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,
2023
☐ 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 ☐
Non-accelerated filer ☐ Smaller reporting company ☐
Emerging growth company☐
☐
☐
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: $667 million based on a price of $8.57 per share, being the closing price of the registrant’s
common stock on March 31, 2023.
Indicate the number of shares outstanding of
each of the registrant’s classes of common stock, as of the latest practicable date: 82,086,511 issued and outstanding as
of November 24, 2023.
DOCUMENTS INCORPORATED BY REFERENCE
None.
ii
TABLE OF CONTENTS
PART I 6
ITEM 1. BUSINESS 6
ITEM 1A. RISK FACTORS 32
ITEM 1B. UNRESOLVED STAFF COMMENTS 60
ITEM 2. PROPERTIES 60
ITEM 3. LEGAL PROCEEDINGS 60
ITEM 4. MINE SAFETY DISCLOSURES 61
ITEM 7A QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 67
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA F-1
ITEM 9A. CONTROLS AND PROCEDURES 69
ITEM 9B OTHER INFORMATION 70
ITEM 9C DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 70
PART III 70
ITEM 10 DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 70
ITEM 11. EXECUTIVE COMPENSATION 74
ITEM 14. PRINCIPAL ACCOUNTING FEES AND SERVICES 86
ITEM 15. EXHIBITS, FINANCIAL STATEMENT SCHEDULES 88
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;
● 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 studies 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
(blarcamesine), 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;
1. EXCELLENCE: Ongoing trial
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 (blarcamesine) 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 (blarcamesine), 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 (blarcamesine)-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 (blarcamesine)
has helped us identify actionable genetic variants. A significant impact of the genomic biomarkers SIGMAR1, the direct target of
ANAVEX®2-73 (blarcamesine) and COMT, a gene involved in memory function, on the drug response level was identified,
leading to an early ANAVEX®2-73 (blarcamesine)-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 (blarcamesine), 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 (blarcamesine) by using genetic biomarkers identified within the trial population itself
to target patients who are most likely to respond to ANAVEX®2-73 (blarcamesine) 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 (blarcamesine) 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 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,
which were treated with a convenient once-daily oral formulation of ANAVEX®2-73 for 48 weeks, randomized 1:1:1 to
two different ANAVEX®2-73 doses or placebo. The trial took place at 52 sites across North America, Europe and Australia.
Primary and secondary endpoints to assess safety and both cognitive and functional efficacy, were measured through the Alzheimer’s
Disease Assessment Scale – Cognitive Subscale test (“ADAS-Cog”), Alzheimer’s Disease Cooperative Study
– Activities of Daily Living (“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 previously identified in the ANAVEX®2-73
Phase 2a clinical trial. The trial was completed in mid-2022 and, in December 2022, the Company presented positive topline results
from the Phase 2b/3 clinical trial.
ANAVEX®2-73 met the co-primary
endpoints ADAS-Cog and ADCS-ADL and key secondary endpoint CDR-SB. ANAVEX®2-73 treatment slowed decline of cognition
and function in patients with early Alzheimer’s disease over 48 weeks. Patients treated with ANAVEX®2-73 had
1.84 times higher odds, or likelihood, to improve cognitively compared to placebo, with a ADAS-Cog score threshold change of -0.5
points or better [Odds Ratio = 1.84 (p = 0.015)]. At clinically significant levels of improvement in function (ADCS-ADL score threshold
change of +3.5 points or better), patients treated with ANAVEX®2-73 had 2.67 times higher odds, or likelihood, to
improve function compared to placebo [Odds Ratio = 2.67 (p = 0.0255)]. Additionally, treatment with
ANAVEX®2-73 reduced cognitive decline at end of treatment, measured with the ADAS-Cog, as compared to placebo, by
45%, representing a treatment difference in mean score change of -1.85 points (p=0.033). Compared to placebo, ANAVEX®2-73
reduced clinical decline of cognition and function by 27% with mean score difference of -0.42 points (p=0.040) as measured by the
CDR-SB. ANAVEX®2-73 was generally safe and well tolerated. All statistical analyses were
performed by outside consultancy companies.
In September 2023, we provided additional
data demonstrating that the clinical effect was complemented by two independent biomarkers. A significant reduction in pathological
amyloid beta levels in plasma, as well as a significant slowing in the rate of pathological brain atrophy on MRI (Magnetic Resonance
Imaging) scans. Validated biomarkers of amyloid beta pathology, plasma Aβ42/40 ratio increased significantly (P = 0.048),
demonstrating strong anti-amyloid effects of ANAVEX®2-73 in Alzheimer’s disease patients, while MRI revealed
significant reduction in brain volume loss, including whole brain (P = 0.0005), comparing treatment to placebo.
Furthermore, all prespecified clinical
endpoints were further analyzed using a mixed model for repeated measures (MMRM). Under the multiplicity control rule, a trial
is successful in meeting the co-primary endpoints if the significance of each endpoint is P < 0.05, or if the significance of
only one co-primary endpoint is P < 0.025. If only one primary endpoint is significant at an α level of 0.025, then the
secondary endpoint will be evaluated at the same level of 0.025. The trial was successful, since the differences in the least-squares
mean (LSM) change from baseline to 48 weeks between the ANAVEX®2-73 and placebo groups were −1.783 [95% CI,
−3.314 to −0.251]; (P = 0.0226) for ADAS-Cog13, and −0.456 [95% CI, −0.831 to −0.080]; (P = 0.0175)
for CDR-SB in patients with early Alzheimer’s disease.
In the respective safety population,
common treatment-emergent adverse events included dizziness, which was transient and mostly mild to moderate in severity, and occurred
in 120 participants (35.8%) during titration and in 76 participants (25.2%) during maintenance with ANAVEX®2-73
and 10 (6.0%) during titration and 9 (5.6%) during maintenance with placebo.
A subsequent long-term open label extension
study of ANAVEX®2-73, entitled the ATTENTION-AD trial was initiated for patients who have completed the 48-week
Phase 2b/3 placebo-controlled trial referenced above. This trial extension for an additional 96 weeks is currently ongoing, and
provides an opportunity to evaluate longer term safety and efficacy of ANAVEX®2-73 in persons with Alzheimer’s
disease.
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 an 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. This trial completed enrollment in February 2023, exceeding
the original enrollment target. In June 2023, this trial completed dosing of all participants, and topline results are expected
in the second half of 2023. 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 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 (“MDS-UPDRS”)
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.
A 48-week Open Label Extension (“OLE”)
ANAVEX2-73-PDD-EP-001 Phase 2 trial was offered to participants after completion of the double-blind placebo-controlled ANAVEX2-73-PDD-001
Phase 2 trial discussed above. The OLE trial assessed safety, tolerability and efficacy, measuring among others, MDS-Unified Parkinson’s
Disease Rating Scale Parts I, II, III, REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Clinical Global Impression
– Improvement (CGI-I), as well as cognitive efficacy endpoint Montreal Cognitive Assessment (MoCA) over a 48-week period.
In March 2023, we reported the preliminary
ANAVEX2-73-PDD-EP-001 OLE trial data, which demonstrated longitudinal beneficial effects of ANAVEX®2-73 on the prespecified
primary and secondary objectives. Preliminary analysis reveals that ANAVEX®2-73 was found to be generally safe and
well tolerated; and safety findings in this trial were consistent with the known safety profile of ANAVEX®2-73.
In respect to efficacy, across all efficacy endpoints, patients performed better while on ANAVEX®2-73. While all
patients were on drug holiday due to COVID-19 between the DB EOT and the OLE Baseline, the respective efficacy endpoints, including
the MDS-UPDRS Part II + III and CGI-I, measured at the end of trial of the double-blind study (DB EOT) and the OLE Baseline, were
worsening, as expected in a progressive disease like Parkinson’s. However, when patients resumed daily oral ANAVEX®2-73
treatment, a consistent improvement was observed during the extension phase from OLE Baseline through OLE Week 24, and OLE Week
48, respectively. These results are consistent with the pattern observed for all efficacy measures in the extension phase. The
two endpoints, MDS-UPDRS Part II + III and CGI-I measured in this study are the planned primary and key secondary endpoints in
our forthcoming pivotal 6-month Parkinson’s disease study.
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, including in people with Parkinson’s
disease.
Schizophrenia, Frontotemporal Dementia and
Alzheimer’s disease
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.
In October
2023 a peer-reviewed publication in the journal Neurobiology of Aging, titled “Early treatment with an M1 and sigma-1 receptor
agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology”, featured the orally
available small molecule ANAVEX®3-71 (AF710B). The preclinical study described the potential disease-modifying
properties of ANAVEX®3-71 on Alzheimer’s disease pathology as a possible drug candidate for a potential once
daily oral preventive strategy for Alzheimer’s disease.
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 a basis for advancing into respective registration trials 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, 30mg and 50mg, 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 50mg 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 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.
We believe preclinical data from our studies
also supports further research into the use of 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 mice. 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 preclinical
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, may 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 twenty-two
U.S. patents, twenty-three 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 one issued U.S. patent
entitled “A2-73 crystalline polymorph compositions of matter and methods of use thereof”. It claims crystals of A2-73
freebase or its fumarate salt, dosage forms and pharmaceutical formulations. This patent is expected to expire in July 2039, absent
any patent term extension for regulatory delays. We own four issued U.S. patents each with claims directed to crystalline forms
of ANAVEX®2-73. The first of these four 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
four 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 2036, absent any patent term extension
for
regulatory delays. The third of these four 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 2036,
absent any patent term extension for regulatory delays. The fourth of these four patents claims method of making certain crystalline
forms ANAVEX®2-73. This patent is expected to expire in October 2036, absent any patent term extension for regulatory
delays. We also own three issued U.S. patents for seizure treatment. The first of these three 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 three patents
further claims a combination seizure treatment involving administration of an anti-epilepsy drug combined with (i) ANAVEX®19-144,