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, 2025
☐ 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)
(State or other jurisdiction of (IRS Employer
incorporation or organization) Identification No.)
630 5th Avenue, 20th Floor, New York, NYUSA
10111
(Address of principal executive offices) (Zip
Code)
1-844-689-3939
(Registrant’s telephone number,
including area code)
Securities Registered Pursuant to Section 12(b)
of the Act:
Title of Each Class Trading Symbol Name of Each Exchange on Which Registered
Common Stock Par Value $0.001 AVXL NASDAQ Stock Market LLC
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: $708 million based on a price of $8.58 per share, being the closing price of the registrant’s common stock on March 31,
2025.
Indicate the number of shares outstanding of each
of the registrant’s classes of common stock, as of the latest practicable date: 89,348,107 issued and outstanding as of November
24, 2025.
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 63
ITEM 1C. CYBERSECURITY 63
ITEM 2. PROPERTIES 64
ITEM 3. LEGAL PROCEEDINGS 64
ITEM 4. MINE SAFETY DISCLOSURES 65
ITEM 7A QUANTITATIVE AND QUALITATIVE DISCLOSURES ABOUT MARKET RISK 72
ITEM 8. FINANCIAL STATEMENTS AND SUPPLEMENTARY DATA F-1
ITEM 9A. CONTROLS AND PROCEDURES 73
ITEM 9B OTHER INFORMATION 73
ITEM 9C DISCLOSURE REGARDING FOREIGN JURISDICTIONS THAT PREVENT INSPECTIONS 73
PART III 74
ITEM 10 DIRECTORS, EXECUTIVE OFFICERS AND CORPORATE GOVERNANCE 74
ITEM 11. EXECUTIVE COMPENSATION 78
ITEM 14. PRINCIPAL ACCOUNTING FEES AND SERVICES 92
ITEM 15. EXHIBITS, FINANCIAL STATEMENT SCHEDULES 94
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;
· competition;
· the anticipated designs of our future clinical trials;
iv
· our ability to attract and retain qualified employees;
We have based these forward-looking statements largely
on our current expectations and projections about future events, including the responses we expect from the FDA, EMA 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.
The Company’s 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.
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.
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. 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 also play a role in modulating
the cellular response to viral infection and ameliorate pathogenesis.
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.
Clinical Program Overview
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 as well as an oral once-daily capsule formulation for diseases such as Alzheimer’s disease and Parkinson’s
disease, and in an oral liquid once-daily formulation for rare diseases such as Rett syndrome and Fragile X.
7
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 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.
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. This larger Phase 2b/3 double-blind,
placebo-controlled trial of ANAVEX®2-73 in early Alzheimer’s disease commenced in August 2018. The 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.
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.
8
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), under the centralized procedure, 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 company seeking to market a new pharmaceutical product through the centralized procedure must
file safety data and efficacy data as part of the MAA. After the EMA evaluates the MAA, it provides a recommendation to the European Commission
(“EC”) and the EC then approves or denies the MAA. On November 14, 2025, we announced that we were informed by the Committee
for Medicinal Products for Human Use (CHMP) of the EMA of a negative trend vote on the MAA following an oral explanation. The CHMP is
expected to adopt a formal opinion on the MAA at its December 2025 meeting. We plan to request a re-examination of the CHMP opinion
upon its formal adoption.
A 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 demonstrated that
blarcamesine-treated patients continued to accrue benefit through up to 192 weeks, as measured by the clinical endpoints ADAS-Cog13
(LS mean difference -3.83; P = 0.0165) and ADCS-ADL (LS mean difference +4.30, P = 0.0206). No new safety findings were observed with
continued blarcamesine treatment over three years, confirming good comparative safety profile and no associated neuroimaging
adverse events. Delayed-start analysis of treatment with oral blarcamesine was significant, reflecting the importance of early treatment initiation.
Additional precision medicine population 48-week data
demonstrates cognitive stabilization in early Alzheimer’s disease. Cognitive outcomes observed in the oral blarcamesine 30 mg precision
medicine cohort move toward normal aging profiles across validated clinical scales. For ADAS-Cog13, blarcamesine showed a 48-week change
from baseline of 0.853 compared to ~1 point typical annual decline in prodromal (pre-dementia) aging adults. For CDR-SB, blarcamesine
demonstrated a change from baseline of 0.465, aligning with the 0-0.5 point annual range seen in prodromal aging. These data are similar
to referenced barely detectable prodromal Alzheimer’s disease decline, in spite of the more advanced stage of Alzheimer’s
disease impairment at baseline of the blarcamesine population.
Further
posthoc analysis demonstrates continued long-term benefit from oral blarcamesine compared to decline observed in the Alzheimer’s
Disease Neuroimaging Initiative (ADNI) control group. Externally matched control participants from the ADNI database were compared with
participants over the 144-week period of ANAVEXÒ2-73-AD-004
and its ATTENTION-AD (ANAVEXÒ2-73-AD-EP-004)
open-label extension (OLE) Phase IIb/III trial.[1] For ADAS-Cog13, total score ranges
from 0 to 85 with higher scores indicating increased cognitive impairment.
[1]Observed raw data was used. Scheduled visits were [OLE Week 0 = Combined Week 48], [OLE Week 48 = Combined
Week 96], [OLE Week 96 = Combined Week 144]; Combined = DB (double-blind) + OLE (open-label-extension) trials. Up to 144 weeks ADNI control
group data was available.
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In the intent-to-treat (ITT) population, significantly
less cognitive decline was observed for the blarcamesine participants compared to the ADNI control group at 48 weeks with a significant,
and clinically meaningful difference in mean change from baseline ADAS-Cog13 total score of −2.68 points (p < 0.0001).[2]
Over the course of the open-label extension study
at time point 96 weeks, these two groups diverged sharply, with statistically significant differences in mean change in ADAS-Cog13 total
score at 96 weeks of −6.41 points (p < 0.0001). The difference between groups continues to increase at 144 weeks (ADAS-Cog13
total score difference of −12.78 points; p < 0.0001).
The results provide evidence of the significant beneficial
therapeutic effect of blarcamesine, which positively separates from the ADNI control group with duration of treatment.
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 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.
[2] ADAS-Cog13 scores
LS mean difference between the treatment groups being larger than 2 points are considered clinically meaningful improvements: Muir RT,
Hill MD, Black SE, Smith EE. Minimal clinically important difference in Alzheimer's disease: Rapid review. Alzheimers Dement. 2024;20(5):3352-3363.
10
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.
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.
Also with respect to Parkinson’s disease, in
January 2021, we were awarded a research grant of $1.0 million from The Michael J. Fox Foundation for Parkinson’s Research to
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. This study is currently in the planning stage.
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.
Our Rett syndrome program includes several clinical trials that were conducted
in a range of patient age demographics and geographic regions, utilizing an oral liquid once-daily formulation of ANAVEX®2-73.
The FDA has granted Orphan Drug Designation and 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. Additionally, the FDA has 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. An earlier application for a proposed Rett syndrome study in the United States resulted in
the FDA requesting additional information. The resulting clinical hold and subsequent partial clinical hold have since been removed after
the Company satisfactorily provided the additional information requested. The following is a summary of clinical trials conducted by the
Company in Rett syndrome. The first Phase 2 trial, (ANAVEX®2-73-RS-001), took place in the United States, and 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.
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This clinical trial was funded, in part, by a financial
grant from the International Rett Syndrome Foundation of $0.6 million. No other clinical trials with ANAVEX®2-73 related
to Rett syndrome have been conducted in the United States.
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.
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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.
Other indications
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®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. 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
certain indications in which ANAVEX®2-73 (blarcamesine) is being studied.
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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 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. The FDA has granted Orphan Drug Designation to ANAVEX®3-71 for the
treatment of Frontotemporal Demetia (“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-in-Human Phase
1 clinical trial of ANAVEX®3-71. The Phase 1 clinical trial was a prospective double-blind,
randomized, placebo-controlled trial conducted 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 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. The first of these trials is being conducted in schizophrenia.
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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.
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.
In May 2025
we announced the completion of enrollment of Part B of the study, which included more participants and a longer treatment duration. The
top-line data of the Phase 2 ANAVEX®3-71-SZ-001 clinical was announced in October 2025. The study successfully achieved
its primary endpoint, demonstrating that ANAVEX®3-71 was safe and well-tolerated. The safety profile was consistent with
previous studies of ANAVEX®3-71 in healthy volunteers, with no serious treatment-emergent adverse events (TEAEs) and no
severe TEAEs reported in either Part A or Part B of the study. In addition to meeting the primary safety endpoint, secondary and exploratory
analyses revealed encouraging trends in several outcome measures. The study demonstrated positive trends in objective electroencephalography
(EEG) and event-related potential (ERP) biomarkers of schizophrenia. Furthermore, neuroinflammatory biomarker assessments showed that
glial fibrillary acidic protein (GFAP), a marker of neuroinflammation, was reduced in participants receiving ANAVEX®3-71
compared to placebo. This reduction in neuroinflammatory markers suggests a potential disease-modifying effect that may become more pronounced
with longer treatment durations.
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.
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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 sigma-1 receptors 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
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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.
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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 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,
or 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 thirty (30)
issued U.S. patents, seventeen (17) pending U.S. patent applications, and numerous PCT and ex-U.S. patents and 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,” which claims a composition of matter of ANAVEX®2-73,
a 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 another 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 five issued U.S. patents each with claims directed
to crystalline forms of ANAVEX®2-73. The first of these five 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