OPC proliferation and maturation in tissue culture.
In March 2018, we presented preclinical data
of ANAVEX®2-73 in a genetic mouse model of tuberous sclerosis complex (“TSC”). TSC is a rare genetic
disorder characterized by the growth of numerous benign tumors in many parts of the body with a high incidence of seizures. The
preclinical data demonstrated that treatment with ANAVEX®2-73 significantly increased survival and reduced seizures
in those mice.
ANAVEX®3-71
ANAVEX®3-71 is a clinical drug
candidate with a novel mechanism of action via SIGMAR1 activation and M1 muscarinic allosteric modulation, which has been shown
to enhance neuroprotection and cognition in Alzheimer’s disease models. ANAVEX®3-71 is a CNS-penetrable potential
disease modifying treatment for cognitive impairments. We believe it is effective in very small doses against the major Alzheimer’s
hallmarks in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, and also has beneficial effects
on inflammation and mitochondrial dysfunctions. ANAVEX®3-71 indicates extensive therapeutic advantages in Alzheimer’s
and other protein-aggregation-related diseases given its ability to enhance neuroprotection and cognition via SIGMAR1 activation
and M1 muscarinic allosteric modulation.
A preclinical study examined the response of
ANAVEX®3-71 in aged transgenic animal models and showed a significant reduction in the rate of cognitive deficit,
amyloid beta pathology and inflammation with the administration of ANAVEX 3-71. In April 2016, the FDA granted Orphan Drug Designation
to ANAVEX®3-71 for the treatment of FTD.
During pathological conditions ANAVEX®3-71
demonstrated the formation of new synapses between neurons (synaptogenesis) without causing an abnormal increase in the number
of astrocytes. In neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, synaptogenesis is believed
to be impaired. Additional preclinical data presented also indicates that in addition to reducing oxidative stress, ANAVEX®3-71
has the potential to demonstrate protective effects of mitochondrial enzyme complexes during pathological conditions, which, if
impaired, are believed to play a role in the pathogenesis of neurodegenerative and neurodevelopmental diseases.
In July 2020, we commenced the first Phase
1 clinical trial of ANAVEX®3-71. The trial took place in Australia and was a double-blind, randomized, placebo-controlled,
Phase 1 trial to evaluate safety and tolerability, and PK of oral escalating doses of ANAVEX®3-71 including effects
of food and gender in healthy volunteers. The trial met its primary and secondary endpoints of safety, respectively with no serious
adverse events (SAEs) or dose-limiting toxicities observed, as more fully described above under Clinical Trials Overview –
Frontotemporal Dementia.
Based on these results, and ANAVEX®3-71
pre-clinical profile, the Company intends to advance ANAVEX®3-71 into a biomarker-driven clinical development dementia
program for the treatment of schizophrenia, FTD and Alzheimer’s disease, evaluating longitudinal effect of treatment with
ANAVEX®3-71. We believe the results of this clinical trial and preclinical study could serve as a basis for advancing
into respective registration trials in the U.S.
ANAVEX®1-41
ANAVEX®1-41 is a sigma-1 agonist.
Pre-clinical tests revealed significant neuroprotective benefits (i.e., protects nerve cells from degeneration or death) through
the modulation of endoplasmic reticulum, mitochondrial and oxidative stress, which damages and impairs cell viability. In addition,
in animal models, ANAVEX®1-41 prevented the expression of caspase-3, an enzyme that plays a key role in apoptosis
(programmed cell death) and loss of cells in the hippocampus, the part of the brain that regulates learning, emotion and memory.
These activities involve both muscarinic and SIGMAR1 systems through a novel mechanism of action.
Preclinical data presented also indicates that
ANAVEX®1-41 has the potential to demonstrate protective effects of mitochondrial enzyme complexes during pathological
conditions, which, if impaired, are believed to play a role in the pathogenesis of neurodegenerative and neurodevelopmental diseases.
ANAVEX®1066
ANAVEX®1066, a mixed
sigma-1/sigma-2 ligand is designed for the potential treatment of neuropathic and visceral pain. ANAVEX®1066 was
tested in two preclinical models of neuropathic and visceral pain that have been extensively validated in rats. In the chronic
constriction injury model of neuropathic pain, a single oral administration of ANAVEX®1066 dose-dependently restored
the nociceptive threshold in the affected paw to normal levels while leaving the contralateral healthy paw unchanged. Efficacy
was rapid and remained significant for two hours. In a model of visceral pain, chronic colonic hypersensitivity was induced by
injection of an inflammatory agent directly into the colon and a single oral administration of ANAVEX®1066 returned
the nociceptive threshold to control levels in a dose-dependent manner. Companion studies in rats demonstrated the lack of any
effects on normal gastrointestinal transit with ANAVEX®1066 and a favorable safety profile in a battery of behavioral
measures.
ANAVEX®1037
ANAVEX®1037 is designed for
the treatment of prostate and pancreatic cancer. It is a low molecular weight, synthetic compound exhibiting high affinity for
SIGMAR1 at nanomolar levels and moderate affinity for sigma-2 receptors and sodium channels at micromolar levels. In advanced pre-clinical
studies, this compound revealed antitumor potential. It has also been shown to selectively kill human cancer cells without affecting
normal/healthy cells and also to significantly suppress tumor growth in immune-deficient mice models. Scientific publications highlight
the possibility that these ligands may stop tumor growth and induce selective cell death in various tumor cell lines. Sigma receptors
are highly expressed in different tumor cell types. Binding by appropriate sigma-1 and/or sigma-2 ligands can induce selective
apoptosis. In addition, through tumor cell membrane reorganization and interactions with ion channels, we believe our drug candidates
may play an important role in inhibiting the processes of metastasis (spreading of cancer cells from the original site to other
parts of the body), angiogenesis (the formation of new blood vessels) and tumor cell proliferation.
ANAVEX®1037 is currently in
the pre-clinical and clinical testing stages of development, and there is no guarantee that the activity demonstrated in pre-clinical
models will be shown in human testing.
We continue to identify and initiate discussions
with potential strategic and commercial partners to most effectively advance our programs and increase stockholder value. Further,
we may acquire or develop new intellectual property and assign, license, or otherwise transfer our intellectual property to further
our goals.
Our Target Indications
We are developing compounds with potential
application to two broad categories and several specific indications, including:
Central Nervous System Diseases
Cancer
Competition
The drug discovery and development industry
is very competitive, characterized by rapid advancements in technology, where protection of proprietary advancements is essential.
Any product candidates that we may successfully develop and commercialize, may compete with existing therapies, or new therapies
that may become available in the future. Our commercial opportunities could be reduced or eliminated if our competitors develop
and commercialize products that are more effective, have fewer side effects, are more convenient or are less expensive than any
products that we may develop.
We believe our approach to the treatment of
Alzheimer’s disease and other CNS diseases differs from our competitors - our platform may offer a disease-modifying approach
in neurodegenerative and neurodevelopmental diseases by activation of SIGMAR1. In our preclinical studies, when activated by SIGMAR1
agonists, such as ANAVEX®2-73, SIGMAR1 demonstrated reduced cellular stress before and after RNA gene transcription.
Our studies confirm the potential existence of a predictive biomarker of response established through SIGMAR1 mRNA expression that
could be used in future clinical trials. Because of its role in maintaining neuronal homeostasis, we believe sigma receptors show
significant promise as viable targets for therapeutic molecules in an effort to treat Alzheimer’s disease and other CNS diseases
and disorders, including Parkinson’s disease and Rett syndrome, by restoring healthy gene expression.
At this time, our competitors are primarily
other biomedical development companies that are aiming to discover and develop compounds to be used in the treatment of Alzheimer’s
disease and other CNS diseases, and those companies already doing so. We also face competition from academic institutions and government
agencies, both in the United States and abroad.
Our competitors may have significantly greater
financial resources, an established presence in the market, expertise in research and development, manufacturing, preclinical and
clinical testing, may be in the process of obtaining regulatory approvals and marketing of approved products. These competitors
also compete with us in recruiting and retaining qualified scientific and technical personnel, establishing clinical trial sites
and patient registration for clinical trials, as well as in acquiring or developing technologies complementary to, or necessary
for, our programs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative
arrangements with large and established companies.
For additional discussion of the risks
related to competition, see Item 1A “Risk Factors.”
Patents, Trademarks and Intellectual
Property
We hold ownership or exclusive rights
to seventeen U.S. patents, nineteen U.S. patent applications, and various PCT or ex-U.S. patent applications relating to our drug
candidates, methods associated therewith, and to our research programs.
We own one issued U.S. patent entitled
“ANAVEX®2-73 and certain anticholinesterase inhibitors composition and method for neuroprotection” claims
a composition of matter of ANAVEX®2-73 directed to a novel and synergistic neuroprotective compound combined with
donepezil and other cholinesterase inhibitors. This patent is expected to expire in June 2034, absent any patent term extension
for regulatory delays. We own three issued U.S. patents each with claims directed to crystalline forms of ANAVEX®2-73.
The first of these three patents claims crystalline forms of ANAVEX®2-73, dosage forms and compositions containing
crystalline ANAVEX®2-73, and methods of treatment for Alzheimer’s disease using them. This patent is expected
to expire in July 2036, absent any patent term extension for regulatory delays. The second of these three patents claims pharmaceutical
compositions containing a crystalline form of ANAVEX®2-73, and methods of treatment for Alzheimer’s disease
using the compositions. This patent is expected to expire in June 2037, absent any patent term extension for regulatory delays.
The third of these three patents claims pharmaceutical compositions containing a crystalline form of ANAVEX®2-73,
and methods of treatment for Alzheimer’s disease using the compositions. This patent is expected to expire in June 2037,
absent any patent term extension for regulatory delays. We also own two issued U.S. patents for seizure treatment. The first of
these two patents claims methods and dosage forms for treating seizures, the dosage forms containing a low-dose anti-epilepsy drug
combined with either: (i) ANAVEX®2-73 and its active metabolite ANAVEX®19-144; or (ii) ANAVEX®19-144.
The second of these two patents further claims a combination seizure treatment involving administration of an anti-epilepsy drug
combined with (i) ANAVEX®19-144, or (ii) ANAVEX 19-144® and ANAVEX 2-73®. Both patents
are expected to expire in October 2035, absent any patent term extension for regulatory delays. We also own three issued U.S. patents
with claims directed to treating neurodevelopmental disorders. These patents claim methods for treating a neurodevelopmental disorder,
multiple sclerosis, or their related biochemical and functional abnormalitiesby administering ANAVEX®2-73, ANAVEX®19-144,
and/or ANAVEX®1-41 (another sigma receptor ligand similar to ANAVEX®2-73), or compositions thereof.
All three patents are expected to expire in January 2037, absent any patent term extension for regulatory delays. In addition,
we own one issued U.S. Patent with claims directed to methods of treating melanoma with a compound related to ANAVEX®2-73.
This patent is expected to expire in February 2030, absent any patent term extension for regulatory delays. We also own an issued
U.S. patent that claims crystalline forms of ANAVEX®19-144, dosage forms and compositions containing the crystalline
forms of ANAVEX®19-144, and methods of treatment for Alzheimer’s disease. This patent is expected to expire
in July 2036, absent any patent term extension for regulatory delays. Further, we own one issued U.S. Patent with claims directed
to methods of treating cardiac dysfunction with ANAVEX®2-73. This patent is expected to expire in July 2038, absent
any patent term extension for regulatory delays. Additionally, we own one issued U.S. Patent with claims directed to methods of
treating insomnia or anxiety with ANAVEX®2-73, ANAVEX®19-144, and/or ANAVEX®1-41.
This patent is expected to expire in September 2038, absent any patent term extension for regulatory delays.
We also own two issued U.S. patents
related to ANAVEX®1066. The first of these two patents claims methods for treating or preventing pain using (+)
ANAVEX®1066 isomer. The second patent claims methods for treating or preventing pain using (-) ANAVEX®1066
isomer. Both patents are expected to expire in November 2036, absent any patent term extension for regulatory delays.
For ANAVEX®2-73, ANAVEX®19-144,
ANAVEX®1-41, and ANAVEX®1066, we also have granted or pending applications in Australia, Canada,
China, Europe, Japan, and Hong Kong, which are expected to expire after 2035.
With regard to ANAVEX®3-71,
we own exclusive rights to two issued U.S. patents with claims respectively directed to the ANAVEX®3-71 compound
and methods of treating various diseases including Alzheimer’s with the same. These patents are expected to expire in April
2030, and January 2030, respectively, absent any patent term extension for regulatory delays. We also own exclusive rights to related
patents or applications that are granted or pending in Australia, Canada, China, Europe, Japan, Korea, New Zealand, Russia, and
South Africa, which are expected to expire in January 2030.
We also own other patent applications
directed to enantiomers, crystals, formulations, uses, and patient selection methods that may provide additional protection for
one or more of our product candidates.
We regard patents and other intellectual
property rights as corporate assets. Accordingly, we attempt to optimize the value of intellectual property in developing our business
strategy including the selective development, protection, and exploitation of our intellectual property rights. In addition to
filings made with intellectual property authorities, we protect our intellectual property and confidential information by means
of carefully considered processes of communication and the sharing of information, and by the use of confidentiality and non-disclosure
agreements and provisions for the same in contractor’s agreements. While no agreement offers absolute protection, such agreements
provide some form of recourse in the event of disclosure, or anticipated disclosure.
Our intellectual property position,
like that of many biomedical companies, is uncertain and involves complex legal and technical questions for which important legal
principles are unresolved. For more information regarding challenges to our existing or future patents, see “Risk Factors”.
Government regulation
Government authorities in the United
States, at the federal, state and local levels, and other countries extensively regulate, among other things, the research, development,
testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution,
marketing and export and import of products such as those we are developing. A new drug must be approved by the FDA through the
NDA or ANDA process before it may be legally marketed in the United States. We are subject to various government regulations in
connection with the development of our pipeline.
U.S. Drug Development and Regulation
In the United States, the FDA regulates drugs
under the Federal Food, Drug, and Cosmetic Act and its implementing regulations (“FDCA”). The process of obtaining
regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations
require the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at
any time during the product development process, approval process or post approval may subject an applicant to administrative or
judicial sanctions. These sanctions could include the FDA’s refusal to approve pending applications, withdrawal of an approval,
import refusal, a clinical hold, warning letters, product recalls, product seizures, total or partial suspension of production
or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.
Any agency or judicial enforcement action could have a material adverse effect on us.
Once a drug candidate is identified for development,
it enters the preclinical testing stage and an Investigational New Drug Application (“IND”) may be opened for the regulatory
development of the product. Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as
well as other preclinical studies. An IND sponsor must submit the results of the preclinical tests, together with manufacturing
information and analytical data, to the FDA as part of the IND to conduct clinical trials. The sponsor must also include a protocol