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, 2024
☐ 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)
Indicate
by checkmark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.
Yes ☒
No ☐
Indicate
by checkmark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act.
Yes ☐
No ☒
Indicate
by checkmark whether the registrant has (1) filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange
Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2)
has been subject to such filing requirements for the past 90 days.
Yes ☒
No ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule
405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit and post such files).
Yes ☒
No ☐
Indicate
by checkmark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting
company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer”,
“smaller reporting company” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act
☐
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal controls over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered
public accounting firm that prepared or issued its audit report.
Yes ☐
No ☒
If
securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant
included in the filing reflect the correction of an error to previously issued financial statements
☐
Indicate
by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation
received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b).
☐
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act).
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: $412 million based on a price of $5.09 per share, being the closing price of the registrant’s common stock on March 31,
2024.
Indicate the number of shares outstanding of each
of the registrant’s classes of common stock, as of the latest practicable date: 84,815,517 issued and outstanding as of December
23, 2024.
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 62
ITEM 1C. CYBERSECURITY 62
ITEM 2. PROPERTIES 63
ITEM 3. LEGAL PROCEEDINGS 63
ITEM 4. MINE SAFETY DISCLOSURES 64
ITEM 7A QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 70
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA F-1
ITEM 9A. CONTROLS AND PROCEDURES 71
ITEM 9B OTHER INFORMATION 71
ITEM 9C DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 71
PART III 72
ITEM 10 DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 72
ITEM 11. EXECUTIVE COMPENSATION 77
ITEM 14. PRINCIPAL ACCOUNTING FEES AND SERVICES 87
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;
iv
· 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.
v
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 focus is on developing innovative
treatments for Alzheimer’s disease, Parkinson’s disease, schizophrenia, neurodevelopmental, neurodegenerative, and rare diseases,
including Rett syndrome, and other central nervous system (CNS) disorders.
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
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.
6
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, 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.
7
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 either confirm the mechanism of action of ANAVEX®2-73 (blarcamesine)
or 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 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 early Alzheimer’s disease commenced in August 2018. The Phase 2b/3 trial enrolled 508 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 these 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 topline results from the Phase 2b/3 clinical trial. All statistical
analyses were performed by outside consultancy companies.
8
Furthermore, all pre-specified clinical endpoints were 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,
the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the ANAVEX®2-73 and placebo groups
for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, in the patients with
early Alzheimer’s disease.
The comparison of individual dose groups vs placebo
also supports blarcamesine’s efficacy. For the primary endpoint ADAS-Cog13, blarcamesine is significantly better than placebo (−2.027;
P = 0.0079) as well as for both the 50 mg (−2.149; P = 0.021) and the 30 mg (−1.934; P = 0.026) blarcamesine dosage groups
at Week 48, representing that blarcamesine slowed clinical progression at 48 weeks by 36.3% and by 38.5% and 34.6% in 50 mg and 30 mg
groups vs. placebo, respectively. The functional co-primary endpoint, ADCS-ADL, was trending in a positive direction but did not reach
significance at Week 48. The key secondary endpoint CDR-SB was significantly improved vs. placebo (−0.483, P = 0.0104) as well as
in both 50 mg (−0.465; P = 0.045) and 30 mg (−0.502; P = 0.020) groups at Week 48. Clinical Global Impression – Improvement
(“CGI-I”) was also significantly improved vs. placebo (−0.278, P = 0.004) as well as in both the 50 mg (−0.314;
P = 0.008) and the 30 mg (−0.248; P = 0.024) groups at Week 48. The findings are supported by biomarkers, including plasma Aβ42/40-ratio
and reduction of brain atrophy. Blarcamesine significantly slowed brain atrophy in key regions of interest, including the whole brain
by 37.6%, total grey matter by 63.5%, and lateral ventricles by 25.1%.
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.
In November 2024, we announced the submission of a
Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for ANAVEX®2-73 for the treatment of
Alzheimer's disease and, in December 2024, the EMA accepted the submission for scientific review. The MAA, if approved, would allow direct
market access throughout the European Union for oral ANAVEX®2-73 (blarcamesine) for the treatment of Alzheimer’s
disease.
A subsequent long-term open label extension study
of ANAVEX®2-73, referred to as the ATTENTION-AD trial, was initiated for patients who completed the 48-week Phase 2b/3
placebo-controlled trial referenced above. This trial extension for a duration of up to 96/144 additional weeks was completed in June
2024. The trial extension will provide additional longer-term safety and efficacy data of ANAVEX®2-73 in persons with early
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 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.
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 were 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 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. No other clinical trials with
ANAVEX®2-73 related to Rett syndrome have been conducted in the United States.
9
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, Anxiety, Depression, and Mood Scale (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 and subsequent Compassionate Use Program.
The very first trial of ANAVEX®2-73
in pediatric Rett syndrome patients, the EXCELLENCE trial, completed enrollment in February 2023. This randomized, double-blind, placebo-controlled
Phase 2/3 trial in pediatric patients with Rett syndrome included trial sites in Canada, Australia, and the United Kingdom. 92 pediatric
patients with Rett syndrome between the ages of 5 through 17 years were treated daily with up to 30 mg ANAVEX®2-73. Participants
were randomized 2:1 (ANAVEX®2-73:placebo) for 12 weeks, followed by a week 16 safety visit and topline results from this
trial were announced in early January 2024.
After 12 weeks, the study showed improvement on the
key co-primary endpoint RSBQ, which is a detailed 45-item questionnaire for assessing multiple Rett syndrome characteristics by the patients’
caregivers. The other co-primary endpoint, the CGI-I, which represents a less granular assessment by the site investigators using a seven-point
scoring (one=“very much improved” to seven=“very much worse”), was not met.
In an ad-hoc analysis, using the predefined mixed-effect
model for repeated measure (MMRM) method, after 12 weeks of treatment, ANAVEX®2-73-treated patients improved LS Mean (SE)
-12.93 (2.150) points on their RSBQ total score compared to LS Mean (SE) -8.32 (2.537) points in placebo-treated patients. The LS Mean
difference (SE) of -4.61 (2.439) points between treated and placebo groups did not reach statistical significance (n=77; p=0.063). ANAVEX®2-73-treated
patients demonstrated a rapid onset of action with improvements at 4 weeks after treatment with a RSBQ total score LS Mean (SE) -10.32
(2.086) points in the drug-treated group compared to a LS Mean (SE) -5.67 (2.413) points in placebo-treated patients. The LS Mean difference
of -4.65 (2.233) points between treated and placebo groups was statistically significant (n=77; p=0.041).
The key secondary endpoint, the ADAMS, trended favorably.
In the same analysis, scores for all RSBQ and ADAMS subscales improved over the course of the study. Collectively, the RSBQ and ADAMS
demonstrated improvements in multiple areas, impacting positively in particular repetitive movements, nighttime disruptive behaviors,
and social avoidance.
A preliminary review of the safety results indicates
there were no new safety signals in the EXCELLENCE study, reinforcing the favorable and manageable safety profile observed with ANAVEX®2-73
to date.
All patients who participated in the trial were eligible
to receive ANAVEX®2-73 under a voluntary open label extension protocol, which was completed in June 2024.
A high enrollment rate in the Open Label Extension
(“OLE”) of over 91% and the high level of requests for the Compassionate Use Program (93%) provide solid numerical evidence
for the reported positive Real World Evidence (RWE) from patients with Rett syndrome under Compassionate Use Authorization. Families whose
children were previously on drug or placebo in the placebo-controlled trial commented favorably on the improvement of their child’s
daily life due to ANAVEX®2-73 treatment in the Compassionate Use Program.
10
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 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), 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 pre-specified 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 >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.
11
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.
In January 2024,
in another peer-reviewed publication in the journal Clinical Pharmacology in Drug Development, entitled, ‘Population-Based
Characterization of the Pharmacokinetics and Food Effect of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor
Agonist in Development for Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer Disease’, reported the population-based
characterization of the PK and food effect of ANAVEX®3-71 as part of the single ascending dose study in healthy participants
with the primary objective of assessing dose proportionality of ANAVEX®3-71, and to characterize the effect of food on
the PK of ANAVEX®3-71. The results from this PK evaluation demonstrated that ANAVEX®3-71, at single ascending
doses of 5 to 200 mg, is linear, dose proportional, and time invariant. Food had no effect on the PK of ANAVEX®3-71. This
data also expands the safety objectives met in this first-in-human study of ANAVEX®3-71, further supporting its drug development
program.
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.
Schizophrenia
In March 2024,
we commenced the U.S. FDA-cleared ANAVEX®3-71-SZ-001 clinical trial: a double-blind, placebo-controlled Phase 2 trial in
schizophrenia. The trial consists of two parts to explore multiple ascending doses in individuals with schizophrenia followed by a 28-day
treatment period in a larger cohort. The trial will utilize standard clinical outcome measures for schizophrenia including the Positive
and Negative Symptoms Scale (PANSS), and novel fluid and electrophysiological biomarkers will also be assessed, leveraging several advances
in electroencephalography/event-related potential (EEG/ERP) biomarkers in schizophrenia developed in collaboration with the industry-led
ERP Biomarker Qualification Consortium. In addition to the electrophysiological biomarkers, we are also applying novel neuroinflammatory,
metabolomic, and transcriptomic biomarkers at the intersection of schizophrenia pathophysiology and ANAVEX®3-71’s
novel, dual mechanism of action.
12
Preliminary
results from Part A of the ANAVEX®3-71-SZ-001 clinical trial, consisting of a multiple ascending dose study in 16 participants,
demonstrated a dose-dependent effect of ANAVEX®3-71 on two key EEG biomarkers in patients with schizophrenia. The effects
were most pronounced in the higher dose group indicating a dose-dependent pharmacodynamic effect. The observed changes reversed known
electroencephalography (EEG) and ERP biomarker abnormalities associated with schizophrenia. These EEG biomarkers correlate with positive,
negative, and cognitive symptoms of schizophrenia.
The currently
ongoing Part B of the placebo-controlled Phase 2 study, which includes more participants and a longer treatment duration, will provide
more comprehensive data on the efficacy and safety of ANAVEX®3-71 in schizophrenia.
Our Pipeline
Our research and development pipeline includes ANAVEX®2-73
currently in three different clinical trial indications, and ANAVEX®3-71 currently in one clinical trial 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 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.
13
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 regulatory authorities 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.
14
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 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 and oligodendrocyte
precursor cells (“OPCs”), 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 an orally available
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 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.
15
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 – Schizophrenia, Frontotemporal Dementia and Alzheimer’s disease.
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.
The first of
these trials, the ANAVEX®3-71-SZ-001 clinical trial, commenced in March 2024 and is more fully described above under
Clinical Trials Overview – Schizophrenia.
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.