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Item 1. Business

2022-11-28 compared with 2021-11-24 · 662 added, 583 removed, 705 unchanged (64% of the section changed)

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system (“CNS”) diseases with high unmet need.

We analyze genomic data from clinical studies to identify biomarkers,

which we use to select patients that will receive the therapeutic benefit for the treatment of neurodegenerative and neurodevelopmental

Our lead compound, ANAVEX ® 2-73,

We analyze genomic data from clinical trials to identify biomarkers,

which we use in the analysis of our clinical trials.

Our lead product candidate, ANAVEX ® 2-73,

is being developed to treat Alzheimer’s disease, Parkinson’s disease and potentially other central nervous system diseases,

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* = Orphan Drug Designation by the FDA;

Dashed lines indicate planned clinical studies

Dashed lines indicate planned clinical trials to-date

Anavex has a portfolio of compounds varying

in sigma-1 receptor (S1R) binding activities.

The SIGMAR1 gene encodes the S1R protein, which is an intracellular chaperone protein

with important roles in cellular communication.

S1R is also involved in transcriptional regulation at the nuclear envelope and

restores homeostasis and stimulates recovery of cell function when activated.

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 S1R, we performed, in collaboration with Stanford University, a quantitative Positron Emission Tomography

(PET) imaging scan in mice, which demonstrated a dose-dependent ANAVEX ® 2-73 target engagement or receptor occupancy

(RO) with S1R in the brain.

to activate quantitatively the SIGMAR1, we performed, in collaboration with Stanford University, a quantitative Positron Emission

Tomography (PET) imaging scan in mice, which demonstrated a dose-dependent ANAVEX ® 2-73 target engagement or receptor

occupancy with SIGMAR1 in the brain.

Reyes S et al., Sci Rep.

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by chronic homeostatic imbalances or cellular stress of brain cells.

In pediatric diseases like Rett syndrome or infantile spasms,

the chronic cellular stress is possibly caused by the presence of a constant genetic mutation.

In neurodegenerative diseases, such

as Alzheimer’s and Parkinson’s diseases, chronic cellular stress is possibly caused by age-correlated buildup of cellular

insult and hence chronic cellular stress.

In pediatric diseases, such as Rett syndrome or infantile

spasms, the chronic cellular stress is possibly caused by the presence of a constant genetic mutation.

In neurodegenerative diseases,

such as Alzheimer’s and Parkinson’s diseases, chronic cellular stress is possibly caused by age-correlated buildup

of cellular insult and hence chronic cellular stress.

Specifically, defects in homeostasis of protein or ribonucleic acid (“RNA”)

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The spreading of protein aggregates resulting in a proteinopathy,

a characteristic finding 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, 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.

a characteristic found in Alzheimer’s and Parkinson’s diseases that results from disorders of protein synthesis, trafficking,

folding, processing or degradation in cells.

The clearance of macromolecules in the brain is particularly susceptible to imbalances

that result in aggregation and degeneration in nerve cells.

For example, Alzheimer’s disease pathology is characterized by

the presence of amyloid plaques, and neurofibrillary tangles, which are aggregates of hyperphosphorylated Tau protein that are

a marker of other diseases known as tauopathies as well as inflammation of microglia.

With the SIGMAR1 activation through SIGMAR1

agonists like ANAVEX ® 2-73, our approach is to restore cellular balance (i.e.

homeostasis).

Therapies that correct

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ANAVEX ® 2-73-specific Biomarkers

A full genomic analysis of Alzheimer’s

disease (AD) patients treated with ANAVEX ® 2-73 resulted in the identification of actionable genetic variants.

significant impact of the genomic biomarkers SIGMAR1, the direct target of ANAVEX ® 2-73 and COMT, a gene involved

in memory function, on the drug response level was identified, leading to an early ANAVEX ® 2-73-specific biomarker

It is expected 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

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.

our clinical trials, a full genomic analysis of Alzheimer’s disease patients treated with ANAVEX ® 2-73 has

helped us identify actionable genetic variants.

A significant impact of the genomic biomarkers SIGMAR1, the direct target of ANAVEX ® 2-73

and COMT, a gene involved in memory function, on the drug response level was identified, leading to an early ANAVEX ® 2-73-specific

biomarker hypothesis.

We believe that excluding patients with SIGMAR1 identified biomarker variant (approximately 10%-20%

of the population) in prospective studies would identify approximately 80%-90% patients that would display clinically significant

improved functional and cognitive scores.

The consistency between the identified DNA and RNA data related to ANAVEX ® 2-73,

which are considered independent of AD pathology, as well as multiple endpoints and time-points, provides support for precision

medicine clinical development of ANAVEX ® 2-73 by using genetic biomarkers identified within the study population

itself to target patients who are most likely to respond to ANAVEX ® 2-73 treatment in AD as well as indications

like Parkinson’s disease dementia (PDD) or Rett syndrome (RTT) in which ANAVEX ® 2-73 is currently studied.

Clinical Studies Overview

which are considered independent of Alzheimer’s disease pathology, as well as multiple endpoints and time-points, provides

support for the potential precision medicine clinical development of ANAVEX ® 2-73 by using genetic biomarkers identified

within the trial population itself to target patients who are most likely to respond to ANAVEX ® 2-73 treatment.

may in the future utilize such an approach in Alzheimer’s disease as well as indications like Parkinson’s disease dementia

or Rett syndrome in which ANAVEX ® 2-73 is currently being studied.

Clinical Trials Overview

Alzheimer’s Disease

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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

This open-label randomized trial 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.

The Phase 2a trial demonstrated positive pharmacokinetic (PK)

and pharmacodynamic (PD) data, which established a concentration-effect relationship between ANAVEX ® 2-73 and study

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 study appears to show that ANAVEX ® 2-73

activity is enhanced by its active metabolite (ANAVEX19-144), which also targets the sigma-1 receptor and has a half-life approximately

twice as long as the parent molecule.

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 study 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 (TGA) compassionate use Special Access Scheme.

2a trial have allowed participants who completed the 52-week Part B of the trial to continue taking ANAVEX ® 2-73,

providing us an opportunity to gather extended safety data for a cumulative time period of five years.

In August 2020, patients

completing these Phase 2a trial extensions were granted continued access to treatment with ANAVEX ® 2-73 through the

Australian Government Department of Health – Therapeutic Goods Administration’s compassionate use Special Access Scheme.

A larger Phase 2b/3 double-blind, placebo-controlled

study of ANAVEX ® 2-73 in Alzheimer’s disease commenced in August 2018.

The Phase 2b/3 study enrolled 509 patients

trial of ANAVEX ® 2-73 in Alzheimer’s disease commenced in August 2018.

The Phase 2b/3 trial enrolled 509 patients

for 48 weeks, randomized 1:1:1 to two different ANAVEX ® 2-73 doses or placebo.

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and during fiscal 2020 additional regions were added in the United Kingdom, The Netherlands, Germany and Canada.

The ANAVEX ® 2-73

Phase 2b/3 study design incorporates genomic precision medicine biomarkers identified in the ANAVEX ® 2-73 Phase 2a

Primary and secondary endpoints will assess safety and both cognitive and functional efficacy, measured through Alzheimer’s

Disease Assessment Scale – Cognition (ADAS-Cog), ADCS-ADL and Clinical Dementia Rating – Sum of Boxes for cognition

and function (CDR-SB).

The study completed enrollment in June 2021, exceeding the 450 patients enrollment target at 52 sites across

North America, Europe and Australia.

In October 2019, we initiated a long-term open

label extension study of ANAVEX ® 2-73, entitled the ATTENTION-AD study, for patients who have completed the 48-week

Phase 2b/3 placebo-controlled trial referenced above.

This study is expected to last two years and will give patients the opportunity

to continue their treatment.

Upon request by patients, caretakers and investigators, this extension study was extended by one further

Primary and secondary

endpoints will assess safety and both cognitive and functional efficacy, measured through Alzheimer’s Disease Assessment

Scale – Cognition (ADAS-Cog), ADCS-ADL and Clinical Dementia Rating – Sum of Boxes for cognition and function (CDR-SB).

In addition to the primary endpoints, the ANAVEX ® 2-73 Phase 2b/3 trial design incorporated pre-specified statistical

analyses related to potential genomic precision medicine biomarkers identified in the ANAVEX ® 2-73 Phase 2a clinical

The trial completed enrollment in June 2021, exceeding the 450 patient enrollment target at 52 sites across Canada, Europe

and Australia.

In October 2019, we initiated a long-term

open label extension study of ANAVEX ® 2-73, entitled the ATTENTION-AD trial, for patients who have completed the

48-week Phase 2b/3 placebo-controlled trial referenced above.

This trial extension for an additional two years gives patients

the opportunity to continue their treatment.

Upon request by patients, caretakers and investigators, this extension trial was

extended by one additional year.

Rett Syndrome

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data for ANAVEX ® 2-73 in Rett syndrome, a rare neurodevelopmental disease.

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.

The data demonstrated dose related and

significant improvements in an array of behavioral and gait paradigms in a mouse model with a MECP2-null mutation that causes neurological

symptoms that mimic Rett syndrome.

The study was funded by the International Rett Syndrome Foundation (“Rettsyndrome.org”).

In January 2017, we were awarded a financial grant

from Rettsyndrome.org of a minimum of $0.6 million to cover some of the costs of a multicenter Phase 2 clinical trial of ANAVEX ® 2-73

for the treatment of Rett syndrome.

This award was received in quarterly instalments which commenced during fiscal 2018.

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2 clinical trial in a planned Rett syndrome program of ANAVEX ® 2-73 for the treatment of Rett syndrome.

are being conducted in a range of patient age demographics and geographic regions, utilizing a convenient oral liquid once-daily

formulation of ANAVEX ® 2-73.

The first Phase 2 study, which took

place in the United States, was completed in December 2020.

This trial was a randomized double-blind, placebo-controlled safety,

tolerability, pharmacokinetic and efficacy study 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.

trials are being conducted in a range of patient age demographics and geographic regions, utilizing an oral liquid once-daily formulation

of ANAVEX ® 2-73.

The first Phase 2 trial, (ANAVEX®2-73-RS-001), which took place in the

United States, was completed in December 2020.

This trial was a randomized double-blind, placebo-controlled safety, tolerability, PK and

efficacy trial of oral liquid ANAVEX ® 2-73 formulation in 25 adult female patients with Rett syndrome over a 7-week treatment

period including ANAVEX ® 2-73-specific genomic precision medicine biomarkers.

The primary endpoint of the trial was safety.

The dosing of 5 mg ANAVEX ® 2-73 was well-tolerated and demonstrated

dose-proportional PK (pharmacokinetics).

All secondary efficacy endpoints of the trial showed statistically significant and clinically

meaningful, drug exposure-dependent response in the Rett Syndrome Behaviour Questionnaire (RSBQ) Total scores, when compared to

placebo, in the ITT cohort (all participants, p = 0.048).

66.7% of ANAVEX ® 2-73 treated subjects showed a statistically

significant improvement in drug exposure-dependent RSBQ response as compared to 10% of the subjects on placebo in the ITT cohort

The dosing of 5 mg ANAVEX ® 2-73 was well-tolerated and demonstrated dose-proportional PK.

All secondary efficacy endpoints

of the trial showed statistically significant and clinically meaningful response in the Rett Syndrome Behaviour Questionnaire (“RSBQ”)

response, when compared to placebo, in the intent to treat (“ITT”) cohort (all participants, p = 0.011).

66.7% of ANAVEX ® 2-73

treated subjects showed a statistically significant improvement in RSBQ response as compared to 10% of the subjects on placebo in the

ITT cohort (all participants, p = 0.011).

ANAVEX ® 2-73 treatment resulted in a sustained improvement in Clinical Global

Impression Improvement (“CGI-I”) response throughout the 7-week clinical trial, when compared to placebo in the ITT cohort

(all participants, p = 0.014).

ANAVEX ® 2-73 treatment resulted in a sustained improvement in Clinical Global Impression

Improvement (CGI-I) scores throughout the 7-week study, when compared to placebo in the ITT cohort (all participants, p = 0.014).

86.7% of ANAVEX ® 2-73 treated subjects showed a statistically significant CGI-I response, defined as sustained improvement

to treatment, as compared to 40% of the subjects on placebo in the ITT cohort (all participants, p = 0.014).

Consistent with previous

ANAVEX ® 2-73 clinical trials, patients carrying the common form of the SIGMAR1 gene treated with ANAVEX ® 2-73

experienced stronger improvements in the prespecified efficacy endpoints.

The second Phase 2 study of ANAVEX ® 2-73

for the treatment of Rett syndrome, called the AVATAR study, commenced in June 2019.

This study is taking place in Australia and

the United Kingdom using a higher dose than the U.S.

based Phase 2 study for Rett syndrome.

This randomized, placebo-controlled

study will evaluate the safety and efficacy of ANAVEX ® 2-73 in approximately 33 patients over a 7-week treatment

period including ANAVEX ® 2-73 specific precision medicine biomarkers.

All patients who participate in the study will

be eligible to receive ANAVEX ® 2-73 under a voluntary open label extension protocol.

The AVATAR study is expected

to read out topline data around year end 2021.

In July 2020, we commenced the third

study of ANAVEX ® 2-73 for the treatment of Rett syndrome, called the EXCELLENCE study.

This Phase 2/3 study in pediatric

patients with Rett syndrome will evaluate the safety and efficacy of ANAVEX ® 2-73 in approximately 84 pediatric patients,

aged 5 to 18, over a 12-week treatment period incorporating ANAVEX ® 2-73 specific precision medicine biomarkers.

All patients who participate in the study will be eligible to receive ANAVEX ® 2-73 under a voluntary open label extension

Consistent with previous ANAVEX ® 2-73 clinical trials, patients carrying the common form

of the SIGMAR1 gene treated with ANAVEX ® 2-73 experienced stronger improvements in the prespecified efficacy endpoints.

The second, international

trial of ANAVEX ® 2-73 for the treatment of Rett syndrome, called the AVATAR trial, commenced in June 2019.

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.

trial met all primary and secondary efficacy and safety endpoints, with consistent improvements in primary efficacy endpoint, RSBQ response

(p = 0.037), and secondary efficacy endpoints, ADAMS (p = 0.010) and CGI-I (p = 0.037) response.

Efficacy endpoints demonstrated statistically

significant and clinically meaningful reductions in Rett syndrome symptoms.

Convenient once daily oral liquid doses of up to 30 mg of

ANAVEX ® 2-73 were also well tolerated with good medication compliance.

All patients who participated in the trial were

eligible to receive ANAVEX ® 2-73 under a voluntary open label extension protocol.

In July 2020, we commenced the third trial

of ANAVEX ® 2-73 for the treatment of Rett syndrome, called the EXCELLENCE trial.

This Phase 2/3 trial in pediatric

patients with Rett syndrome includes trial sites in Australia, the United Kingdom, and Canada, and will evaluate the safety and

efficacy of ANAVEX ® 2-73 in approximately 84 pediatric patients, aged 5 to 18, over a 12-week treatment period incorporating

ANAVEX ® 2-73 specific precision medicine biomarkers.

All patients who participate in the trial will be eligible

to receive ANAVEX ® 2-73 under a voluntary open label extension protocol, which is currently ongoing.

Parkinson’s Disease

In September 2016, we presented positive

preclinical data for ANAVEX ® 2-73 in an animal model of Parkinson’s disease, which demonstrated significant

improvements on behavioral, histopathological, and neuroinflammatory endpoints.

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 indicates that ANAVEX ® 2-73 induces robust neurorestoration in experimental

Parkinsonism.

The encouraging results we have gathered in this model, coupled with the favorable profile of this compound in the

Alzheimer’s disease trial, support the notion that ANAVEX ® 2-73 is a promising clinical candidate drug for

Parkinson’s disease dementia.

data announced in October 2017 indicated that ANAVEX ® 2-73 induced robust neurorestoration in experimental Parkinsonism.

We believe that the encouraging results we have gathered in this preclinical model, coupled with the favorable profile of this

product candidate in the Alzheimer’s disease trial, support the notion that ANAVEX ® 2-73 has the potential

to treat Parkinson’s disease dementia.

In October 2020, we completed a double-blind,

randomized, placebo-controlled proof-of-concept Phase 2 trial with ANAVEX ® 2-73 in Parkinson’s disease dementia

(PDD), to study the effect of the compound on both the cognitive and motor impairment of Parkinson’s disease.

study enrolled approximately 132 patients for 14 weeks, randomized 1:1:1 to two different ANAVEX ® 2-73 doses, 30mg

and 50mg, or placebo.

The ANAVEX ® 2-73 Phase 2 PDD study design incorporated genomic precision medicine biomarkers

identified in the ANAVEX ® 2-73 Phase 2a Alzheimer’s disease study.

Within this study ANAVEX ® 2-73

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 show 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-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 global capability of slowing and reversing

symptoms that progress in Parkinson’s disease.

The study confirmed the precision medicine approach of targeting SIGMAR1 as

a genetic biomarker in response to ANAVEX ® 2-73.

In January 2021, we announced we were

awarded a research grant of $1.0 million from The Michael J.

Foundation for Parkinson’s Research (MJFF) to develop ANAVEX ® 2-73 for the treatment of Parkinson’s

The award will explore utilization of PET imaging biomarkers to enable measurement of target engagement and pathway activation

of the sigma-1 receptor (SIGMAR1) with clinically relevant doses in people with Parkinson’s disease.

The results showed clinically meaningful, dose-dependent, and

statistically significant improvements in the Cognitive Drug Research (“CDR”) computerized assessment system analysis.

Treatment with ANAVEX ® 2-73 also resulted in clinically meaningful improvements as measured by the global composite

score of Parkinson’s disease symptom severity, MDS-Unified Parkinson’s Disease Rating Scale total score on top of standard

of care including dopaminergic therapy, levodopa and other anti-PD medications after 14 weeks of treatment, suggesting ANAVEX ® 2-73’s

potential capability of slowing and reversing symptoms that progress in Parkinson’s disease.

In addition, the trial confirmed

the precision medicine approach of targeting SIGMAR1 as a genetic biomarker in response to ANAVEX ® 2-73 may result

in improved clinical outcomes.

In January 2021, we were awarded a research

grant of $1.0 million from The Michael J.

Fox Foundation for Parkinson’s Research to develop ANAVEX ® 2-73

for the treatment of Parkinson’s disease.

The award will explore utilization of PET imaging biomarkers to enable measurement

of target engagement and pathway activation of the SIGMAR1 with clinically relevant doses in people with Parkinson’s disease.

Frontotemporal Dementia

In July 2020, we commenced the First-in-Human

Phase 1 clinical trial of ANAVEX ® 3-71, which 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.

1 clinical trial will be a prospective double-blind, randomized, placebo-controlled study.

A total of at least 36 healthy male

and female subjects will be included.

Single escalating doses of ANAVEX ® 3-71 will be administered in order to evaluate

the safety, tolerability, and pharmacokinetics (PK) of ANAVEX ® 3-71 and the effects of food and gender on its PK

in healthy volunteers.

This study is expected to be followed by longer duration dosing including patients with FTD or other dementia

indications with unmet medical need, incorporating exploratory efficacy and disease biomarker measures .

Phase 1 clinical trial of ANAVEX ® 3-71.

ANAVEX ® 3-71 was previously granted orphan drug designation

for the treatment of Frontotemporal Dementia (“FTD”) by the FDA.

ANAVEX ® 3-71 is an orally administered small molecule

targeting sigma-1 and M1 muscarinic receptors that is designed to be beneficial for neurodegenerative diseases.

In preclinical

studies, ANAVEX ® 3-71 demonstrated disease-modifying activity against the major hallmarks of Alzheimer’s disease

in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, as well as beneficial effects on mitochondrial

dysfunction and neuroinflammation.

The Phase 1 clinical trial was a prospective

double-blind, randomized, placebo-controlled trial in Australia.

A total of 36 healthy male and female subjects were included.

Single escalating doses of ANAVEX ® 3-71 were administered in order to evaluate the safety, tolerability, and PK of

ANAVEX ® 3-71 and the effects of food and gender on its PK in healthy volunteers.

The trial met its primary and secondary endpoints

of safety, with no serious adverse events (“SAEs”) or dose-limiting toxicities observed.

ANAVEX ® 3-71

was well tolerated in all cohorts receiving ANAVEX ® 3-71 in single doses ranging from 5 mg to 200 mg daily with no

SAEs and no significant lab abnormalities in any subject.

In the trial, ANAVEX ® 3-71 exhibited linear PK.

Its pharmacokinetics

was also dose proportional for doses up to 160 mg.

Gender had no effect on the PK of the drug and food had no effect on the bioavailability

of ANAVEX ® 3-71.

The trial also met the secondary objective of characterizing the effect of ANAVEX ® 3-71

on electrocardiogram (“ECG”) parameters.

There were no clinically significant ECG parameters throughout the trial.

Participant QTcF measures were normal across all dose groups with no difference between ANAVEX ® 3-71 and placebo.

Based on these results, and ANAVEX ® 3-71’s

pre-clinical profile, we intend to advance ANAVEX ® 3-71 into a biomarker-driven clinical development dementia program

for the treatment of schizophrenia, FTD and Alzheimer’s disease, evaluating longitudinal effect of treatment with ANAVEX ® 3-71.

We believe the results of these clinical trials and preclinical study could serve as the basis for advancing into respective registration

studies in the U.S.

Our research and development pipeline includes

ANAVEX ® 2-73 currently in three different clinical study indications, and several other compounds in different stages

of clinical and pre-clinical study.

ANAVEX ® 2-73 currently in three different clinical trial indications, and several other compounds in different stages

of clinical and pre-clinical development.

Our proprietary SIGMACEPTOR™ Discovery

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processes, in order to ensure survival and replication.

Hence, it is possible that S1R could play a role in modulating the cellular

response to viral infection and ameliorate pathogenesis.

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

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ANAVEX ® 2-73 (blarcamesine)

ANAVEX ® 2-73 may offer a disease-modifying

approach in neurodegenerative and neurodevelopmental diseases by activation of sigma-1 receptors.

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

resulted in both significant and dose related improvements in an array of behavioral paradigms in the MECP2 HET Rett syndrome disease

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 mouse.

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 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.

which took place in the United States, was completed in December 2020, however two other clinical trials in Rett syndrome, the

AVATAR study and the EXCELLENCE study, are still underway.

The studies are being conducted in a range of patient age demographics

and geographic regions, as more fully described above under Clinical Studies Overview – Rett Syndrome .

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

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Rett syndrome.

The RPD designation provides priority review by the FDA to encourage the development of treatments for rare pediatric

The RPD designation is intended to encourage the development of treatments for rare pediatric diseases.

Further, in February 2020, the FDA granted

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we completed a double-blind, randomized, placebo-controlled proof-of-concept Phase 2 trial with ANAVEX ® 2-73 in Parkinson’s

Disease Dementia (PDD), to study the effect of the compound on both the cognitive and motor impairment of Parkinson’s disease.

The Phase 2 study enrolled approximately 132 patients for 14 weeks, randomized 1:1:1 to two different ANAVEX ® 2-73

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 PDD study design incorporated genomic precision medicine

biomarkers identified in the ANAVEX ® 2-73 Phase 2a Alzheimer’s disease study.

The study found that ANAVEX ® 2-73

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 show clinically meaningful, dose-dependent, and statistically

significant improvements in the Cognitive Drug Research (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

study to the FDA to obtain regulatory guidance.

In Alzheimer’s disease (AD) animal models,

The results showed clinically meaningful, dose-dependent, and

statistically significant improvements in the CDR computerized assessment system analysis.

We anticipate conducting further clinical

trials of ANAVEX ® 2-73 in Parkinson’s disease dementia after submitting the results of the trial to the FDA

to obtain regulatory guidance.

In Alzheimer’s disease animal models,

ANAVEX ® 2-73 has shown pharmacological, histological and behavioral evidence as a potential neuroprotective, anti-amnesic,

anti-convulsive and anti-depressive therapeutic agent, due to its potent affinity to sigma-1 receptors 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 AD 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.

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

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This dose is above the equivalent dose shown

to have positive effects in mouse models of AD.

There were no significant changes in laboratory or electrocardiogram (ECG) parameters.

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.

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and reversible.

These side effects are often seen with drugs that target CNS conditions, including AD.

In December 2014, a Phase 2a clinical trial

was initiated 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

ANAVEX ® 2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1

and muscarinic receptors.

Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer’s.

The Phase 2a study met both primary and secondary objectives of the study.

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

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 study.

More than 33,000 genes were analyzed

using unbiased, data driven, machine learning, artificial intelligence (AI) system for analyzing DNA & RNA data in patients

exposed to ANAVEX ® 2-73.

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 Sigma-1 receptor (SIGMAR1), the target for ANAVEX ® 2-73.

Results showed that study

participants with the common SIGMAR1 wild type gene variant, which is about 80 percent of the population worldwide, demonstrated

improved cognitive (MMSE) and the functional (ADCS-ADL) scores.

The results from this evaluation have been used to establish a

precision medicine approach in subsequent clinical trials, since these signatures can now be applied to neurological indications

tested in clinical studies with ANAVEX ® 2-73 including Alzheimer’s disease, Parkinson’s disease dementia

and Rett syndrome.

among them variants related to the SIGMAR1, the target for ANAVEX ® 2-73.

Results showed that trial participants with

the common SIGMAR1 wild type gene variant, which is estimated to be about 80% of the population worldwide, demonstrated improved

cognitive (MMSE) and the functional (ADCS-ADL) scores.

The results from this evaluation supported the continued evaluation of genomic

information in subsequent clinical trials, since these signatures can now be applied to neurological indications tested in future

clinical trials with ANAVEX ® 2-73 including Alzheimer’s disease, Parkinson’s disease dementia and Rett

ANAVEX ® 2-73

data presented met prerequisite information in order to progress into a Phase 2b/3 placebo-controlled study.

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.

trial sites in Canada, the United Kingdom, the Netherlands and Germany were also added.

This Phase 2b/3 study design incorporates

inclusion of genomic precision medicine biomarkers identified in the ANAVEX ® 2-73 Phase 2a study.

The Phase 2b/3

study, which has completed enrollment, randomized 1:1:1 to either two different ANAVEX ® 2-73 doses or placebo, commenced

in October 2018.

Preclinical data also validates ANAVEX ® 2-73

as a prospective platform drug for other neurodegenerative diseases beyond Alzheimer’s disease, Parkinson’s disease

or Rett syndrome, more specifically, epilepsy, infantile spasms, Fragile X syndrome, Angelman syndrome, multiple sclerosis and,

more recently, tuberous sclerosis complex (TSC).

ANAVEX ® 2-73 demonstrated significant improvements in all of these

indications in the respective preclinical animal models.

In a study sponsored by the Foundation for

Angelman Syndrome, ANAVEX ® 2-73 was assessed in a mouse model for the development of audiogenic seizures.

indicated that ANAVEX ® 2-73 administration significantly reduced audiogenic-induced seizures.

In a study sponsored

by FRAXA Research Foundation regarding Fragile X syndrome, data demonstrated that ANAVEX ® 2-73 restored hippocampal

brain-derived neurotrophic factor (BDNF) expression to normal levels.

BDNF under-expression has been observed in many neurodevelopmental

and neurodegenerative pathologies.

data met prerequisite information in order to progress into a Phase 2b/3 placebo-controlled trial.

On July 2, 2018, the Human Research

Ethics Committee in Australia approved the initiation of our Phase 2b/3, double-blind, randomized, placebo-controlled 48-week safety

and efficacy trial of ANAVEX ® 2-73 for the treatment of early Alzheimer’s disease.

Clinical trial sites in

Canada, the United Kingdom, the Netherlands and Germany were also added.

This Phase 2b/3 trial design incorporates inclusion of

genomic precision medicine biomarkers identified in the ANAVEX ® 2-73 Phase 2a trial.

The Phase 2b/3 trial, which

has completed enrollment, randomized 1:1:1 to either two different ANAVEX ® 2-73 doses or placebo.

We believe preclinical data from our studies

also supports ANAVEX ® 2-73 as a potential platform drug for other neurodegenerative diseases beyond Alzheimer’s

disease, Parkinson’s disease or Rett syndrome, more specifically, epilepsy, infantile spasms, Fragile X syndrome, Angelman

syndrome, multiple sclerosis and, more recently, tuberous sclerosis complex (TSC).

ANAVEX ® 2-73 demonstrated significant

improvements in all of these indications in the respective preclinical animal models.

In a preclinical study sponsored by the Foundation

for Angelman Syndrome, ANAVEX ® 2-73 was assessed in a mouse model for the development of audiogenic seizures.

results indicated that ANAVEX ® 2-73 administration significantly reduced audiogenic-induced seizures.

sponsored by FRAXA Research Foundation regarding Fragile X syndrome, data demonstrated that ANAVEX ® 2-73 restored

hippocampal brain-derived neurotrophic factor (BDNF) expression to normal levels.

BDNF under-expression has been observed in many

neurodevelopmental and neurodegenerative pathologies.

BDNF signaling promotes maturation of both excitatory and inhibitory synapses.

ANAVEX ® 2-73

normalization of BDNF expression could be a contributing factor for the positive data observed in both neurodevelopmental and neurodegenerative

disorders like Angelman and Fragile X syndromes.

Preclinical data presented also indicates that

ANAVEX ® 2-73 demonstrates 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.

Preclinical data on ANAVEX ® 2-73

ANAVEX ® 2-73 normalization of BDNF expression could be a contributing factor for the positive data observed in both

neurodevelopmental and neurodegenerative disorders like Angelman and Fragile X syndromes.

In addition, preclinical data to-date also

indicates that ANAVEX ® 2-73 has the potential to demonstrate protective effects of mitochondrial enzyme complexes

during pathological conditions, which, if impaired, are believed to play a role in the pathogenesis of neurodegenerative and neurodevelopmental

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, data also demonstrates that ANAVEX ® 2-73 provides protection for oligodendrocytes (“OL’s”)

and oligodendrocyte precursor cells (“OPC’s”), as well as central nervous system neurons in addition to helping

repair by increasing OPC proliferation and maturation in tissue culture.

Further, our data also demonstrates that ANAVEX ® 2-73 has the potential to provide protection for oligodendrocytes

(“OL’s”) and oligodendrocyte precursor cells (“OPC’s”), as well as central nervous system neurons

in addition to helping repair by increasing OPC proliferation and maturation in tissue culture.

In March 2018, we presented preclinical data

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disorder characterized by the growth of numerous benign tumors in many parts of the body with a high incidence of seizures.

new preclinical data demonstrates that treatment with ANAVEX ® 2-73 significantly increases survival and reduces seizures.

preclinical data demonstrated that treatment with ANAVEX ® 2-73 significantly increased survival and reduced seizures

in those mice.

ANAVEX ® 3-71

ANAVEX ® 3-71 is a clinical drug

candidate with a novel mechanism of action via sigma-1 receptor 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.

It is highly effective in very small doses against the major Alzheimer’s

candidate with a novel mechanism of action via SIGMAR1 activation and M1 muscarinic allosteric modulation, which has been shown

to enhance neuroprotection and cognition in Alzheimer’s disease models.

ANAVEX ® 3-71 is a CNS-penetrable potential

disease modifying treatment for cognitive impairments.

We believe it is effective in very small doses against the major Alzheimer’s

hallmarks in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies, and also has beneficial effects

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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 sigma-1 receptor

activation and M1 muscarinic allosteric modulation.

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

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In April 2016, the FDA granted Orphan Drug Designation

to ANAVEX ® 3-71 for the treatment of Frontotemporal dementia (FTD).

to ANAVEX ® 3-71 for the treatment of FTD.

During pathological conditions ANAVEX ® 3-71

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Additional preclinical data presented also indicates that in addition to reducing oxidative stress, ANAVEX ® 3-71

demonstrates 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.

has the potential to demonstrate protective effects of mitochondrial enzyme complexes during pathological conditions, which, if

impaired, are believed to play a role in the pathogenesis of neurodegenerative and neurodevelopmental diseases.

In July 2020, we commenced the first Phase

1 clinical trial of ANAVEX ® 3-71, with focus on the treatment of Frontotemporal Dementia (FTD) and other

dementia indications with unmet medical need .

The study is more fully described above under Clinical Studies Overview

1 clinical trial of ANAVEX ® 3-71.

The trial took place in Australia and was a double-blind, randomized, placebo-controlled,

Phase 1 trial to evaluate safety and tolerability, and PK of oral escalating doses of ANAVEX ® 3-71 including effects

of food and gender in healthy volunteers.

The trial met its primary and secondary endpoints of safety, respectively with no serious

adverse events (SAEs) or dose-limiting toxicities observed, as more fully described above under Clinical Trials Overview –

Frontotemporal Dementia .

Based on these results, and ANAVEX ® 3-71

pre-clinical profile, the Company intends to advance ANAVEX ® 3-71 into a biomarker-driven clinical development dementia

program for the treatment of schizophrenia, FTD and Alzheimer’s disease, evaluating longitudinal effect of treatment with

ANAVEX ® 3-71.

ANAVEX ® 1-41 is a sigma-1 receptor

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

These activities involve both muscarinic and sigma-1 receptor systems through a novel mechanism of action.

We believe the results of this clinical trial and preclinical study could serve as a basis for advancing

into respective registration trials in the U.S.

ANAVEX ® 1-41

ANAVEX ® 1-41 is a sigma-1 agonist.

Pre-clinical tests revealed significant neuroprotective benefits (i.e., protects nerve cells from degeneration or death) through

the modulation of endoplasmic reticulum, mitochondrial and oxidative stress, which damages and impairs cell viability.

in 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 demonstrates 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 ® 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

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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.

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.

publications highlight the possibility that these ligands may stop tumor growth and induce selective cell death in various tumor

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, 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.

Our compounds are 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.

SIGMAR1 at nanomolar levels and moderate affinity for sigma-2 receptors and sodium channels at micromolar levels.

In advanced pre-clinical

studies, this compound revealed antitumor potential.

It has also been shown to selectively kill human cancer cells without affecting

normal/healthy cells and also to significantly suppress tumor growth in immune-deficient mice models.

Scientific publications highlight

the possibility that these ligands may stop tumor growth and induce selective cell death in various tumor cell lines.

Sigma receptors

are highly expressed in different tumor cell types.

Binding by appropriate sigma-1 and/or sigma-2 ligands can induce selective

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 realize maximum shareholder value.

Further, we may acquire or develop new intellectual property and assign, license, or otherwise transfer our intellectual property

to further our goals.

with potential strategic and commercial partners to most effectively advance our programs and increase stockholder value.

we may acquire or develop new intellectual property and assign, license, or otherwise transfer our intellectual property to further

Our Target Indications

We have developed compounds with potential

application to two broad categories and several specific indications.

We are developing compounds with potential

application to two broad categories and several specific indications, including:

Central Nervous System Diseases

Alzheimer’s disease – In 2021, an estimated 5.7 million

Americans were suffering from Alzheimer’s disease.

The Alzheimer’s Association ® estimates that by 2050,

this number will rise to nearly 14 million Americans.

Medications on the market today treat only the symptoms of Alzheimer’s

disease and do not have the ability to stop its onset or its progression.

There is an urgent and unmet need for both a disease

modifying cure for Alzheimer’s disease as well as for better symptomatic treatments.

Parkinson’s disease – Parkinson’s disease is a progressive

disease of the nervous system marked by tremors, muscular rigidity, and slow, imprecise movement.

It is associated with degeneration

of the basal ganglia of the brain and a deficiency of the neurotransmitter dopamine.

Parkinson’s disease afflicts more than

10 million people worldwide, typically middle-aged and elderly people.

The Parkinson’s disease market is expected to expand

to $11.5 billion by 2029, according to business intelligence provider GBI Research.

Rett syndrome – Rett syndrome is a rare X-linked genetic neurological

and developmental disorder that affects the way the brain develops, including protein transcription, which is altered and as a

result lead to severe disruptions in neuronal homeostasis.

It is considered a rare, progressive neurodevelopmental disorder and

is caused by a single mutation in the MECP2 gene.

Because males have a different chromosome combination from females, boys who

have the genetic MECP2 mutation are affected in devastating ways.

Most of them die before birth or in early infancy.

who survive infancy, Rett syndrome leads to severe impairments, affecting nearly every aspect of the child’s life;

mental retardation, their ability to speak, walk and eat, sleeping problems, seizures and even the ability to breathe easily.

Alzheimer’s disease – In 2022, an estimated 6.5 million Americans were suffering from Alzheimer’s disease.

The Alzheimer’s Association ® estimates that by 2050, this number is expected to rise to 12.7 million Americans.

Medications on the market today treat only the symptoms of Alzheimer’s disease and do not have the ability to stop its onset or its progression.

We believe there is an urgent and unmet need for both a disease modifying cure for Alzheimer’s disease as well as for better symptomatic treatments.

Parkinson’s disease – Parkinson’s disease is a progressive disease of the nervous system marked by tremors, muscular rigidity, and slow, imprecise movement.

It is associated with degeneration of the basal ganglia of the brain and a deficiency of the neurotransmitter dopamine.

Parkinson’s disease currently is estimated to afflict more than 10 million people worldwide, typically middle-aged and elderly people.

The Parkinson’s disease market is expected to reach to $11.5 billion by 2029, according to GlobalData.

Rett syndrome – Rett

syndrome is a rare X-linked genetic neurological and developmental disorder that affects the way the brain develops, including protein

transcription, which is altered and as a result leads to severe disruptions in neuronal homeostasis.

It is considered a rare, progressive

neurodevelopmental disorder and is caused by a single mutation in the MECP2 gene.

Because males have a different chromosome combination

from females, boys who have the genetic MECP2 mutation are affected in devastating ways.

Most of them die before birth or in early

For females who survive infancy, Rett syndrome leads to severe impairments, affecting nearly every aspect of the child’s

severe mental retardation, their ability to speak, walk and eat, sleeping problems, seizures and even the ability to breathe

Rett syndrome affects approximately 1 in every 10,000-15,000 females.

Depression – Depression is a major cause of morbidity worldwide

according to the World Health Organization.

Pharmaceutical treatment for depression is dominated by blockbuster brands, with the

leading nine brands historically accounting for approximately 75% of total sales.

However, the dominance of the leading brands

is waning, largely due to the effects of patent expiration and generic competition.

Epilepsy – Epilepsy is a common chronic neurological disorder

characterized by recurrent unprovoked seizures.

These seizures are transient signs and/or symptoms of abnormal, excessive or synchronous

neuronal activity in the brain.

According to the Centers for Disease Control and Prevention, in 2015 epilepsy affected 3.4 million

Today, epilepsy is often controlled, but not cured, with medication that is categorized as older traditional anti-epileptic

drugs and second generation anti-epileptic drugs.

Because epilepsy afflicts sufferers in different ways, there is a need for drugs

used in combination with both traditional anti-epileptic drugs and second generation anti-epileptic drugs.

Neuropathic Pain – We define neuralgia, or neuropathic pain,

as pain that is not related to activation of pain receptor cells in any part of the body.

Neuralgia is more difficult to treat

than some other types of pain because it does not respond well to normal pain medications.

Special medications have become more

specific to neuralgia and typically fall under the category of membrane stabilizing drugs or antidepressants.

Malignant Melanoma – Predominantly a skin cancer, malignant melanoma

can also occur in melanocytes found in the bowel and the eye.

Malignant melanoma accounts for 75% of all deaths associated with

Depression – Depression is a major cause of morbidity worldwide according to the World Health Organization.

The global antidepressant drug market is projected to reach $21 Billion by 2030 according to Allied Market Research.

Pharmaceutical treatment for depression has been historically dominated by blockbuster brands.

However, the dominance of the leading brands is waning, largely due to an increase in the number of approvals for antidepressant drugs.

Epilepsy – Epilepsy

is a common chronic neurological disorder characterized by recurrent unprovoked seizures.

These seizures are transient signs and/or

symptoms of abnormal, excessive or synchronous neuronal activity in the brain.

According to the Centers for Disease Control and Prevention,

in 2015 epilepsy affected 3.4 million Americans.

Today, epilepsy is often controlled, but not cured, with medication that is categorized

as older traditional anti-epileptic drugs and second generation anti-epileptic drugs.

Because epilepsy afflicts sufferers in different

ways, there is a need for drugs used in combination with both traditional anti-epileptic drugs and second generation anti-epileptic

Neuropathic Pain –

We define neuralgia, or neuropathic pain, as pain that is not related to activation of pain receptor cells in any part of the body.

Neuralgia is more difficult to treat than some other types of pain because it does not respond well to normal pain medications.

medications have become more specific to neuralgia and typically fall under the category of membrane stabilizing drugs or antidepressants.

Malignant Melanoma – Predominantly a skin cancer, malignant melanoma can also occur in melanocytes found in the bowel and the eye.

Malignant melanoma accounts for a large majority of skin cancer deaths.

The treatment includes surgical removal of the tumor, adjuvant treatment, chemo and immunotherapy, or radiation therapy.

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the worldwide malignant melanoma market is expected to grow to $7.5 billion by 2029.

Prostate Cancer – Specific to men, prostate cancer is a form

of cancer that develops in the prostate, a gland in the male reproductive system.

The cancer cells may metastasize from the prostate

to other parts of the body, particularly the bones and lymph nodes.

Drug therapeutics for prostate cancer are expected to increase

to nearly $13.5 billion in 2024 according to Datamonitor Healthcare.

Pancreatic Cancer – Pancreatic cancer is a malignant neoplasm

of the pancreas.

In the United States, approximately 55,000 new cases of pancreatic cancer will be diagnosed this year and approximately

44,000 patients will die as a result of their cancer, according to the American Cancer Society.

Sales predictions by FutureWise

forecast that the market for the global pharmaceutical treatment of pancreatic cancer will increase to $4.7 billion by 2027.

Prostate Cancer

– Specific to men, prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive

Cancer cells may metastasize from the prostate to other parts of the body, particularly the bones and lymph nodes.

Drug therapeutics for prostate cancer are expected to increase to nearly $10.1 billion by the end of 2030 according to Market

Research Future.

Pancreatic Cancer

– Pancreatic cancer is a malignant neoplasm of the pancreas.

In the United States, approximately 62,000 new cases of

pancreatic cancer will be diagnosed this year and approximately 50,000 patients will die as a result of their cancer, according

to the American Cancer Society.

Sales predictions by Market Data Forecast predict that the market for the global pharmaceutical

treatment of pancreatic cancer will increase from $2.59 billion in 2022 to $3.73 billion by 2027.

The drug discovery and development industry

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products that we may develop.

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 sigma-1 receptors.

When activated by SIGMAR1 agonists, such as ANAVEX ® 2-73,

SIGMAR1 reduces cellular stress before and after RNA gene transcription.

Studies confirm the predictive biomarker of response established

through SIGMAR1 mRNA expression.

Because of its role in maintaining neuronal homeostasis, sigma receptors show significant promise

as viable targets for therapeutic molecules in an effort to treat Alzheimer’s disease and other CNS diseases and disorders,

including Parkinson’s disease and Rett syndrome, by restoring healthy gene expression.

We believe our approach to the treatment of

Alzheimer’s disease and other CNS diseases differs from our competitors - our platform may offer a disease-modifying approach

in neurodegenerative and neurodevelopmental diseases by activation of SIGMAR1.

In our preclinical studies, when activated by SIGMAR1

agonists, such as ANAVEX ® 2-73, SIGMAR1 demonstrated reduced cellular stress before and after RNA gene transcription.

Our studies confirm the potential existence of a predictive biomarker of response established through SIGMAR1 mRNA expression that

could be used in future clinical trials.

Because of its role in maintaining neuronal homeostasis, we believe sigma receptors show

significant promise as viable targets for therapeutic molecules in an effort to treat Alzheimer’s disease and other CNS diseases

and disorders, including Parkinson’s disease and Rett syndrome, by restoring healthy gene expression.

At this time, our competitors are primarily

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agencies, both in the United States and abroad.

Our competitors may have significantly

greater financial resources, an established presence in the market, expertise in research and development, manufacturing, preclinical

and clinical testing, may be in the process of obtaining regulatory approvals and marketing of approved products.

Our competitors may have significantly greater

financial resources, an established presence in the market, expertise in research and development, manufacturing, preclinical and

clinical testing, may be in the process of obtaining regulatory approvals and marketing of approved products.

These competitors

also compete with us in recruiting and retaining qualified scientific and technical personnel, establishing clinical study sites

and patient registration for clinical studies, as well as in acquiring or developing technologies complementary to, or necessary

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.

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We hold ownership or exclusive rights

to fifteen U.S.

patents, sixteen U.S.

to seventeen U.S.

patents, nineteen U.S.

patent applications, and various PCT or ex-U.S.

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are expected to expire in October 2035, absent any patent term extension for regulatory delays.

We also own two issued U.S.

We also own three issued U.S.

with claims directed to treating neurodevelopmental disorders.

These patents claim methods for treating a neurodevelopmental disorder,

or multiple sclerosis by administering ANAVEX ® 2-73, ANAVEX ® 19-144, and/or ANAVEX ® 1-41

(another sigma receptor ligand similar to ANAVEX ® 2-73), or compositions thereof.

Both patents are expected to expire

in January 2037, absent any patent term extension for regulatory delays.

In addition, we own one issued U.S.

Patent with claims

directed to methods of treating melanoma with a compound related to ANAVEX ® 2-73.

multiple sclerosis, or their related biochemical and functional abnormalitiesby administering ANAVEX ® 2-73, ANAVEX ® 19-144,

and/or ANAVEX ® 1-41 (another sigma receptor ligand similar to ANAVEX ® 2-73), or compositions thereof.

All three patents are expected to expire in January 2037, absent any patent term extension for regulatory delays.

we own one issued U.S.

Patent with claims directed to methods of treating melanoma with a compound related to ANAVEX ® 2-73.

This patent is expected to expire in February 2030, absent any patent term extension for regulatory delays.

We also own an issued

patent that claims crystalline forms of ANAVEX ® 19-144, dosage forms and compositions containing the crystalline

forms of ANAVEX ® 19-144, and methods of treatment for Alzheimer’s disease.

This patent is expected to expire

in February 2030, absent any patent term extension for regulatory delays.

We also own an issued U.S.

patent that claims crystalline

forms of ANAVEX ® 19-144, dosage forms and compositions containing the crystalline forms of ANAVEX ® 19-144,

and methods of treatment for Alzheimer’s disease.

This patent is expected to expire in July 2036, absent any patent term

extension for regulatory delays.

in July 2036, absent any patent term extension for regulatory delays.

Further, we own one issued U.S.

Patent with claims directed to methods of treating cardiac dysfunction

with ANAVEX ® 2-73 .

This patent is expected to expire in July 2038, absent any patent term extension for regulatory

Patent with claims directed

to methods of treating cardiac dysfunction with ANAVEX ® 2-73.

This patent is expected to expire in July 2038, absent

any patent term extension for regulatory delays.

Additionally, we own one issued U.S.

Patent with claims directed to methods of

treating insomnia or anxiety with ANAVEX ® 2-73, ANAVEX ® 19-144, and/or ANAVEX ® 1-41.

This patent is expected to expire in September 2038, absent any patent term extension for regulatory delays.

We also own two issued U.S.

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A new drug must be approved by the FDA through the

NDA process before it may be legally marketed in the United States.

We are subject to various government regulations in connection

with the development of our pipeline.

NDA or ANDA process before it may be legally marketed in the United States.

We are subject to various government regulations in

connection with the development of our pipeline.

Drug Development and Regulation

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requirements at

any time during the product development process, approval process or after approval may subject an applicant to administrative

or judicial sanctions.

These sanctions could include the FDA’s refusal to approve pending applications, withdrawal of an

approval, a clinical hold, warning letters, product recalls, product seizures, total or partial suspension of production or distribution,

injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

Any agency or judicial

enforcement action could have a material adverse effect on us.

any time during the product development process, approval process or post approval may subject an applicant to administrative or

judicial sanctions.

These sanctions could include the FDA’s refusal to approve pending applications, withdrawal of an approval,

import refusal, a clinical hold, warning letters, product recalls, product seizures, total or partial suspension of production

or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

Any agency or judicial enforcement action could have a material adverse effect on us.

Once a drug candidate is identified for development,

it enters the preclinical testing stage.

Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation,

as well as other preclinical studies.

An Investigational New Drug application (“IND”) sponsor must submit the results

of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of the IND.

must also include a protocol detailing, among other things, the objectives of the first phase of clinical trials, the parameters

to be used in monitoring the safety of the trial, and the effectiveness criteria to be evaluated should the first phase lend itself

to an efficacy evaluation.

it enters the preclinical testing stage and an Investigational New Drug Application (“IND”) may be opened for the regulatory

development of the product.

Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as

well as other preclinical studies.

An IND sponsor must submit the results of the preclinical tests, together with manufacturing

information and analytical data, to the FDA as part of the IND to conduct clinical trials.

The sponsor must also include a protocol

detailing, among other things, the objectives of the first phase of clinical trials, the parameters to be used in monitoring the

safety of the trial, and the effectiveness criteria to be evaluated should the first phase lend itself to an efficacy evaluation.

Some preclinical testing may continue even after the IND is filed.

The IND automatically becomes effective

thirty (30) days after receipt by the FDA, unless the FDA, within the 30-day time period, places the clinical trial on a clinical

Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns about ongoing

or proposed clinical trials or non-compliance with specific FDA requirements, and the trials may not begin or continue until the

FDA notifies the sponsor that the hold has been lifted.

The IND automatically becomes effective thirty (30) days after

receipt by the FDA, unless the FDA, within the 30-day time period, places the clinical trial on a clinical hold.

Clinical holds

also may be imposed by the FDA at any time before or during clinical trials due to safety concerns about ongoing or proposed clinical

trials or non-compliance with specific FDA requirements, and the trials may not begin or continue until the FDA notifies the sponsor

that the hold has been lifted.

All clinical trials must be conducted under

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trial must review and approve each protocol before a clinical trial may commence at the institution and must also approve the information

regarding the trial as well as the consent form that must be provided to each trial participant or his or her legal representative,

regarding the trial as well as the informed consent form that must be provided to each trial participant or his or her legal representative,

monitor the study until completed and otherwise comply with all applicable IRB regulations.

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1a and Phase 1b clinical trials.

Phase 1b clinical trials are typically aimed at confirming dosage, pharmacokinetics and safety

in a larger number of patients.

Some Phase 1b studies evaluate biomarkers or surrogate markers that may be associated with efficacy

in patients with specific types of diseases or conditions.

Phase 1b clinical trials are typically aimed at confirming dosage, PK and safety in a larger number

Some Phase 1b clinical trials evaluate biomarkers or surrogate markers that may be associated with efficacy in patients

with specific types of diseases or conditions.

This phase involves clinical trials

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to further evaluate dosage, clinical efficacy and safety in an expanded patient population, generally at geographically dispersed

clinical study sites.

clinical trial sites.

These clinical trials, often referred to as “pivotal” or “confirmatory” clinical

trials, are intended to establish the overall risk-benefit ratio of the compound and provide, if appropriate, an adequate basis

for product labeling.

for product approval and labeling.

The FDA or the sponsor may suspend a clinical

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the sponsor, known as a data safety monitoring board or committee.

Depending on its charter, this committee may determine whether

a trial may move forward at designated check points based on access to certain data from the trial.

Depending on its charter, this board or committee may determine

whether a trial may move forward at designated check points based on access to certain data from the trial.

Phase 4 or post-approval trials may

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In certain instances,

the FDA may mandate the performance of such clinical trials as a condition of approval of an NDA.

the FDA may mandate the performance of such clinical trials as a condition of approval of continued marketing of the product.

During the development of a new drug, sponsors

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Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the

Meetings at other times may be made upon request.

Meetings at other times may be made upon request and are subject to approval by the FDA.

Concurrent with clinical trials, companies

typically complete additional, animal or other non-clinical studies, develop additional information about the chemistry and physical

typically complete additional, animal or other non-clinical studies, develop additional information about the chemistry and physicochemical

characteristics of the drug, and finalize a process for manufacturing the product in commercial quantities in accordance with the

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under certain limited circumstances.

The FDA reviews NDAs to determine, among other

things, whether the product is safe and effective for its intended use and whether it is manufactured in a cGMP-compliant manner,

which will assure and preserve the product’s identity, strength, quality and purity.

Under the Prescription Drug User Fee

Act (“PDUFA”), the FDA has a goal of ten months from the date of “filing” of a standard, completed NDA

for a new molecular entity to review and act on the submission.

This review typically takes twelve months from the date the NDA

is submitted to the FDA because the FDA has approximately two months to make a “filing” decision after the application

The FDA reviews NDAs to determine, among

other things, whether the product is safe and effective for its intended use and whether it is manufactured in a cGMP-compliant

manner, which will assure and preserve the product’s identity, strength, quality and purity.

Under the Prescription Drug

User Fee Act (“PDUFA”), the FDA has a goal of ten months from the date of “filing” of a standard, completed

NDA for a new molecular entity to review and act on the submission.

This review typically takes twelve months from the date the

NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision after the application

is submitted.

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The FDA may refer an application for a new

drug to an advisory committee within the FDA.

An advisory committee is a panel of independent experts, including clinicians and

other scientific experts, that reviews, evaluates and provides a recommendation as to whether and under what conditions the application

should be approved.

The FDA is not bound by the recommendations of such an advisory committee, but it considers advisory committee

recommendations carefully when making decisions.

drug to an advisory committee.

An advisory committee is a panel of independent experts, including clinicians and other scientific

experts, that reviews, evaluates and provides a recommendation as to whether and under what conditions the application should be

The FDA is not bound by the recommendations of such an advisory committee, but it considers advisory committee recommendations

carefully when making decisions.

Before approving an NDA, the FDA will also

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Before approving an NDA, the FDA may also inspect one or more clinical trial sites to assure compliance

with GCP requirements.

with GCP requirements and inspect the clinical trial records.

After the FDA evaluates an NDA, it will issue

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deficiencies in the NDA identified by the FDA and may require additional clinical data, such as an additional pivotal Phase 3 trial

or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing.

If a Complete

Response Letter is issued, the sponsor must resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw

the application.

Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria

for approval.

An approval letter authorizes commercial marketing of the drug with prescribing information for specific indications.

or other significant and time-consuming requirements related to clinical trials, nonclinical studies or product manufacturing.

If a Complete Response Letter is issued, the sponsor must resubmit the NDA, addressing all of the deficiencies identified in the

letter, or withdraw the application.

Even if such data and information are submitted, the FDA may decide that the NDA does not

satisfy the criteria for approval.

An approval letter authorizes commercial marketing of the drug with prescribing information

for specific indications.

The Pediatric Research Equity Act (“PREA”),

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may require testing and surveillance programs to monitor the safety of approved products which have been commercialized and may

require a sponsor to conduct post-marketing clinical trials, which are designed to further assess a drug’s safety and effectiveness

after NDA approval.

The FDA may also place other conditions on approval, including a requirement for a risk evaluation and mitigation

strategy (“REMS”) to assure the safe use of the drug.

If the FDA concludes a REMS is needed, the sponsor of the NDA

must submit a proposed REMS.

require a sponsor to conduct post-marketing clinical trials (Phase 4 clinical trials), which are designed to further assess a drug’s

safety and effectiveness after NDA approval.

The FDA may also place other conditions on approval, including a requirement for a

risk evaluation and mitigation strategy (“REMS”) to assure the safe use of the drug.

If the FDA concludes a REMS is

needed, the sponsor of the NDA must submit a proposed REMS.

The FDA will not approve the NDA without an approved REMS, if required.

A REMS could include medication

guides, physician communication plans or elements to assure safe use, such as restricted distribution methods, patient registries

and other risk minimization tools.

Any of these limitations on approval or marketing could restrict the commercial promotion, distribution,

prescribing or dispensing of products.

Marketing approval may be withdrawn for non-compliance with REMS or other regulatory requirements,

or if problems occur following initial marketing.

A REMS could include medication guides, physician communication plans or elements to assure safe use, such as restricted distribution

methods, patient registries and other risk minimization tools.

Any of these limitations on approval or marketing could restrict

the commercial promotion, distribution, prescribing or dispensing of products.

Marketing approval may be withdrawn for non-compliance

with REMS or other regulatory requirements, or if problems occur following initial marketing.

Post-approval requirements

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sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical holds on post-marketing clinical

trials, enforcement letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions,

fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment, restitution,

disgorgement of profits, or civil or criminal penalties.

trials, enforcement letters, import refusals, product recalls, product seizures, total or partial suspension of production or distribution,

injunctions, fines, refusals of government contracts, mandated corrective advertising or communications with doctors, debarment,

restitution, disgorgement of profits, or civil or criminal penalties.

Expedited development and review programs

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to orphan exclusivity.

Marketing exclusivity

Abbreviated New Drug Applications, 505(b)(2)

Applications, and Marketing exclusivity

In seeking approval for a drug through an NDA,

applicants are required to list with the FDA each patent with claims that cover the applicant’s drug or an approved method

of use of the drug.

Upon approval of a drug, each of the patents listed in the application for the drug is then published in the

FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the “Orange Book.” Drugs

listed in the Orange Book can, in turn, be cited by competitors in support of approval of an Abbreviated New Drug Application,

or ANDA, or a 505(b)(2) application.

In this case, the original NDA (the so-called pioneer drug) is known as the

“listed” drug or “reference-listed” drug.

An ANDA provides for marketing of a drug that has the same active

ingredient and the same strength, route of administration and dosage form as the listed drug and has been shown through testing

to be bioequivalent to the listed drug or receives a waiver from bioequivalence testing.

ANDA applicants are generally not required

to conduct or submit results of preclinical or clinical tests to prove the safety or effectiveness of their drug, other than the

requirement for bioequivalence testing.

Drugs approved in this way are considered therapeutically equivalent, and are commonly

referred to as “generic equivalents” to the listed drug.

These drugs then generally can be substituted by pharmacists

under prescriptions written for the original listed drug.

A 505(b)(2) application is a type of NDA that

relies, in part, upon data the applicant does not own and to which it does not have a right of reference.

Such applications often

are submitted for changes to previously approved drug products, and rely on the FDA’s prior findings of safety and effectiveness

for a third party’s NDA to abbreviate the showings the sponsor of the 505(b)(2) application must make to establish that its

product is safe and effective.

The ANDA or 505(b)(2) applicant is required

to certify to FDA concerning any patents listed for the referenced approved drug in FDA’s Orange Book.

Specifically, for

each listed patent, the applicant must certify that:

(1) the required patent information has not been filed;

listed patent has expired;

(3) the listed patent has not expired but will expire on a particular date and approval is sought

after patent expiration;

or (4) the listed patent is invalid, unenforceable or will not be infringed by the new drug.

A certification

that the new drug will not infringe the already approved drug’s listed patents or that such patents are invalid or unenforceable

is called a Paragraph IV certification.

If the ANDA or 505(b)(2) applicant does not include a Paragraph IV certification,

the ANDA or 505(b)(2) application will not be approved until all of the listed patents claiming the referenced drug have expired,

except for any listed patents that only apply to uses of the drug not being sought by the ANDA or 505(b)(2) applicant.

If the ANDA or 505(b)(2) applicant has

made a Paragraph IV certification, the applicant must also send notice of a Paragraph IV Notice Letter to the NDA and patent holders

once the ANDA or 505(b)(2) application has been accepted for filing by FDA.

The NDA and patent holders may then initiate a

patent infringement lawsuit in response to the notice of the Paragraph IV Notice Letter.

The filing of a patent infringement lawsuit

within 45 days of the receipt of notice of a Paragraph IV Notice Letter automatically prevents FDA from approving the ANDA

until the earlier of 30 months, expiration of the patent, settlement of the lawsuit, modification by a court or a decision

in the infringement case that is favorable to the ANDA or 505(b)(2) applicant.

As discussed below, the ANDA or 505(b)(2) application

also will not be approved until any applicable non-patent exclusivity listed in the Orange Book for the reference-listed

drug has expired.

Market exclusivity provisions under the FDCA

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for review an abbreviated new drug application (“ANDA”), or an NDA submitted under Section 505(b)(2) (a “505(b)(2)

NDA”), submitted by another company for another drug based on the same active moiety, regardless of whether the drug is intended

for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal

right of reference to all the data required for approval.

However, an application may be submitted after four years if it contains

a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

NDA”), submitted by another company for another drug containing the same active moiety, regardless of whether the drug is

intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or

have a legal right of reference to all the data required for approval.

However, an application may be submitted after four years

if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator

The FDCA alternatively provides three years

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orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances.

United States Patent Term Restoration

Depending upon the timing, duration and specifics

of FDA approval of our future product candidates, some of our United States patents may be eligible for limited patent term extension

under the Drug Price Competition and Patent Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Amendments.

The Hatch-Waxman Amendments permit restoration of the patent term of up to five years as compensation for patent term lost during

the FDA regulatory review process for a drug that has not been previously approved for commercial marketing.

Patent-term restoration,

however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date and only

those claims covering such approved drug product, a method for using it or a method for manufacturing it may be extended.

The patent-term

restoration period is generally one-half the time between the effective date of an IND and the submission date of an

NDA plus the time between the submission date of an NDA and the approval of that application, except that the review period is

reduced by any time during which the applicant failed to exercise due diligence.

Only one patent applicable to an approved drug

is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent.

Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension

or restoration.

In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent

life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in

the filing of the relevant NDA.

Foreign Sales

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in any one of the following:

the European Union, Canada, Australia, New Zealand, Japan, Israel, Switzerland and South Africa.

are specific FDA regulations that govern this process.

the European Union or a country in the European Economic Area (the countries in the European Union

and the European Free Trade Association) if the drug or device is marketed in that country or the drug or device is authorized

for general marketing in the European Economic Area, Canada, Australia, New Zealand, Japan, Israel, Switzerland and South Africa.

There are specific FDA regulations that govern this process.

coverage and reimbursement

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successful commercialization of, and obtaining a satisfactory financial return on, any product we develop may not be possible.

Third-party payors are increasingly

challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition

to their safety and efficacy.

In order to obtain coverage and reimbursement for any product that might be approved for marketing,

we may need to conduct expensive studies in order to demonstrate the medical necessity and cost-effectiveness of any products,

which would be in addition to the costs expended to obtain regulatory approvals.

Third-party payors may not consider our compounds

to be medically necessary or cost-effective compared to other available therapies, or the rebate percentages required to secure

favorable coverage may not yield an adequate margin over cost or may not enable us to maintain price levels sufficient to realize

an appropriate return on our investment in drug development.

Third-party payors are increasingly challenging

the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety

and efficacy.

In order to obtain coverage and reimbursement for any product that might be approved for marketing, we may need to

conduct expensive studies in order to demonstrate the medical necessity and cost-effectiveness of any products, which would be

in addition to the costs expended to obtain regulatory approvals.

Third-party payors may not consider our compounds to be medically

necessary or cost-effective compared to other available therapies, or the rebate percentages required to secure favorable coverage

may not yield an adequate margin over cost or may not enable us to maintain price levels sufficient to realize an appropriate return

on our investment in drug development.

Additionally,

we or our collaborators may develop companion diagnostic tests for use with our product candidates.

Companion diagnostic tests

require coverage and reimbursement separate and apart from the coverage and reimbursement for their companion pharmaceutical or

biological products.

Similar challenges to obtaining coverage and reimbursement, applicable to pharmaceutical or biological products,

will apply to companion diagnostics.

Fraud and Abuse Laws

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referral of an individual for the:

or arranging for the furnishing of items or services reimbursable in whole or in part under

Medicare, Medicaid or other federal healthcare programs;

lease, or order of, or the arrangement or recommendation of the purchasing, leasing, or ordering

of any item or service reimbursable in whole or in part under Medicare, Medicaid or other

federal healthcare programs.

furnishing or arranging for the furnishing of items or services reimbursable in whole or in part under Medicare, Medicaid or other federal healthcare programs;

purchase, lease, or order of, or the arrangement or recommendation of the purchasing, leasing, or ordering of any item or service reimbursable in whole or in part under Medicare, Medicaid or other federal healthcare programs.

There are a number of narrow safe harbors

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False Claims Act and the civil monetary penalties statute.

The federal Health Insurance Portability and Accountability

Act of 1996 (“HIPAA”) among other things, enacted numerous provisions that prohibit knowingly and willfully executing, or

attempting to execute, a scheme or artifice to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses,

representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program,

regardless of the payor (e.g., public or private), willfully obstructing a criminal investigation of a healthcare offense, and knowingly

and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false, fictitious

or fraudulent statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare

These provisions include 18 U.S.C.

§§ 286, 287, 669, 1035, 1347, and 1518, all as described further below.

The Ethics in Patient Referrals Act,

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Exclusion from federal

health care programs—whether mandatory or permissive—may mean that we would not be entitled to participation in federal

and/or state health care programs for services rendered.

health care programs—whether mandatory or permissive—may mean that our customers may not be able to get reimbursed

by federal and/or state health care programs for use or dispensing of our products .

State Fraud and Abuse Provisions

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could adversely affect the ability to operate the business, financial condition, and the results of operations.

Sunshine Act requires manufacturers of products reimbursed by Medicare, Medicaid or the Children’s Health Insurance Program

(“CHIP”) to collect and annually report detailed data to the Centers for Medicare and Medicaid Services (“CMS”)

regarding payments or other transfers of value to physicians, certain other health care providers (such

as physicians assistants and nurse practitioners), and teaching hospitals (“covered recipients”), as well as

any ownership or investment interest held by physicians and their immediate family members.

The reporting data must be accompanied

by an attestation as to the accuracy of the data and failure to timely and accurately submit required information may result in

civil monetary penalties.

Health Insurance Portability and

Accountability Act

The Health Insurance Portability and

Accountability Act, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”),

and implementing regulations thereunder (collectively, “HIPAA”) requires certain healthcare providers, health plans

and healthcare clearinghouses who conduct specified electronic healthcare transactions (“covered entities”), as well

as their independent contractors and agents who conduct certain activities involving protected health information on their behalf

(“business associates”) to comply with enumerated requirements relating to the privacy, security and transmission of

protected health information.

Failure to comply with HIPAA can result in corrective action, as well as civil fines and penalties

and government oversight.

Among other changes, HITECH made HIPAA security standards directly applicable to business associates,

increased the tiered civil and criminal fines and penalties that may be imposed against covered entities, business associates and

possibly other persons, and gave state attorneys general new authority to file actions to enforce HIPAA.

Further, the breach notification

rule implemented under HITECH requires covered entities to notify affected individuals, the U.S.

Department of Health and Human

Services Office of Civil Rights (“OCR”), the agency that enforces HIPAA, and for breaches affecting more than 500 individuals,

the media, of any breaches of unsecured protected health information.

HIPAA does not create a private right of action for individuals,

though individuals may submit complaints related to HIPAA to OCR.

Patient Protection and Affordable

In the United States, there have been,

and continue to be multiple legislative and regulatory changes and proposed changes regarding the healthcare system that could

impact our business.

Policymakers and third party reimbursement programs (i.e.

payors) have articulated the goals of controlling

healthcare costs, improving quality and/or expanding access in connection with these healthcare reform efforts.

As a leading example,

in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (collectively,

the “ACA”), was passed, ushering in significant changes to the way healthcare is financed in the United States.

respect to impacts specific to the U.S.

pharmaceutical industry, among other things, the ACA:

the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program and extended the rebate program to

include Medicaid managed care organizations as well as Medicaid fee-for-service programs;

expanded eligibility criteria for Medicaid programs by, among other

things, allowing states to offer Medicaid coverage to additional individuals, correspondingly increasing manufacturers’

Medicaid rebate liability;

created a new methodology by which average manufacturing price is calculated

for drugs that are inhaled, infused, instilled, implanted or injected and not generally dispensed through retail community pharmacies;

established an annual, nondeductible fee on any entity that manufactures

or imports certain specified branded prescription drugs and biologic products;

expanded the availability of lower drug pricing under the 340B drug

pricing program to additional types of covered entities;

created a new partial prescription drug benefit for Medicare recipients

under the Medicare Part D coverage gap discount program, in which manufacturers must agree to offer point-of-sale discounts off

negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the

manufacturer’s outpatient drugs to be covered under Medicare Part D;

amended the Public Health Service Act to create an abbreviated approval

pathway for biological products that are demonstrated to be biosimilar to or interchangeable with an FDA-approved biological product;

added a requirement to annually report product samples that manufacturers

and distributors provide to physicians;

established new requirements, known as ―Sunshine Act requirements

for manufacturers of products reimbursed by Medicare, Medicaid or the Children’s Health Insurance Program (―CHIP )

to collect and annually report detailed data to the Centers for Medicare and Medicaid Services (―CMS ) regarding payments

or other transfers of value to physicians and teaching hospitals (―covered recipients ), as well as any ownership or investment

interest held by physicians and their immediate family members.

The reporting data must be accompanied by an attestation as to

the accuracy of the data and failure to timely and accurately submit required information may result in civil monetary penalties;

established a Center for Medicare & Medicaid Innovation at CMS,

to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription

created a new Patient-Centered Outcomes Research Institute to oversee,

identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;

expanded healthcare fraud and abuse laws, including the civil False

Claims Act and the federal Anti- Kickback Statute, and enhanced penalties for noncompliance, which are applicable beyond the U.S.

pharmaceutical industry (e.g.

to other types of healthcare entities) but also are of specific relevance to the U.S.

pharmaceutical

The Bipartisan Budget Act of 2018 amended

the ACA, effective January 1, 2019, to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut

hole.” Further, the Substance-Use Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities

Act (“SUPPORT Act”) amended the Sunshine Act to expand the definition of covered recipient for whom applicable manufacturers

must collect ad report data to include physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists

and certified nurse mid-wives for data reported on or after January 1, 2022.

There have been multiple judicial challenges

to certain aspects of the ACA, as well as Congressional efforts to repeal or replace the ACA, and efforts by the Trump administration

to delay or circumvent the implementation of certain ACA requirements.

For example, the Tax Cuts and Jobs Act of 2017 repealed,

effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain

minimum essential health care insurance, commonly known as the “individual mandate.” On December 14, 2018, a U.S.

Court in the Northern District of Texas ruled that the individual mandate is a critical and inseverable feature of the ACA, and

therefore, because it was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well.

On December 18, 2019, the U.S.

Court of Appeals for the 5th Circuit affirmed the District Court’s decision that the individual

mandate was unconstitutional but remanded the case back to the District Court to determine whether the remaining provisions of

the ACA are invalid as well.

Supreme Court has agreed to review the case and oral arguments heard oral arguments in November

Therefore, ongoing force and effect of certain or all of the provisions of the ACA remain in a state of uncertainty at this

current time.

Besides enacting the program integrity provisions described above, HIPAA, also

created a new set of privacy and security requirements.

As amended by the Health Information Technology for Economic and Clinical Health

Act, and implementing regulations thereunder, HIPAA requires certain healthcare providers, health plans and healthcare clearinghouses

who conduct specified electronic healthcare transactions (“covered entities”), as well as their independent contractors and

agents who conduct certain activities involving protected health information on their behalf (“business associates”) to comply

with enumerated requirements relating to the privacy, security and transmission of protected health information.

Failure to comply with

HIPAA can result in corrective action, as well as civil fines and penalties and government oversight.

Among other changes, HITECH made

HIPAA security standards directly applicable to business associates, increased the tiered civil and criminal fines and penalties that

may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority

to file actions to enforce HIPAA.

Further, the breach notification rule implemented under HITECH requires covered entities to notify affected

individuals, the U.S.

Department of Health and Human Services Office of Civil Rights (“OCR”), the agency that enforces HIPAA,

and for breaches affecting more than 500 individuals, the media, of any breaches of unsecured protected health information.

not create a private right of action for individuals, though individuals may submit complaints related to HIPAA to OCR.

Legislative Activities Aimed at Controlling

In the United States, there have been, and continue to be proposed and enacted

legislation at the federal and state levels designed to, among other things, bring more transparency to drug pricing, review the relationship

between pricing and manufacturer patient programs, reduce the cost of drugs under Medicare, and reform government program reimbursement

methodologies for drugs.

For example, in July 2021, the Biden administration released an executive order, “Promoting Competition

in the American Economy,” with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on

September 9, 2021, the U.S.

Department of Health and Human Services (“HHS”) released a Comprehensive Plan for Addressing High

Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could

pursue as well as potential administrative actions HHS can take to advance these principles.

In addition, the Inflation Reduction Act

(“IRA”) passed on August 16, 2022.

The IRA, among other things, (1) directs HHS to negotiate the price of certain highly-utilized

single-source drugs and biologics covered under Medicare and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize

price increases that outpace inflation.

These provisions will take effect progressively starting in fiscal year 2023, although they may

be subject to legal challenges.

It is currently unclear how the IRA will be implemented but is likely to have a significant impact on

the pharmaceutical industry.

Further, the Biden administration released an additional executive order on October 14, 2022, directing HHS

to submit a report within 90 days on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for

lowering drug costs for Medicare and Medicaid beneficiaries.

We expect that additional U.S.

federal healthcare reform measures will be

adopted in the future, any of which could limit the amounts that the U.S.

federal government will pay for healthcare products and services,

which could result in reduced demand for our product candidates or additional pricing pressures.

Research and Development Expenses

9 unchanged sentences

include clinicians and scientists who are affiliated with a number of highly regarded medical institutions.

We currently have twenty-five full-time

We currently have approximately thirty-eight full-time

employees, and we retain several independent contractors on a regular or as-needed basis.

We believe that we have good relations

with our employees.

We believe that we have good relations with

our employees.

Available Information

5 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business