Use of anavex3-71 for medical treatments

Abstract

The present disclosure relates to the novel use of ANAVEX3-71 and related compounds in medical treatments, such as Parkinson's Disease, Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease.

Description

USE OF ANAVEX3-71 FOR MEDICAL TREATMENTSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 661 ,490 filed June 18, 2024, and U.S. Provisional Patent Application Serial No. 63 / 764,235 filed February 27, 2025, each of which is entitled “USE OF ANAVEX3-71 FOR MEDICAL TREATMENTS,” the disclosures of which are hereby incorporated by reference in their entirety.FIELD OF THE DISCLOSURE

[0002] This application relates to disease treatment, such as treating or preventing neurodegenerative or neuropsychiatric diseases.BACKGROUND

[0003] Neurodegenerative diseases are severe and progressive disorders involving numerous cascading disruptions to pathways involved in proteostasis, cellular stress responses, synaptic function, and glial perturbations that accompany neuronal loss. Clinical manifestations are highly heterogenous and disease-modifying treatments remain a critical unmet need. Neuropsychiatric diseases encompass a broad range of medical conditions that involve both neurology and psychiatry. Very few therapies are available for patients and thus demand exists for new therapy developments.SUMMARY OF THE DISCLOSURE

[0004] The present disclosure encompasses a method for treating a neuropsychiatric disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sigma-1 receptor agonist selected from 1-[2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1 -one (AF710); 1 -[(2 R)-2, 8-dim ethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (AF710A); 1 -[(2S)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]- 3-(1 H-indol-3-yl)propan-1 -one (ANAVEX 3-71 , AF710B); a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof; and the therapeutically effective amountis the amount effective in controlling one or more symptoms associated with the neuropsychiatric disorder. In one aspect, the neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid Personality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder. In another aspect, the one or more symptoms comprises hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, or any combination thereof. In yet another aspect, the schizotypal personality disorder is schizophrenia or bipolar disorder. In yet another aspect, the schizophrenia is selected from paranoid type, disorganized type, catatonic type, and undifferentiated type. In one aspect, the bipolar disorder comprises bipolar I, bipolar II, cyclothymic disorder, or rapid cycling bipolar.

[0005] In one aspect, the method comprises administering the polymorph of ANAVEX 3-71 as characterized by PXRD of FIG. 1 B. In yet another aspect, the method comprises administering a compound having the structure of Formula (I), Formula (II), and / or Formula (III) (see structures herein). In one aspect, the administration is once per day, twice per daily, or three times per day. In another aspect, the therapeutically effective amount is from about 10 mg / day to about 600 mg / day. In yet another aspect, the therapeutically effective amount is delivered orally or intravenously. In one aspect, the therapeutically effective amount is from about 15 mg / day to about 600 mg / day when administered orally. In yet another aspect, the therapeutically effective amount is from about 10 mg / day to about 50 mg / day when administered intravenously.

[0006] The present disclosure encompasses a method for treating a neurodegenerative disorder, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sigma-1 receptor agonist selected from 1 -[2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1 - one (AF710); 1-[(2R)-2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol- 3-yl)propan-1-one (AF710A); 1-[(2S)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3- yl]-3-(1 H-indol-3-yl)propan-1 -one (ANAVEX 3-71 , AF710B), a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof; and the therapeutically effective amount is the amount effective in controlling one or moresymptoms associated with the neurodegenerative disorder. In one aspect, the one or more symptoms of the neurodegenerative disorder comprises dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof. In yet another aspect, the dementia is associated with a disorder selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, and Progressive supranuclear palsy and infections. In yet another aspect, the dementia is selected from AIDS related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, Fronto-temporal dementia (FTD), and idiopathic dementia. In yet another aspect, the dementia is associated with Alzheimer’s disease or Parkinson disease.

[0007] In one aspect, the method comprises administering the polymorph of ANAVEX 3-71 as characterized by PXRD of FIG. 1 B. In yet another aspect, the method comprises administering the compound having the structure of Formula (I), Formula (II), and / or Formula (III) (see structures herein). In one aspect, the administration is once per day, twice per daily, or three times per day. In another aspect, the therapeutically effective amount is from about 10 mg / day to about 600 mg / day. In yet another aspect, the therapeutically effective amount is delivered orally or intravenously. In one aspect, the therapeutically effective amount is from about 15 mg / day to about 600 mg / day when administered orally. In yet another aspect, the therapeutically effective amount is from about 10 mg / day to about 50 mg / day when administered intravenously. In one aspect, the therapeutically effective amount does not impact cardiodynamic functions of the subject.

[0008] In another aspect, the present disclosure encompasses a pharmaceutical composition or dosage form comprising (i) a sigma-1 receptor agonist and (ii) an excipient, and the sigma-1 receptor agonist is in an amount effective in controlling one or more symptoms associated with a neuropsychiatric or neurodegenerative disorder. In one aspect, the sigma-1 receptor agonist is selected from one or more of 1-[2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol- 3-yl)propan-1 -one (AF710); 1 -[(2R)-2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3- yl]-3-( 1 H-indol-3-yl)propan-1 -one (AF710A); 1 -[(2S)-2 , 8-dimethyl-1 -thia-3,8- diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1 -one (ANAVEX 3-71 , AF710B); a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof. In one aspect, the sigma-1 receptor agonist is A3-71. In yet another aspect, the sigma-1 receptor agonistis the polymorph of ANAVEX 3-71 characterized by PXRD of FIG. 1 B. In yet another aspect, the metabolite is M8-S enantiomer ( / .e., the structure of Formula (II), below). In yet another aspect, the compound is selected from one or more of Formula (I), Formula (II), and Formula (III). In one aspect, the neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid Personality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder. In yet another aspect, the one or more symptoms of the neuropsychiatric disorder comprises hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, or any combination thereof. In another aspect, the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections, and any combination thereof. In another aspect, the one or more symptoms of neurodegenerative disorder comprises dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof.

[0009] In one aspect, the pharmaceutical composition or dosage form is an oral composition or an injectable composition comprising a therapeutically effective amount of one or more of 1-[2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H- i nd ol-3-y I )propan- 1 -one (AF710); 1 -[(2 R)-2 , 8-d i m ethy I- 1 -thia-3,8- diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1 -one (AF710A); 1 -[(2 S)-2 , 8- dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1-one (ANAVEX 3-71 , AF710B); a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof. In yet another aspect, the pharmaceutical composition or dosage form comprises a tablet, a capsule, or an oral liquid. In yet another aspect, the pharmaceutical composition or dosage form is for immediate release, modified release, or extended release. In one aspect, the pharmaceutical composition or dosage form releases the sigma-1 receptor agonist over a period of about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours or about 14 hours. In yet another aspect, the excipient comprises a release-controlling agent, a filler, a glidant, a lubricant, a pH modifier, water for injection, or any combination thereof. In another aspect, the excipient comprises one or more of hypromellose K100 LV,hypromellose K15M, lactose monohydrate, microcrystalline cellulose, fumaric acid, silica colloidal anhydrous, or magnesium stearate. In one aspect, the therapeutically effective amount is from about 2 mg to about 300 mg. In yet another aspect, the therapeutically effective amount is from about 5 mg to about 300 mg in an oral composition. In yet another aspect, the therapeutically effective amount is from about 2 mg to about 20 mg in an injectable composition. In yet another aspect, the pharmaceutical composition or dosage form is an immediate release capsule, and the therapeutically effective amount is selected from about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 55 mg, about 75 mg, about 100 mg, about 125 mg, about 135 mg, about 160 mg, about 180 mg, and about 200 mg. In yet another aspect, the composition is a modified release tablet, and the therapeutically effective amount is selected from about 150 mg, about 180 mg, about 200 mg, and about 300 mg.

[0010] Yet in another aspect, the present disclosure encompasses a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), an enantiomer, a diastereomer, an isomer, a crystal, or a pharmaceutically acceptable salt thereof:Formula (III)

[0011] ln another aspect, the present disclosure encompasses a dosage form or a composition comprising such compound of Formula (I), Formula (II), or Formula (III). In one particular embodiment, the dosage form or composition comprises the compound of Formula (I). In another particular embodiment, the dosage form or composition comprises the compound of Formula (II). In another particular embodiment, the dosage form or composition comprises the compound of Formula (III). In another particular embodiment, the dosage form or composition comprises one or more of the compounds of Formula (I), Formula (II), and Formula (III). Another aspect of the present disclosure encompasses use of the compound, the dosage form, or the composition in treating a neuropsychiatric disorder, or a neurodegenerative disorder, or one or more symptoms thereof. In one aspect, the neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder,Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid Personality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder. In another aspect, the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections, and any combination thereof. In another aspect, the one or more symptoms comprise hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof.

[0012] In another aspect, the present disclosure encompasses a method of treating a neuropsychiatric disorder, or a neurodegenerative disorder, or one or more symptoms thereof by administering a therapeutically effective amount of a compound of having the structure of Formula (I), Formula (II), and / or Formula (III) (see structures herein). In one aspect, the neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid Personality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder. In another aspect, the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections, and any combination thereof. In another aspect, the one or more symptoms comprise hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof. In another aspect, the therapeutically effective amount is about 2 mg to about 300 mg.REFERENCE TO COLOR FIGURES

[0013] The application file contains at least one drawing or photograph executed in color. Copies of this patent application publication with color photographs will be provided by the Office upon request and payment of the necessary fee.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIGS. 1A-1C provide characterizations of ANAVEXO3-71. FIG. 1A provides the XRPD pattern for the single crystal of ANAVEXO3-71 from -5° to 50° 2Q. FIG. 1 B-1 C provide the chiral HPLC graphs of the single crystal of ANAVEXO3-71 and the racemate counterpart, respectively.

[0015] FIGS. 2A-2C provide the characterization of the compound having the structure of Formula (II) ( / .e., metabolite M8-S enantiomer), including Mass Spectra (FIG. 2A),1H NMR (FIG. 2B), and13C NMR (FIG. 2C).

[0016] FIG. 3 depicts the dosing chart, wherein P refers to placebo. Doses are in milligrams (mg). Dosing periods are split between “a” and “b” sub-periods, where the “a” period is the sentinel dosing period, which is followed by the rest of the Panel in the “b” sub-period. The doses studied are 5 mg, 10 mg, 20 mg, 40 mg, 55 mg, 75 mg, 100 mg, 135 mg, 160 mg, and 200 mg. Each dosing period (1-10) was at least 6 days long.

[0017] FIG. 4 depicts change-from-baseline HR (AHR) across time points with statistical modeling (QT / QTc population), wherein LS mean is based on a linear mixed- effects model: AHR = Time + Treatment + TimexTreatment + Baseline HR. An unstructured covariance structure was used to specify the repeated measures (time within period*subject). The model also included a participant-specific random effect.

[0018] FIG. 5 depicts placebo-corrected change-from-baseline HR (AAHR) across time points with statistical modeling (QT / QTc population), wherein LS mean is based on a linear mixed-effects model: AHR = Time + Treatment + TimexTreatment + Baseline HR. An unstructured covariance structure was used to specify the repeated measures (time within period*subject). The model also included a participant-specific random effect.

[0019] FIG. 6A-6B depict change-from-baseline QTcF (AQTcF) and corrected change from baseline (AAQTcF) respectively across time points with statistical modeling (QT / QTc population), wherein LS mean is based on a linear mixed-effects model: AHR = Time + Treatment + TimexTreatment + Baseline HR. An unstructured covariance structure was used to specify the repeated measures (time within period*subject).

[0020] FIG. 7 depicts mean ANAVEXO3-71 plasma concentrations over time (PK / QTc population) from descriptive statistics at different doses of ANAVEXO3-71 .

[0021] FIG. 8 depicts mean M8-S enantiomer ( / .e., Formula (II) plasma concentrations over time (PK / QTc population) from descriptive statistics at different doses of ANAVEXO3-71.

[0022] FIG. 9 depicts scatter plot of QTcF versus RR by treatment (QT / QTc population) at different doses of ANAVEXO3-71. The solid black line denotes the simple linear regression across all pairs of (RR, QTc). This line is based on the equation QTcF = 375.38 + 0.017 x RR with a value of < .0001 for the slope. The R- squared value of the regression line (black) is 0.031 .

[0023] FIG. 10 depicts QTcF-RR quantile plot by treatment (QT / QTc population). The solid gray and blue lines with gray and blue shaded areas denote the 90% Cl from the linear mixed-effect model QTcF = intercept + slope x RR. The black circles and blue squares with vertical bars denote the observed mean QTcF with 90% Cl displayed at the median RR within each decile for placebo and ANAVEX3-71 , respectively. The slope for placebo was 0.010 with a P-value of .0005. The slope for ANAVEX3-71 was 0.0068 with a P-value of 0.0339.

[0024] FIGs. 11A-B depict scatter plot of observed ANAVEX3-71 and M8 plasma concentrations and QTcF (PK / QTc population), respectively. The red line with the blue shaded area denotes the LOESS regression and 90% confidence limits. The black solid line denotes the simple linear regression line. The plotted points denote the pairs of observed ANAVEX3-71 plasma concentrations and QTcF (FIG. 11 A). The plotted points denote the pairs of observed M8-S enantiomer plasma concentrations and QTcF (FIG. 11 B).

[0025] FIGs. 12A-B depict placebo-adjusted AQTcF (mean and 90% Cl) across deciles of ANAVEX3-71 (FIG. 12A) and M8-S enantiomer (FIG. 12B) plasma concentrations (PK / QTc population). Prediction is based on a linear mixed-effects model with AQTcF as the dependent variable, time-matched ANAVEXO3-71 or M8-S enantiomer plasma concentration as an explanatory variate, centered baseline QTcF as an additional covariate, treatment (active = 1 or placebo = 0) and time as fixed effects, and a random intercept and slope per participant. The horizontal red line with notches shows the range of concentrations divided into deciles for ANAVEX3-71 (FIG. 12A) or M8-S enantiomer (FIG. 12B). The area between each decile represents the point at which 10% of the data are present; the first notch to second notch denotes the first 10% of the data, the second notch to third notch denotes the 10-20% of the data and so on.

[0026] FIGs. 13A-B depict mean ANAVEX3-71 APR over time at different doses of ANAVEX3-71 (FIG. 13A) and ANAVEX3-71 AQRS over time (FIG. 13B).

[0027] FIG. 14 depicts formulation design space created by the prototype formulations FPA, FPB, FPC and FPD.

[0028] FIG. 15 shows the observed and predicted Cp-t profiles of the PO administration of 200 mg MR to healthy subjects with the updated model with a lower hepatic CL, longer gastric transit time and longer ascending colon transit time.

[0029] FIG. 16 depicts the observed arithmetic mean Cp-t profiles after the administration of ANAVEX® 3-71 PO as 125 mg IR and 200 mg MR t80% 14 hour.

[0030] FIG. 17 depicts the in vitro dissolution profile of MR prototype dosed in the clinic, 80% dissolved at 14 hour.

[0031] FIG. 18 provides representative chromatograms of ANAVEX3-71 near the ULOQ, in a treated subject with ANAVEX3-71 IS (Internal Standard) and ANAVEX 3-71 M8-S enantiomer IS.

[0032] FIG. 19 provides geometric mean (x / Geometric SD) plasma ANAVEX3-71 concentrations following administration of ANAVEX3-71 IR Oral Capsules and ANAVEX3-71 MR Prototype 1 Tablet (Log10 / Linear).DETAILED DESCRIPTION

[0033] The present disclosure is based in part on the discovery that ANAVEX®3-71 (also referred to herein as ANAVEX3-71 , ANAVEX 3-71 , Anavex3-71 , Anavex 3-71 , A3-71 , and AF710B), a dual agonist of Sigma-1 receptor and M1 muscarinic receptor, has broad therapeutic applications in disease treatment, such as in treating neurological disorders encompassing neurodegenerative and neuropsychiatric disorders. ANAVEX®3-71 is a novel, orally available, dual sigma-1 receptor (S1 R) and allosteric M1 muscarinic receptor (M1 R) agonist. The activation of S1 Rs is associated with a beneficial cascade of neuroprotective, proteostatic, and immune calming effects. Allosteric modulation of M1 Rs is expected to reduce or prevent side effects associated with previous generations of cholinergic drugs and is associated with pro-cognitive effects in neurodegenerative and neuropsychiatric diseases. The US Food and Drug Administration has granted Orphan Drug Designation to ANAVEX3-71 for the treatment of frontotemporal dementia (FTD). ANAVEX3-71 is also being developed for the treatment of other neurodegenerative diseases including Alzheimer’s disease (AD) and neuropsychiatric disorders includingschizophrenia. The present disclosure expressly encompasses compounds of ANAVEX®3-71 ; a metabolite of A3-71 referred to herein as “M8-S enantiomer”, the stereoisomer of A3-71 referred to herein as “AF710A,” and the racemic form of A3-71 referred to herein as “AF710”, as well as compositions and uses thereof. Both in vitro and in vivo preclinical studies indicate that ANAVEX3-71 binds selectively to sigma-1 receptors (S1 Rs) and muscarinic 1 receptors (M1 Rs), has a high safety margin, and appears to cross the blood-brain barrier easily in rats and mice.COMPOUNDS1-[2, 8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-( 1 H-indol-3-yl)propan-1 -one1 -[(2S)-2, 8-dimethyl-1 -th i a-3 , 8-d iazas pi ro[4.5]deca n-3-y l]-3-( 1 H-indol-3-yl)propan-1 -one1-[(2R)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1-oneFormula (III)

[0034] The present disclosure expressly encompasses the structures of ANAVEXO3-71 ; a metabolite of A3-71 referred to herein as “M8-S enantiomer” (Formula (II)), M8-R enantiomer (Formula (III)), racemic M8 (Formula (I)), the stereoisomer of A3-71 referred to herein as “AF710A,” and the racemic form of A3-71 referred to herein as “AF710”, as well as compositions and uses thereof. ANAVEX3- 71 (also referred to herein as ANAVEX 3-71 , Anavex3-71 , Anavex 3-71 , A3-71 , AF710B) bears the IUPAC name of 1 -[(2S)-2,8-dimethyl-1 -thia-3,8- diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1-one and has the optical rotation of -56°. Pre-clinical data indicates ANAVEXO3-71 is a potent and selective Sigma-1 Receptor (S1 R) and M1 muscarinic agonist. Such a combined biological functionrepresents a unique approach to neurodegenerative and / or neuropsychiatric disorders, with the potential to impact major clinical manifestations by addressing the underlying pathophysiology. ANAVEXO3-71 is being developed as a treatment for neurodegenerative and / or neuropsychiatric disorders such as schizophrenia, Alzheimer’s disease and frontotemporal dementia. ANAVEXO3-71 is an orally available drug candidate that is believed to restore cellular homeostasis and neural plasticity by targeting S1 Rs and the M1 type of muscarinic receptors. Its stereocounterpart, 1 -[(2 R)-2 , 8-d i m ethy I- 1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (AF710A) is distinguishable from Anavex3-71 by bearing the positive optical rotation of +56°. The racemate of A3-71 comprises an equal amount of Anavex3-71 and AF710A, and may be expressed as 1 -[2,8-dimethyl-1 -thia-3,8- diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1 -one. As used herein, the racemate may be referred to as AF710 or “Anavex3-71 Racemate.” M8 is the metabolite of A3-71 and has the optical rotation of -57.7°. Both ANAVEXO3-71 and M8-S enantiomer have undergone an extensive series of nonclinical studies to elucidate the pharmacokinetics, metabolism, and toxicity of both compounds prior to the first-in-human study. In one aspect, the present disclosure encompasses any one or more of compounds A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and AF710, as well as their crystals, enantiomers, their pharmaceutically acceptable salts, and crystals and / or enantiomers of such salts. In other aspects, the present disclosure encompasses pharmaceutical compositions including one or more of A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A and AF710 (as well as their crystals, enantiomers, their pharmaceutically acceptable salts, and crystals and / or enantiomers of such salts). In still other aspects, the present disclosure encompasses uses of the various compounds and pharmaceutical compositions provided herein.

[0035] Pharmaceutically acceptable salts of the compounds disclosed herein (e.g., ANAVEXO3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, stereoisomer AF710A, and racemic AF710) include, without limitation, acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate,valerate, and the like. In one embodiment, the pharmaceutically acceptable salt comprises a hydrochloride salt, an acetate salt, a citrate salt, a formate salt, a hydrogen phosphate salt, or dihydrogen phosphate salt, a salicylate salt, or a stearate salt.DISORDERS AND TREATMENT

[0036] One aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710) in disease treatment or prevention. In one aspect, the disease is a neurological disorder, including but not limited to a neurodegenerative or a neuropsychiatric disorder. ANAVEX3-71 , for example, is an orally administered small molecule agonist at the Sigma-1 receptor (S1 R) and muscarinic 1 (M1) receptor, being developed for the treatment of various disorders, such as neurodevelopmental, neuropsychological, and / or personality disorders, including but not limited to Schizophrenia, Alzheimer’s Disease (AD), and Frontotemporal Dementia (FTD). Any of A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds) may therefore be used to treat neurological disorders in accordance with the present disclosure.

[0037] Sigma-1 receptor (S1 R) is a molecular chaperone in the endoplasmic reticulum (ER) and other cellular compartments and has been implicated in many disease states and their potential amelioration based largely on pre-clinical studies. Of particular relevance to neurological disorders is the role of S1 R in the cellular stress response. Enhanced ER stress can lead to cell death and accelerate neurodegenerative processes. Although the exact function(s) of S1 Rs has not been fully elucidated, there is evidence in the central nervous system (CNS) that S1 Rs have a role in neuronal homeostasis, including modulation of mitochondrial function and homeostatic synaptic scaling, regulation of neurotransmitter release, neuronal survival, and modulation of neuroinflammatory mechanisms. This functional profile makes S1 Rs particularly suitable for lessening pathogenic processes and enhancing compensatory mechanisms in neurodegenerative and other neurologic disorders.

[0038] Agonism of the M1 muscarinic receptor has been shown to reduce memory deficits and enhance cognition in human and animal studies of AD and other pathological protein brain disease (proteinopathies). Previous generations ofmuscarinic receptor agonists were not highly specific, leading to many undesirable adverse effects. ANAVEX3-71 is a positive allosteric modulator of M1 and therefore exhibits heightened specificity for M1 over other muscarinic receptors.

[0039] ANAVEX3-71 is believed to restore cellular homeostasis and neural plasticity by targeting S1 Rs and the M1 type of muscarinic receptors, which are especially relevant to various neurologic disorders, including but not limited to neurodevelopmental, neuropsychiatric, and / or personality disorders. Such a combination represents a unique approach to neurological disorders, including both neurodegenerative disorders and neuropsychiatric disorders, with the potential to impact major clinical manifestations by addressing the underlying pathophysiological effects. In one aspect, treating a disease or disorder means to halt or stop the underlying cause(s) and / or reverse the progression of the disease or disorder. In another aspect, treating a disease or disorder may also mean to control one or more symptoms or clinical signs related to the disorder, which includes to relieve, alleviate, ameliorate, eliminate, or slow the appearance of one or more symptoms and / or clinical signs. In another aspect, preventing a disease or disorder means to prevent and / or suppress the onset or development of the underlying causes.

[0040] One aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing neurodegenerative disorders. Neurodegenerative disorders are a group of debilitating conditions characterized by declining motor, cognitive, and other neurologic functions. Examples of neurodegenerative disorders include Alzheimer’s disease (AD) including early-onset AD, Parkinson disease, Huntington disease, Pick's disease, confusion, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, and Cushing's Disease, a cognitive impairment associated with auto-immune diseases. In one embodiment, the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease (AD), Parkinson’s Disease (PD), frontotemporal dementia (FTD), Huntington’s Disease, multiple sclerosis, Pick's disease (PiD), progressive supranuclear palsy (PSP), spinocerebellar corticobasal degeneration (CBD), Lewy body dementia, tangle- predominant senile dementia, argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases, Guam parkinsonism-dementia complex, FTDP-17,Lytico-Bodig disease, ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Fragile X Syndrome (FXS), infantile spasm, Smith-Magenis syndrome, post-traumatic stress disorder (PTSD), and traumatic brain or neuronal injury resulting from a stroke and spinal cord injury. In another embodiment, the neurodegenerative disorder comprises Alzheimer’s disease (AD) including early-onset AD, Parkinson disease, Huntington disease, or Pick's disease. In one aspect, treating a neurodegenerative disorder means to halt or stop the underlying causes and / or reverse the progression of the disorder. In another aspect, treating a neurodegenerative disorder means to control one or more symptoms related to the disorder, which includes to relieve, alleviate, ameliorate, control, manage, and / or improve the one or more symptoms. As used herein, preventing a neurodegenerative disorder means to prevent the onset or development of the disorder. The compounds of the present disclosure, including but not limited to A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and AF710, their pharmaceutically acceptable salts, their enantiomers, and their crystals are found to be useful in managing, treating, and / or preventing the neurodegenerative disorders. These compounds and their pharmaceutical compositions may halt or reverse progression of the neurodegenerative disorders, and / or reduce or ameliorate one or more symptoms, including but not limited to dementia, memory loss, forgetfulness, loss of language, impaired thinking, declined social skills, and / or abnormal motor activities.

[0041] According to the U.S. Centers for Disease Control and Prevention (CDC), dementia is not a specific disease. It is an overall term that describes a decline in mental ability that interferes with daily life. It affects memory, thinking, and behavior. People with dementia often have symptoms like forgetfulness, trouble in remembering or thinking, or failure to make everyday decisions. A person with dementia may have problems with short-term memory, paying bills, preparing meals, remembering appointments, or getting lost in familiar areas. These symptoms tend to get worse over time. Dementia may be associated with Alzheimer’s disease, Parkinson’s disease and / or other neuro-related disorders. Dementia may be subcategorized as AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, frontotemporal dementia (FTD), and idiopathic dementia. Vascular dementia is the second most common type of dementia andaccounts for about 5%-10% of cases. It results from strokes or other problems with blood flow to the brain. Symptoms gradually become worse as blood vessels get damaged. Symptoms of vascular dementia vary depending on the area of the brain that is affected. Conditions that damage blood vessels can also increase a person's risk of developing vascular dementia, such as diabetes, high blood pressure, and high cholesterol. Lewy body dementia is caused by abnormal deposits of a protein in the brain, called “Lewy bodies.” These deposits affect chemicals in the brain and can cause problems with thinking, movement, behavior, and mood. Symptoms include memory loss, as well as movement or balance issues like stiffness or trembling. Many people with Lewy body dementia also experience daytime sleepiness, confusion, staring spells, sleep disturbances, or visual hallucinations. Frontotemporal dementia (FTD) affects the frontal (front) and temporal (side) lobes in the front of the brain. It often leads to changes in personality and behavior. FTD is a common cause of dementia that affects younger people. FTD may be caused by damages to nerve cells in the frontal and temporal lobes of the brain. Symptoms of FTD include difficulty in planning or organizing activities, acting inappropriately in social or work settings, and having trouble communicating with others. Studies show about one-third of all FTD cases are inherited through genes. Having a family history of FTD or a similar disorder are known risk factors. Currently, there are no treatment for FTD.

[0042] Another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing Alzheimer's Disease (AD). AD is a progressive neurodegenerative disorder characterized by insidious onset of dementia, loss of memory and other cognitive functions, thereby interfering with daily life. Early symptoms include impairment of memory, judgment, attention span, and problem-solving skills. In late stage, severe apraxia and a global loss of cognitive abilities may occur. The disease is marked pathologically by severe cortical atrophy and the triad of senile plaques, neurofibrillary tangles, and neuropil threads. Further, the present disclosure encompasses the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A and AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing early- onset AD. Early-onset Alzheimer's disease (EOAD) is a rare form of Alzheimer’sdisease that affects people under the age of 65. EOAD is also known as "younger Alzheimer's" to distinguish it from early-stage Alzheimer's. EOAD may present atypical symptoms, with some people not experiencing noticeable memory loss, but instead showing visual symptoms, such as tunnel vision, impaired depth perception, or difficulty recognizing faces. They may also have difficulty speaking or coming up with words. More than 5.4 million Americans and 35 million people worldwide have Alzheimer’s disease. Currently, the only definitive way to diagnose Alzheimer's disease is by direct examination of brain tissue after a patient dies. Diagnostic methods include brain imaging, evaluation of behavior and / or psychiatric tests, and other means to in the patients suspected of having Alzheimer’s disease, but none are highly accurate, and many are costly or not practical. Currently, there are very few treatments for Alzheimer’s disease.

[0043] Yet another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing Parkinson's Disease (PD). PD is a highly heterogeneous multisystem disorder commonly associated with cognitive impairment. PD is considered the second largest CNS disorder with over 10,000 patients worldwide. It is fairly common in older adults, estimated to affect nearly 2 percent of those older than age 65. It is estimated that PD prevalence in US is over 1 ,000,000 patients. PD is a progressive, degenerative neurologic disease characterized by a tremorthat is maximal at rest, retropulsion ( / .e., a tendency to fall backwards), rigidity, stooped posture, slowness of voluntary movements, and a masklike facial expression. Pathologic features include loss of melanin containing neurons in the substantia nigra and other pigmented nuclei of the brainstem. The brain changes caused by PD begin in a region that plays a key role in movement, but etiology of cognitive impairment in PD has not yet been fully elucidated. As Parkinson’s brain changes gradually spread, they often begin to affect mental functions, including memory and the ability to pay attention, make sound judgments and plan the steps needed to complete a task. Lewy bodies are present in the substantia nigra and locus coeruleus but may also be found in a related condition characterized by dementia in combination with varying degrees of parkinsonism. Symptoms of Parkinson’s disease may include, but are not limited to, tremors and shakiness, muscle stiffness, a shuffling step, stooped posture, difficulty initiatingmovement, lack of facial expression, and dementia. Parkinson's Disease with Dementia (PDD) is a decline in thinking and reasoning skills that develops in some people living with Parkinson's disease. Parkinson patients may have movement problems before cognitive symptoms in dementia associated with Parkinson's disease. In dementia with Lewy bodies, cognitive symptoms occur before, or at the same time as, problems with movement. Secondary Parkinson’s disease refers to conditions which feature clinical manifestations resembling primary Parkinson’s disease that are caused by a known or suspected condition, such as parkinsonism caused by vascular injury, drugs, trauma, toxin exposure, neoplasms, infections and degenerative or hereditary conditions. Clinical features may include bradykinesia, rigidity, parkinsonian gait, and masked facies. In general, tremor is less prominent in secondary parkinsonism than in the primary form. As used herein, Parkinson’s disease expressly incorporates the pathological features, the clinical manifestations, the symptoms, as well as those symptoms or features related to secondary Parkinsonism ( / .e., symptoms similar to Parkinson disease caused by certain medicines (or toxins), a different nervous system disorder, or another illness). Specifically, Parkinson disease used herein expressly incorporates Parkinson’s Disease with Dementia (PDD). Currently, there are very few treatments for Parkinson’s disease.

[0044] Yet another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing Huntington’s Disease (HD). HD is a familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive chorea and dementia in the fourth or fifth decade of life. Initial manifestations include paranoia, poor impulse control, depression, hallucinations, and delusions. Late symptoms include intellectual impairment, loss of fine motor control, athetosis, and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. Its juvenile variant has a more fulminant course including seizures, ataxia, dementia, and chorea. Currently, there is no cure for Huntington’s disease.

[0045] Yet another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing Priondisease. Prion disease, also called “transmissible spongiform encephalopathies", is a group of genetic, infectious, or sporadic degenerative human and animal nervous system disorders associated with abnormal prions. These diseases are characterized by conversion of the normal prion protein to an abnormal configuration via a post- translational process. In humans, these conditions generally feature dementia, ataxia, and a fatal outcome. Pathologic features include a spongiform encephalopathy without evidence of inflammation. Some older literature may occasionally refer to these as unconventional slow virus diseases. Prion disease is distinguished by long incubation periods, characteristic spongiform changes associated with neuronal loss, and a failure to induce inflammatory response. The term “prions” refers to abnormal pathogenic agents that are transmissible and able to induce abnormal folding of specific normal cellular proteins called prion proteins that are found most abundantly in the brain. The abnormal folding of the prion proteins leads to brain damage and the characteristic signs and symptoms of the disease. Prion diseases are usually rapidly progressive and always fatal. Human Prion disease comprises at least Creutzfeldt- Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann- Straussler- Scheinker Syndrome, Fatal Familial Insomnia and Kuru. Animal Prion disease comprises at least Bovine Spongiform Encephalopathy (BSE), Chronic Wasting Disease (CWD), Scrapie, Transmissible mink encephalopathy, Feline spongiform encephalopathy, and Ungulate spongiform encephalopathy. Currently, there is no cure for Prion disease.

[0046] Yet another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing Pick’s disease (PiD). Pick’s disease is a type of frontotemporal dementia (FTD). It is a rare brain disease that causes a gradual decline in cognitive function and personality changes. It affects neurons and / or brain cells in specific areas and causes atrophy. It has some similarities to Alzheimer’s disease but usually happens earlier. Pick’s disease tends to affect specific parts of the brain but not others, causing behavior or language ability changes. People with Pick’s disease often can’t recognize they have a problem or medical condition, because their brains can’t process information related to the condition as it happens. Symptoms may include, but not limited to, loss of inhibitions, apathy, loss of empathy, compulsive behaviors, changes in diet or mouth-centered behaviors, and / or loss of executive functions. Currently, there is no cure for Pick’s disease.

[0047] Yet another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8 AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing progressive supranuclear palsy (PSP). PSP is a rare, degenerative brain disease that affects movement, balance, and thinking. It's a type of atypical parkinsonism and usually begins in a person’s mid- to late-60s. Symptoms may include, but are not limited to, difficulty in moving the eyes (especially up and down), and blurred or double vision, loss of balance, stiffness and awkwardness while walking, slurred speech, difficulty speaking, difficulty swallowing, mood changes like depression, apathy, irritability, and impulsivity. Some also experience personality changes like changes in behavior and poor judgment, and cognitive impairment, such as dementia, insomnia, and REM sleep behavior disorder. Symptoms worsen rapidly, and most people develop severe disability within three to five years. Currently, there is no cure for PSP.

[0048] Yet another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing Amyotrophic lateral sclerosis, or “ALS”. ALS is also called Lou Gehrig’s disease (after the baseball player who was diagnosed with it). ALS is a degenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord. It is a progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control. Disease onset is usually after the age of 50 and the process is usually fatal within 3 to 6 years. ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Its impact often starts in the hands, feet or limbs, and then spreads to other parts of your body. As the disease advances and nerve cells are destroyed, your muscles get weaker. This eventually affects chewing, swallowing, speaking and breathing. Symptoms include, but not limited to, difficulty walking or doing normal daily activities, tripping and falling, weakness in your legs, feet or ankles, hand weakness or clumsiness, slurred speech or trouble swallowing, muscle cramps and twitching in your arms, shoulders and tongue, inappropriate crying, laughing or yawning, and cognitive andbehavioral changes. Clinical manifestations include progressive weakness, atrophy, fasciculation, hyperreflexia, dysarthria, dysphagia, and eventual paralysis of respiratory function. Pathologic features include the replacement of motor neurons with fibrous astrocytes and atrophy of anterior spinal nerve roots and corticospinal tracts. Currently, there is no cure for ALS disease. There is no cure for ALS.

[0049] Another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing neuropsychiatric disorders, which are interchangeably referred to herein as “neuropsychological disorders”. Neuropsychiatric or neuropsychological disorders relates to dysfunctions in the physiological or psychiatric processes related to behavior, cognition and / or emotion, which may or may not be associated with brain damage. Neuropsychological or neuropsychiatric disorders may manifest as personality disorders, defined as experiences and behaviors that deviate from social norms and expectations. Personality disorders (PD) are a class of mental health conditions characterized by enduring maladaptive patterns of behavior, cognition, emotiveness, interpersonal functioning, impulse control, and / or inner experience. The behavior patterns of personality disorders are typically recognized by adolescence, the beginning of adulthood or sometimes even childhood and often have a pervasive negative impact on the quality of life. Personality disorders are associated with considerable stigma in popular and clinical discourse alike. Despite various methodological schemes designed to categorize personality disorders, many issues exist on their classifications because the theory and diagnosis of such disorders occur within prevailing cultural expectations; thus, their validity is contested by some experts on the basis of inevitable subjectivity. The diseases’ definitions vary by source and remain a matter of controversy. Official criteria for diagnosing personality disorders are listed in the sixth chapter of the International Classification of Diseases (ICD) and in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM). The ICD is a collection of alpha-numerical codes which have been assigned to all known clinical states, and provides uniform terminology for medical records, billing, statistics and research. The DSM defines psychiatric diagnoses based on research and expert consensus. Current treatment for personality disorders relies on evidence-based psychotherapies, including cognitive behavioral therapy anddialectical behavior therapy (mainly for borderline personality disorders). Both have deliberately aligned their diagnoses to some extent, but some differences remain. For example, the ICD-10 includes narcissistic personality disorder in the group of other specific personality disorders, while DSM-5 does not include enduring personality change after catastrophic experience. The ICD-10 classified the DSM-5 schizotypal personality disorder as a form of schizophrenia rather than as a personality disorder. Dissociative identity disorder, previously known as multiple personality disorder, has always been classified as a dissociative disorder and never was regarded as a personality disorder. DSM-5 lists ten specific personality disorders: paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dependent and obsessive-compulsive personality disorder. The DSM-5 also contains three diagnoses for personality patterns not matching these ten disorders, which nevertheless exhibit characteristics of a personality disorder.

[0050] Personality disorders may be grouped into three clusters based on descriptive similarities: Cluster A, B, and C. Cluster A (odd or eccentric disorders) includes personality disorders often associated with schizophrenia. People with these disorders can be paranoid and have difficulty being understood by others, as they often have odd or eccentric modes of speaking and an unwillingness and inability to form and maintain close relationships. Paranoid personality disorder refers to pattern of irrational suspicion and mistrust of others, interpreting motivations as malevolent. Schizoid personality disorder refers to cold affect and detachment from social relationships, apathy, and restricted emotional expression. Schizotypal personality disorder refers to pattern of extreme discomfort interacting socially, and distorted cognition and perceptions. Schizotypal personality disorder has the potential to develop schizophrenia and other psychotic disorders. These disorders also have a higher probability of occurring among individuals whose first-degree relatives have either schizophrenia or a Cluster A personality disorder. Cluster B personality disorders (emotional or erratic disorders) include those characterized by dramatic, impulsive, self-destructive, emotional behavior and sometimes incomprehensible interactions with others. Antisocial personality disorder refers to pervasive pattern of disregard for and violation of the rights of others, lack of empathy, lack of remorse, callousness, bloated self-image, and / or manipulative and impulsive behavior. Borderline personality disorder refers to pervasive pattern of abrupt emotional outbursts, fear of abandonment, unhealthy attachment, altered empathy, andinstability in relationships, self-image, identity, behavior and affect, often leading to self-harm and impulsivity. Histrionic personality disorder refers to pervasive pattern of attention-seeking behavior, including excessive emotions, an impressionistic style of speech, inappropriate seduction, exhibitionism, and egocentrism. Narcissistic personality disorder refers pervasive pattern of superior grandiosity, haughtiness, need for admiration, deceiving others, and lack of empathy (and, in more severe expressions, criminal behavior without remorse). Cluster C (anxious or fearful disorders) includes personality disorders characterized by a consistent pattern of anxious thinking or behavior. Avoidant personality disorder refers to pervasive feelings of social inhibition and inadequacy, and extreme sensitivity to negative evaluation. Dependent personality disorder refers to pervasive psychological need to be cared for by other people. Obsessive-compulsive personality disorder refers to rigid conformity to rules, perfectionism, and control to the point of exclusion of leisurely activities and friendships (distinct from obsessive-compulsive disorder). Personality disorders may overlap with and / or encompass mood disorders, which include major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania and anxiety.

[0051] One aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds) in treating and / or preventing neuropsychiatric disorders, such as bipolar disorder, antisocial personality disorder, borderline personality disorder, compulsive personality disorder, dependent personality disorder, histrionic personality disorder, hysteria, narcissistic personality disorder, paranoid personality disorder, passive-aggressive personality disorder, schizoid personality disorder, and schizotypal personality disorder.

[0052] Another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing schizophrenia. Schizophrenia is a serious mental health condition that affects how people think, feel, and behave. As used herein, the term schizophrenia expressly encompasses all subtypes, such as paranoid type, disorganized type, catatonic type and undifferentiated type. Persons with schizophrenia may experience one or moresymptoms of hallucination, psychosis, cognitive difficulties, delusions, and disorganized thinking and behavior. Hallucinations involve seeing things or hearing voices that aren't observed by others. Schizophrenia may be associated or related to schizo-affective disorder, psychosis, delusional disorders, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar with psychosis or any other disease with psychotic features. There are very limited therapies for schizophrenia.

[0053] Another aspect of the present disclosure relates to the use of the compounds disclosed herein (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (and pharmaceutical compositions and / or dosage forms including one or more such compounds)) in treating and / or preventing bipolar disorder. Bipolar disorder, also known as manic-depressive disorder, is a mental illness that causes extreme mood swings, which can affect a person’s energy, sleep, thinking, and behavior. Bipolar disorder includes subtypes of bipolar I, bipolar II, cyclothymic disorder, and rapid cycling bipolar. Bipolar patients may swing between manic episodes and / or depressive episodes, such as feeling elated, irritable, and / or energized, then switching to feeling sad, indifferent, or hopeless. Other symptoms include but not limited to difficulty concentrating, changes in appetite, suicidal thoughts, fatigue, and / or lack of motivation. There are very few treatments for bipolar disorder.PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

[0054] One aspect of the present disclosure encompasses a pharmaceutical composition and / or dosage form containing a pharmaceutical active comprising ASTI , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710, any pharmaceutically acceptable salt thereof, or any combination thereof (hereinafter “the active”). The present disclosure encompasses both immediate release (IR) and modified-release (MR) release forms. Modified release forms, may also be called “controlled release” forms, include pharmaceutical active ingredients and one or more excipients to modify the release of the active. Such modified release includes, but not limited to, delayed release, sustained release, extended release, and / or continuous release. Another aspect of the present disclosure encompasses various oral dosage forms, including but not limited to capsules, tablets, capsulets, and oral liquids. Tablets may include disintegrated tablets, buccal tablets, and sublingual tablets.Pharmaceutically acceptable salts of A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 include, without limitation, acetate, aspartate, benzoate, bitartrate, citrate, formate, gluconate, glucuronate, glutamate, fumarate, hydrochloride, hydrobromide, hydroiodide, hypophosphite, isobutyrate, isocitrate, lactate, malate, maleate, meconate, methylbromide, methanesulfonate, monohydrate, mucate, nitrate, oxalate, phenylpropionate, phosphate, phthalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tannate, tartrate, terephthalate, valerate, and the like. In one embodiment, the pharmaceutically acceptable salt comprises a hydrochloride salt, an acetate salt, a citrate salt, a formate salt, a hydrogen phosphate salt, or dihydrogen phosphate salt, a salicylate salt, or a stearate salt.

[0055] The amount of the active in the pharmaceutical composition or dosage form may be a therapeutically effective amount. As used herein “therapeutically effective amount” or “therapeutically effective dosage” refers to an amount that is sufficient and / or effective to produce or achieve a desired therapeutic result. Actual dosage levels of active agents in a pharmaceutical composition may be varied so as to administer an amount of the active agent(s) that is effective to achieve the desired therapeutic response for a particular subject. In some embodiments, the desired therapeutic result is reducing the symptoms and / or improving cognition. For example, the therapeutically effective amount may be an amount that increases cognition by at least 10%, preferably 20% or more, preferably 25% or more, preferably 30% or more, preferably 35% or more, preferably 40% or more, preferably 45% or more, preferably 50% or more, preferably 60% or more, preferably 70% or more, preferably 80% or more, preferably 90% or more. The therapeutically effective amount may be an amount that reduces one or more symptoms (including but not limited to hallucination, delusion, psychosis, cognitive difficulty, or disorganized thinking) by at least 10%, preferably 20% or more, preferably 25% or more, preferably 30% or more, preferably 35% or more, preferably 40% or more, preferably 45% or more, preferably 50% or more, preferably 60% or more, preferably 70% or more, preferably 80% or more, preferably 90% or more.

[0056] In some cases, the amount of the active in the composition may be more than about 1 pg. For example, the amount may be about 2 pg or more, about 5 pg or more, about 10 pg or more, about 100 pg or more, about 500 pg or more, about 1000 pg or more, about 1500 pg or more, about 2000 pg or more, about 2500 pg or more,about 3000 g or more, about 3500 pg or more, about 4000 pg or more, about 4500 pg or more, about 5000 pg or more, about 5500 pg or more, about 6000 pg or more, about 6500 pg or more, about 7000 pg or more, about 7500 pg or more, about 8000 pg or more, about 8500 pg or more, about 9000 pg or more, about 9500 pg or more, about 10 mg or more, about 20 mg or more, about 30 mg or more, about 40 mg or more, about 50 mg or more, about 60 mg or more, about 70 mg or more, about 80 mg or more, about 90 mg or more, about 100 mg or more, about 150 mg or more, about 170 mg or more, about 180 mg or more, about 190 mg or more, about 200 mg or more, about 220 mg or more, about 240 mg or more, about 250 mg or more, about 300 mg or more, about 350 mg or more, about 400 mg or more, about 450 mg or more, about 500 mg or more, about 550 mg or more, about 600 mg or more, about 650 mg or more, about 700 mg or more, about 800 mg or more, about 900 mg or more, or about 1 g or more.

[0057] Additional ly or alternatively, the amount of the active in the composition or the dosage form may be, relative to the total weight of the composition or the dosage form, about 0.01 wt.% to about 95 wt.%, about 0.1 wt.% to about 95 wt.%, about 1 wt.% to about 95 wt.%, about 5 wt.% to about 95 wt.%, about 10 wt.% to about 95 wt.%, about 15 wt.% to about 95 wt.%, about 20 wt.% to about 95 wt.%, about 30 wt.% to about 95 wt.%, about 40 wt.% to about 95 wt.%, about 50 wt.% to about 95 wt.%, about 60 wt.% to about 95 wt.%, about 70 wt.% to about 95 wt.%, about 80 wt.% to about 95 wt.%; about 0.01 wt.% to about 85 wt.%, about 0.1 wt.% to about 85 wt.%, about 1 wt.% to about 85 wt.%, about 5 wt.% to about 85 wt.%, about 10 wt.% to about 85 wt.%, about 15 wt.% to about 85 wt.%, about 20 wt.% to about 85 wt.%, about 30 wt.% to about 85 wt.%, about 40 wt.% to about 85 wt.%, about 50 wt.% to about 85 wt.%, about 60 wt.% to about 85 wt.%, about 70 wt.% to about 85 wt.%; about 0.01 wt.% to about 75 wt.% about 0.1 wt.% to about 75 wt.%, about 1 wt.% to about 75 wt.%, about 5 wt.% to about 75 wt.%, about 10 wt.% to about 75 wt.%, about 15 wt.% to about 75 wt.%, about 20 wt.% to about 75 wt.%, about 30 wt.% to about 75 wt.%, about 40 wt.% to about 75 wt.%, about 50 wt.% to about 75 wt.%, about 60 wt.% to about 75 wt.%; about 0.01 wt.% to about 65 wt.%, about 0.1 wt.% to about 65 wt.%, about 1 wt.% to about 65 wt.%, about 5 wt.% to about 65 wt.%, about 10 wt.% to about 65 wt.%, about 15 wt.% to about 65 wt.%, about 20 wt.% to about 65 wt.%, about 30 wt.% to about 65 wt.%, about 40 wt.% to about 65 wt.%, about 50 wt.% to about 65 wt.%; about 0.01 wt.% to about 55 wt.%, about 0.1 wt.% to about 55 wt.%, about 1wt.% to about 55 wt.%, about 5 wt.% to about 55 wt.%, about 10 wt.% to about 55 wt.%, about 15 wt.% to about 55 wt.%, about 20 wt.% to about 55 wt.%, about 30 wt.% to about 55 wt.%, about 40 wt.% to about 55 wt.%; about 0.01 wt.% to about 45 wt.%, about 0.1 wt.% to about 45 wt.%, about 1 wt.% to about 45 wt.%, about 5 wt.% to about 45 wt.%, about 10 wt.% to about 45 wt.%, about 15 wt.% to about 45 wt.%, about 20 wt.% to about 45 wt.%, about 30 wt.% to about 45 wt.%; about 0.01 wt.% to about 35 wt.%, about 0.1 wt.% to about 35 wt.%, about 1 wt.% to about 35 wt.%, about 5 wt.% to about 35 wt.%, about 10 wt.% to about 35 wt.%, about 15 wt.% to about 35 wt.%, about 20 wt.% to about 35 wt.%; about 0.01 wt.% to about 25 wt.%, about 0.1 wt.% to about 25 wt.%, about 1 wt.% to about 25 wt.%, about 5 wt.% to about 25 wt.%, about 10 wt.% to about 25 wt.%; about 0.1 wt.% to about 15 wt.%, about 1 wt.% to about 15 wt.%, about 5 wt.% to about 15 wt.%, about 10 wt.% to about 15 wt.%; about 0.01 wt.% to about 25 wt.%, about 0.1 wt.% to about 10 wt.%, about 1 wt.% to about 10 wt.%, or about 5 wt.% to about 10 wt.%, including ranges and subranges thereof, based on the total weight of the composition or the dosage form.

[0058] Alternatively or additionally, the composition may contain a combination of the active (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710) with another neurological active. Such combination thereof may be in an amount of about 0.01 wt.% to about 95 wt.% of the total weight of the composition, or about 0.1 wt.% to about 95 wt.%, about 1 wt.% to about 95 wt.%, about 5 wt.% to about 95 wt.%, about 10 wt.% to about 95 wt.%, about 15 wt.% to about 95 wt.%, about 20 wt.% to about 95 wt.%, about 30 wt.% to about 95 wt.%, about 40 wt.% to about 95 wt.%, about 50 wt.% to about 95 wt.%, about 60 wt.% to about 95 wt.%, about 70 wt.% to about 95 wt.%, about 80 wt.% to about 95 wt.%; about 0.01 wt.% to about 85 wt.%, about 0.1 wt.% to about 85 wt.%, about 1 wt.% to about 85 wt.%, about 5 wt.% to about 85 wt.%, about 10 wt.% to about 85 wt.%, about 15 wt.% to about 85 wt.%, about 20 wt.% to about 85 wt.%, about 30 wt.% to about 85 wt.%, about 40 wt.% to about 85 wt.%, about 50 wt.% to about 85 wt.%, about 60 wt.% to about 85 wt.%, about 70 wt.% to about 85 wt.%; about 0.01 wt.% to about 75 wt.%, about 0.1 wt.% to about 75 wt.%, about 1 wt.% to about 75 wt.%, about 5 wt.% to about 75 wt.%, about 10 wt.% to about 75 wt.%, about 15 wt.% to about 75 wt.%, about 20 wt.% to about 75 wt.%, about 30 wt.% to about 75 wt.%, about 40 wt.% to about 75 wt.%, about 50 wt.% to about 75 wt.%, about 60 wt.% to about 75 wt.%; about 0.01 wt.% to about 65 wt.% about 0.1 wt.% to about 65 wt.%, about 1 wt.% to about 65 wt.%, about 5 wt.% toabout 65 wt.%, about 10 wt.% to about 65 wt.%, about 15 wt.% to about 65 wt.%, about 20 wt.% to about 65 wt.%, about 30 wt.% to about 65 wt.%, about 40 wt.% to about 65 wt.%, about 50 wt.% to about 65 wt.%; about 0.01 wt.% to about 55 wt.%, about 0.1 wt.% to about 55 wt.%, about 1 wt.% to about 55 wt.%, about 5 wt.% to about 55 wt.%, about 10 wt.% to about 55 wt.%, about 15 wt.% to about 55 wt.%, about 20 wt.% to about 55 wt.%, about 30 wt.% to about 55 wt.%, about 40 wt.% to about 55 wt.%; about 0.01 wt.% to about 45 wt.%, about 0.1 wt.% to about 45 wt.%, about 1 wt.% to about 45 wt.%, about 5 wt.% to about 45 wt.%, about 10 wt.% to about 45 wt.%, about 15 wt.% to about 45 wt.%, about 20 wt.% to about 45 wt.%, about 30 wt.% to about 45 wt.%; about 0.01 wt.% to about 35 wt.%, about 0.1 wt.% to about 35 wt.%, about 1 wt.% to about 35 wt.%, about 5 wt.% to about 35 wt.%, about 10 wt.% to about 35 wt.%, about 15 wt.% to about 35 wt.%, about 20 wt.% to about 35 wt.%; about 0.01 wt.% to about 25 wt.%, about 0.1 wt.% to about 25 wt.%, about 1 wt.% to about 25 wt.%, about 5 wt.% to about 25 wt.%, about 10 wt.% to about 25 wt.%; about 0.01 wt.% to about 15 wt.% about 0.1 wt.% to about 15 wt.%, about 1 wt.% to about 15 wt.%, about 5 wt.% to about 15 wt.%, about 10 wt.% to about 15 wt.%; about 0.01 wt.% to about 10 wt.% about 0.1 wt.% to about 10 wt.%, about 1 wt.% to about 10 wt.%, or about 5 wt.% to about 10 wt.%, including ranges and subranges thereof, based on the total weight of the composition or the dosage form.

[0059] Additionally or alternatively, the composition may contain a combination selecting two or more from the group consisting of A3-71, M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710, and their pharmaceutically acceptable salts, polymorphs and / or enantiomers. When the combination contains two actives, the weight ratio of the two actives in the composition may range from 1:100 to 100:1, 1:50 to 50:1, 1:20 to 20:1 1 :10 to 10:1, 1:9 to 10:1, 1:8 to 10:1, 1:7 to 10:1, 1:6 to 10:1, 1:5 to 10:1, 1:4 to 10:1, 1:3 to 10:1, 1:2 to 10:1, 1:1 to 10:1, 1:10 to 9:1, 1:10 to 8:1, 1:10 to 7:1, 1:10 to 6:1 , 1:10 to 5:1, 1:10 to 4:1, 1:10 to 3:1, 1:10 to 2:1, or 1:10 to 1:1, including ranges and subranges thereof. In one instance, the weight ratio of the two actives is 1:10 to 10:1, 1:9 to 10:1, 1:8 to 10:1, 1:7 to 10:1, 1:6 to 10:1, 1:5 to 10:1, 1:4 to 10:1, 1:3 to 10:1, 1:2 to 10:1, 1:1 to 10:1, 1:10 to 9:1, 1:10 to 8:1, 1:10 to 7:1, 1:10 to 6:1, 1:1 Oto 5:1, 1:10 to 4:1, 1:10 to 3:1, 1 :10 to 2:1 , or 1 :10 to 1:1, including ranges and subranges thereof.

[0060] In one aspect, the pharmaceutical composition can be formulated and administered to a subject by several different routes and means. For instance, acomposition can generally be administered orally, parenterally, intraperitoneally, intravascularly, topically, transdermally, subcutaneously, or intrapulmonarily in unit dosage forms containing conventional nontoxic pharmaceutically acceptable adjuvants, carriers, excipients, and vehicles as desired. The term orally as used herein includes any composition or dosage form suitable to be ingested through mouth, including but not limited to pills, tablets, capsule, capsulets, and chewables. Tablets may include minitablets, disintegrated tablets, buccal tablets, and sublingual tablets. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrathecal, or infusion deliveries. In one aspect, the therapeutically effective amount of the active e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710) may range from about 0.5 mg to about 500 mg, about 1 mg to about 480 mg, about 5 mg to about 450 mg, about 10 mg to about 420 mg, about 15 mg to about 400 mg, about 20 mg to about 350 mg, about 25 mg to about 320 mg, about 25 mg to about 300 mg, about 30 mg to about 300 mg, about 35 mg to about 300 mg, about 40 mg to about 250 mg, about 45 mg to about 250 mg, about 30 mg to about 250 mg, about 20 mg to about 200 mg, about 25 mg to about 200 mg, about 30 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 150 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 10 mg to about 100 mg, about 10 mg to about 120 mg. The therapeutically effective amount may, in some embodiments, range from about 0.5 mg / day to about 1000 mg / day, from about 10 mg / day to about 800 mg / day, from about 20 mg / day to about 700 mg / day, about 25 mg / day to about 650 mg / day, from about 30 mg / day to about 600 mg / day, from about 35 mg / day to about 600 mg / day, from about 40 mg / day to about 550 mg / day, or from about 45 mg to about 500 mg / day, from about 45 mg / day to about 450 mg / day, from about 40 mg / day to about 400 mg / day, from about 50 mg to about 400 mg / day, from about 40 mg / day to about 300 mg / day, or from about 45 mg to about 300 mg / day, from about 50 mg / day to about 300 mg / day, from about 40 mg / day to about 300 mg / day, orfrom about 30 mg to about 300 mg / day. Administering the composition may result a blood level of the active (e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710) at or about 1 ng / ml, at orabout 2 ng / ml, at or about 4 ng / ml, at or about 5 ng / ml, at or about 6 ng / ml, at or about 8 ng / ml, at or about 10 ng / ml, at or about 12 ng / ml, at or about 15 ng / ml, at or about 20 ng / ml, at or about 22 ng / ml, at or about 24 ng / ml, at or about 26 ng / ml, at or about 28 ng / ml, at or about 30 ng / ml, at or about 32 ng / ml, at or about 34 ng / ml, at or about 36ng / ml, at or about 38 ng / ml, at or about 40 ng / ml, at or about 42 ng / ml, at or about 44 ng / ml, 46 ng / ml, at or about 48 ng / ml, at or about 50 ng / ml.

[0061] In another aspect, the pharmaceutical composition can be administered to the subject daily or more than once daily. For example, the composition can be administered to the subject once daily (QD), twice daily (BID), or three times daily (QID). The duration of each administration can vary from few seconds to about several hours, such as via infusion administration. Further, the composition can be administered every 2, 3, 4, 5, 6, 7, 14, 21 , 28, or every 30 days. Such treatment regimen is subject to alter and adjust based on subject’s individual needs and response sensitivity. The composition can be administered over a period ranging from about 1 day to about 10 years, or indefinite. The composition can also be administered over a period of about 1 day, about 7 days, about 30 days, about 60 days, about 120 days, or about 180 days or more. In some aspects, the composition is administered over a period of about 57 weeks, about 148 weeks, about 208 weeks, indefinitely, or until resolution of the condition being treated.

[0062] ln addition to the active e.g., A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710), pharmaceutical compositions disclosed herein typically comprises one or more pharmaceutically acceptable excipients. Non-limiting examples of excipients include chemical enhancers, humectants, pressure sensitive adhesives, antioxidants, solubilizers, thickening agents, plasticizers, adjuvants, carriers, excipients, vehicles, coatings, and any combinations thereof. One or more excipients can be selected for oral, transdermal, parenteral, intraperitoneal, intravascular, subcutaneous, by inhalation spray, rectal, or intrapulmonary administration.

[0063] In another aspect, the composition is formulated for improving patient compliance, and / or preventing a subject from removing the drug-delivery device. For instance, the composition could be formulated for improved patient compliance and preventing removal of a drug-delivery device by providing formulations for extended delivery. Extended delivery can range for periods ranging from more than one day, to months. This may be especially relevant for patients with compromised cognitive and / or motor-control abilities. Extended delivery for periods can range from about 1 day to about 1 year, from about 1 day to about 1 week, from about 3 days to about 1 month, from about 2 weeks to about 6 months, or from about 2 months to about 4 months.

[0064] A modified-release (MR) composition may be used for delivery of the active at a preselected rate. For example, for crystalline ANAVEXO3-71 , the active can be delivered at a rate from about 1 mg / day to about 400 mg / day, from about 10 mg / day to about 300 mg / day, from about 20 mg / day to about 250 mg / day, from about 25 mg / day to about 225 mg / day, from about 30 mg / day to about 200 mg / day, from about 35 / day mg to about 200 mg / day, from about 37.5 mg / day to about 200 mg / day, or from about 40 mg / day to about 200 mg / day. A therapeutically effective amount of crystalline ANAVEXO3-71 can be readily determined by the ordinarily skilled artisan based upon, for example, the intended duration of administration of the drug by the extended-release composition, the delivery mechanism, the particular formulation, and the relative potency of the active among other factors.Binders

[0065] Non-limiting examples of binders suitable for the formulations of various aspects include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. The polypeptide may be any arrangement of amino acids ranging from about 100 to about 300,000 Daltons.

[0066] The binder can be introduced into the mixture to be granulated in a solid form, including but not limited to a crystal, a particle, a powder, or any other finely divided solid form known in the art. Alternatively, the binder can be dissolved or suspended in a solvent and sprayed onto the mixture in a granulation device as a binder fluid during granulation.Diluents or Fillers

[0067] Non-limiting examples of diluents (also referred to as “fillers” or “thinners”) include carbohydrates, inorganic compounds, and biocompatible polymers, such as polyvinylpyrrolidone (PVP). Other non-limiting examples of diluents include dibasic calcium sulfate, tribasic calcium sulfate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, lactose monohydrate, dibasic calcium phosphate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, saccharides such as sucrose, dextrose, lactose, lactose monohydrate microcrystalline cellulose, fructose, xylitol, and sorbitol, polyhydric alcohols; starches; pre-manufactured direct compression diluents; andmixtures of any of the foregoing. In one aspect, the filler accounts for about 0.01 % to about 10% by weight of the total formulation. In yet another aspect, the filler comprises microcrystalline cellulose and / or lactose monohydrate.Disintegrants

[0068] Disintegrants can be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, lactose monohydrate, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. Suitable effervescent disintegrants include but are not limited to sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.Preservatives

[0069] Non-limiting examples of preservatives include, but are not limited to, ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N- acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, o-aminobenzoic acid, p- aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxantin, alpha-carotene, beta-carotene, beta-caraotene, beta-apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p- coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate, distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetic acid, ellagic acid, erythorbic acid, sodium erythorbate, esculetin, esculin, 6-ethoxy-1 ,2-dihydro-2,2,4-trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechin, epicatechin, epicatechin gallate, epigallocatechin (EGC), epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate), flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g., datiscetin, myricetin, daemfero), flavanones, fraxetin, fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, gum guaiacum, hesperetin, alpha-hydroxybenzyl phosphinic acid, hydroxycinammic acid, hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid, hydroxytryrosol, hydroxyurea, rice bran extract, lactic acid and its salts, lecithin, lecithin citrate; R-alpha-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxy tryptamine, methyl gallate, monoglyceride citrate; monoisopropyl citrate; morin, beta-naphthoflavone, nordihydroguaiaretic acid (NDGA), octyl gallate, oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphates, phytic acid, phytylubichromel, pimento extract, propyl gallate, polyphosphates, quercetin, transresveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol, tocopherols ( / .e., alpha-, beta-, gamma- and delta-tocopherol), tocotrienols ( / .e., alpha- , beta-, gamma- and delta-tocotrienols), tyrosol, vanilic acid, 2,6-di-tert-butyl-4- hydroxymethylphenol ( / .e., lonox 100), 2,4-(tris-3',5'-bi-tert-butyl-4'-hydroxybenzyl)- mesitylene ( / .e., lonox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiary butyl hydroquinone (TBHQ), thiodipropionic acid, trihydroxy butyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof.Flavor-modifying agents

[0070] Suitable flavor-modifying agents include flavorants, taste-masking agents, sweeteners, and the like. Flavorants include, but are not limited to, synthetic flavor oils and flavoring aromatics and / or natural oils, extracts from plants, leaves, flowers, fruits, and combinations thereof. Other non-limiting examples of flavors include cinnamon oils, oil of Wintergreen, peppermint oils, clover oil, hay oil, anise oil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil, grape and grapefruit oil, fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[0071] Taste-masking agents include but are not limited to cellulose hydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFlo HP22; low- substituted hydroxypropyl ethers (L-HPC); cellulose hydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®, Metolose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers such as Methocel® and Metolose®; Ethylcelluloses (EC) and mixtures thereof such as E461 , Ethocel®, Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB; hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; sepifilms such as mixturesof HPMC and stearic acid, cyclodextrins, and mixtures of these materials. In other aspects, additional taste-masking agents contemplated are those described in U.S. Pat. Nos. 4,851 ,226; 5,075,114; and 5,876,759, each of which is hereby incorporated by reference in its entirety.

[0072] Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, sylitol, hydrogenated starch hydrolysates and the synthetic sweetener 3,6- dihydro-6-methyl-1 ,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof.Lubricants and qlidants

[0073] A lubricant or a glidant may be utilized to lubricate ingredients that form a pharmaceutical composition. Non-limiting examples of lubricants and glidants include silica colloidal anhydrous, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The pharmaceutical composition will, in some embodiments, generally comprise from about 0.01 % to about 10% by weight of a lubricant and / or glidant. In some aspects, the pharmaceutical composition will comprise from about 0.01 % to about 5% by weight of a lubricant and / or glidant. In a further aspect, the pharmaceutical composition will comprise from about 0.02% to about 2% by weight of a lubricant or glidant. In another aspect, the glidant is silica colloidal anhydrous and lubricant is magnesium stearate.Dispersants

[0074] Dispersants may include but are not limited to starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high hydrophilic-lipophilic balance (HLB) emulsifier surfactants.Colorants

[0075] Depending upon the aspect of the disclosure, it may be desirable to include a coloring agent. Suitable color additives include but are not limited to food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drugand cosmetic colors (Ext. D&C). These colors or dyes, along with their corresponding lakes, and certain natural and derived colorants, may be suitable for use in various aspects of the disclosure. pH modifiers

[0076] Non-limiting examples of pH modifiers include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate and sodium bicarbonate.Chelating agents

[0077] A chelating agent may be included as an excipient to immobilize oxidative groups, including but not limited to ions, in order to inhibit the oxidative degradation of the morphinan by these oxidative groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamate, aspartate, and disodium ethylenediaminetetraacetate (Na2EDTA).Antimicrobial agents

[0078] An antimicrobial agent may be included as an excipient to minimize the degradation of the compound according to this disclosure by microbial agents, including but not limited to bacteria and fungi. Non-limiting examples of antimicrobials include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites including but not limited to sulfur dioxide, sodium bisulfite, and potassium hydrogen sulfite.Release-controlling polymers

[0079] Release-controlling polymers may be included in the various aspects of the dosage forms or pharmaceutical compositions incorporating compounds according to this disclosure. In one aspect, the release-controlling polymers may be used as a tablet coating. In other aspects, including but not limited to bilayer tablets, a release-controlling polymer may be mixed with the granules and other excipients prior to the formation of a tablet by a known process including but not limited to compression in a tablet mold. Suitable release-controlling polymers include but are not limited to hydrophilic polymers and hydrophobic polymers. Such release controlling polymer may be used to achieve controlled release of the active, including modified release, delayed release, sustained release, extended release, continuous release, prolonged-release or bolus release of the active.

[0080] Suitable hydrophilic release-controlling polymers include, but are not limited to, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, crosslinked starch, agar, casein, chitin, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonia alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, alginate sodium carmellose, calcium carmellose, carrageenan, fucoidan, furcellaran, arabic gum, carrageens gum, ghafti gum, guar gum, karaya gum, locust bean gum, okra gum, tragacanth gum, scleroglucan gum, xanthan gum, hypnea, laminaran, acrylic polymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleic anhydride and styrene, copolymers of maleic anhydride and ethylene, copolymers of maleic anhydride propylene or copolymers of maleic anhydride isobutylene), crosslinked polyvinyl alcohol and poly N-vinyl-2- pyrrolidone, diesters of polyglucan, polyacrylamides, polyacrylic acid, polyamides, polyethylene glycols, polyethylene oxides, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof. In some aspects, the release controlling polymer comprises one or more of hydroxypropyl methylcellulose(s), such as Benecel™ K100M, METHOCEL™ K100LV, Hypromellose K100 LV, or Hypromellose K15M.Coatings

[0081] A pharmaceutical composition ora dosage form may comprise a coating, The coating may act as a moisture barrier, for modifying pH values, or such coating may help to release the active in a controlled manner. A “control releasing coating” or “controlled release coating” as used herein is defined to mean a functional coating which, for example, comprises at least one pH independent polymer, pH dependent polymer (for example enteric or reverse enteric type polymers), soluble polymer, insoluble polymer, lipids, lipidic materials, or combinations thereof. The coating, when applied onto a dosage form, may slow (for example when applied to a normal release matrix dosage form), further slow (for example when applied to a controlled release matrix dosage form) or modify the rate of release of an active when comparing to an uncoated dosage form. Such coating may comprise a polymer, such as cellulose based polymer. Examples of such cellulose based polymer include methylcellulose and hydroxypropyl methylcellulose (HPMC), such as hypromellose in the form of Hypromellose K100 LV or Hypromellose K15M. For example, the control releasing coating can be designed such that when the control releasing coating is applied to adosage form, the composition or the dosage form in conjunction with the control releasing coating can exhibit the release of the active in a controlled manner, such as a manner of “modified-release”, “sustained-release”, “extended-release”, “delayed- release”, “prolonged-release,” “continuous-release”, “bolus-release,” or any combinations thereof. The “control releasing coating” may optionally comprise additional materials that alter the functionality of the control releasing coating.

[0082] The term “moisture barrier” as used herein is one which impedes or retards the absorption of moisture. Compounds according to this disclosure may be hygroscopic and, as such, may be susceptible to decomposition overtime under highly humid conditions. The proportion of the components of the moisture barrier and the amount of the moisture barrier optionally applied onto the control-releasing coating or onto the core are typically such that the moisture barrier does not fall within the USP definition and requirement for an enteric coat. Suitably, the moisture barrier may comprise an enteric and / or acrylic polymer, suitably an acrylic polymer, optionally a plasticizer, and a permeation enhancer. The permeation enhancer is a hydrophilic substance, which allows water to enter without physical disruption of the coating. The moisture barrier may additionally comprise other conventional inert excipients, which may improve processing of an extended-release formulation.

[0083] Coating and matrix materials which may be used in accordance with the present disclosure are those known in the art for use in controlled-release formulations, such as synthetic polymers of the polyvinyl type, e.g., polyvinylchloride, polyvinylacetate and copolymers thereof, polyvinylalcohol, and polyvinylpyrrolidone; synthetic polymers of the polyethylene type, e.g. , polyethylene and polystyrene; acrylic acid polymers; biopolymers or modified biopolymers, such as cellulosic polymers, shellac and gelatin; fats, oils, higher fatty acids and higher alcohols ( / .e., acids and alcohols containing alkyl chains of at least 10 carbon atoms), for example aluminum monostearate, cetylalcohol, hydrogenated beef tallow, hydrogenated castor oil, 12- hydroxystearl alcohol, glyceryl mono- or dipalmitate; glyceryl mono-, di- or tristearate; myristyl alcohol, stearic acid, stearyl alcohol, and polyethyleneglycols; waxes; sugars and sugar alcohols.

[0084] The pH-buffering properties of a coating may be strengthened by introducing into the coating substances chosen from a group of compounds usually used in antacid formulations, for example magnesium oxide, hydroxide or carbonate, aluminum or calcium hydroxide, carbonate or silicate; compositealuminum / magnesium compounds, for example Al2O3-6MgO CO2- 12H2O, (Mg6Al2(OH)16CO3'4H2O), MgO Al2O3'2SiO2.nH2O, aluminum bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH-buffering compounds, for example the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable, weak, inorganic or organic acids; or suitable organic bases, including basic amino acids; and salts or combinations thereof.

[0085] A pH-dependent coating serves to release the drug in desired areas of the gastrointestinal (Gl) tract, e.g., the stomach or small intestine. When a pH- independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the Gl tract. When the coating is formulated to release a compound according to this disclosure in the intestines (especially the upper small intestines), the coating is often called an “enteric coating”. A pH-dependent coating may include, but is not limited to, acrylic acid polymers and copolymers, for example polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate (e.g., Eudragit™); cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; shellac (purified lac); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate (PVAP), vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; zein; and salts and combinations thereof. Oral tablets and capsules typically have coatings.KITS FOR MEDICAL USES

[0086] One aspect of the present disclosure encompasses a kit for a medical use according to any of the monitoring, evaluating, therapy selection, and / or treatment methods disclosed herein. A kit for such uses includes one or more containers for receiving and holding biological samples that may be taken at different points in time, and reagents for carrying out gene expression analysis. For example, the kit may have a first container for receiving a first or control biological sample as used in thedisclosed methods; a second container for receiving a second or test biological sample as used in the disclosed methods; and additional one or more containers for receiving and / or storing reagent(s) useful for sequencing or measuring a gene expression. Additional containers may be included to receive and store composition(s) in a safe, stable and durable way. The composition may comprise a Sigma-1 receptor agonist, such as a composition comprising A3-71 , M8-S enantiomer, M8-R enantiomer, racemic M8, AF710A, and / or AF710 (including salts, enantiomers, polymorphs, and combinations thereof). The kit may include an instruction in hard copy printed from or in a computer readable form, which explains the use of the kit components to perform any of the methods described herein. The instruction may be written with the medical practitioner and / or the patient as the intended reader.

[0087] In one aspect of the present disclosure, the kit may be used for various purposes, such as selection of a therapeutic agent for a subject, monitoring effectiveness of a Sigma-1 receptor agonist therapy, identification of a subject responsive to a Sigma-1 receptor agonist therapy, ordetermining if a subject is having, is suspected of having, or having an increased risk for developing a disorder or a disease. Such disorder or disease may include Alzheimer’s disease (AD) including early-onset AD, Parkinson’s Disease (PD), frontotemporal dementia (FTD), Huntington’s Disease, multiple sclerosis, Pick's disease (PiD), progressive supranuclear palsy (PSP), spinocerebellar corticobasal degeneration (CBD), Lewy body dementia, tangle-predominant senile dementia, argyrophilic grain disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases, Guam parkinsonismdementia complex, FTDP-17, Lytico-Bodig disease, ataxia (SCA), spinal muscular atrophy (SMA), autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, Fragile X Syndrome (FXS), infantile spasm, Smith-Magenis syndrome, post-traumatic stress disorder (PTSD), autism, age-related cognitive decline, and Cushing's Disease, a cognitive impairment associated with auto-immune diseases, confusion, cognitive deficit associated with fatigue, learning disorders, traumatic brain or neuronal injury resulting from a stroke and spinal cord injury, Down's syndrome, William's Beuren syndrome, Prader-Willi syndrome, velo-cardio-facial syndrome, ATR-X syndrome, Barth syndrome, ICF syndrome, Neurofibromatosis, Asperger's syndrome, Smith-Lemli-Opitz syndrome, epilepsy, infantile spasms, fetal alcohol syndrome, hydrocephalus, manic depressiveillness, mental retardation, schizophrenia, spina bifida, Tourette's syndrome, Attention-deficit / hyperactivity disorder (ADHD), multiple sclerosis, an addictive disorder, an anxiety disorder, an autistic disorder, an eating disorder, or any combination thereof.DEFINITIONS

[0088] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art to which present disclosure belongs. The following references provide one of skill with a general definition of many of the terms used in the present disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991 ); and Hale & Marham, The Harper Collins Dictionary of Biology (1991 ). As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

[0089] When introducing elements of the present disclosure or the preferred aspects(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0090] As various changes could be made in the above-described cells and methods without departing from the scope of the present disclosure, it is intended that all matter contained in the above description and in the examples given below, shall be interpreted as illustrative and not in a limiting sense.

[0091] The term “comprising” means “including, but not necessarily limited to”; it specifically indicates open-ended inclusion or membership in a so-described combination, group, series and the like. The terms “comprising” and “including” as used herein are inclusive and / or open-ended and do not exclude additional, unrecited elements or method processes. The term “consisting essentially of” is more limiting than “comprising” but not as restrictive as “consisting of.” Specifically, the term “consisting essentially of” limits membership to the specified materials or items and those that do not materially affect the essential characteristics of the present disclosure.

[0092] As used herein, the term “gene” means a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including promoters, exons, introns, and other untranslated regions that control expression. As used herein, “expression” includes but is not limited to one or more of the following: transcription of the gene into precursor mRNA; splicing and other processing of the precursor mRNA to produce mature mRNA; mRNA stability; translation of the mature mRNA into protein (including codon usage and tRNA availability); and glycosylation and / or other modifications of the translation product, if required for proper expression and function. As used herein, the term “differentially expressed gene” means a gene whose expression levels in two experimental conditions or in two samples possess statistically significant difference or change. As used herein, the terms “overrepresented” genes or gene clusters means genes from a pre-defined set are present more than expected. Similarly, the term “differential gene expression” means the expression levels of a gene in two experimental conditions or in two samples possess statistically significant difference or change. Gene expression can be detected by quantitative PCR (qPCR) technique. It monitors the amplification of a targeted DNA molecule during the PCR ( / .e., in real time), not at its end, as in conventional PCR. Real-time PCR can be used quantitatively and semi-quantitatively ( / .e., above / below a certain amount of DNA molecules). Gene expression can also be observed using a microarray of polynucleotides, an ELISA technique, or a Southern blotting method. As used herein, RT qPCT means Reverse transcription quantitative polymerase chain reaction, which is used to measure a gene expression level.

[0093] As used herein, the term “polynucleotide” means any RNA or DNA, which may be unmodified or modified RNA or DNA. Polynucleotides include, without limitation, single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, RNA that is mixture of single- and double-stranded regions, and hybrid molecules comprising DNA and RNA that may be single-stranded or, more typically, double-stranded or a mixture of single- and double-stranded regions. In addition, polynucleotide refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNAs or RNAs containing one or more modified bases and DNAs or RNAs with backbones modified for stability or for other reasons.

[0094] As used herein, the term “polypeptide” means any polypeptide comprising two or more amino acids joined to each other by peptide bonds or modifiedpeptide bonds, i.e., peptide isosteres. Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins. Polypeptides may contain amino acids other than the 20 gene-encoded amino acids. Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well-known in the art. Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature.

[0095] As used herein, the terms “disease”, “disorder” or “dysfunction” are used interchangeably in the present disclosure. They refer to any condition, disorder or disease manifested as one or more physiological, physical and / or psychological symptoms or dysfunctions for which treatment is desirable, and includes previously and newly identified diseases, disorders or dysfunctions on any organs, tissues or biological activities. As used herein, the term “medical use” is any use or means related to restore, remedy, or preserve health or wellbeing of a subject.

[0096] As used herein, the term “subject” means that preferably the subject is a mammal, such as a human, but can also be an animal, e.g., domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like) and laboratory animals (e.g., cynomolgus monkey, rats, mice, guinea pigs and the like).

[0097] As used herein, the administration of an agent or drug to a subject or patient includes self-administration and the administration by another. It is also to be appreciated that the various modes of treatment or prevention of medical conditions as described are intended to mean “substantial”, which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.

[0098] The publications discussed above are provided solely fortheir disclosure before the filing date of the present application. Nothing herein is to be construed as an admission that the present disclosure is not entitled to antedate such disclosure by virtue of prior disclosure.EXAMPLESEXAMPLE 1 : COMPOUNDS AND CHEMISTRY

[0099] ANAVEX3-71 (ANAVEX 3-71 , Anavex3-71 , Anavex 3-71 , A3-71 , AF710B) bears the IUPAC name of 1 -[(2S)-2,8-dimethyl-1 -thia-3,8- diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1 -one and with the optical rotation of -56°. It is a highly potent and selective allosteric M1 muscarinic agonist and sigma- 1 receptor agonist. Its stereo-counterpart, 1 -[(2R)-2,8-dimethyl-1 -thia-3,8- diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1 -one (AF710A) is distinguishable from Anavex3-71 in its direction of optical rotation.CRYSTAL FORM OF ANAVEX3-71

[0100] Approximately 10 mg of Anavex3-71 was dissolved in 0.1 mL ethanol at ambient temperature (25°C). Applying the vapor diffusion method, diisopropyl ether was slowly diffused into the system over the course of three weeks. Over the three weeks, crystals grew that were suitable for analysis by single crystal X-ray analysis. Single crystal X-ray analysis was collected at 120 K using Cu Ka radiation (A = 1 .54184 A) generated by a sealed tube using on an Agilent Supernova single crystal X-ray diffractometer. All data was reduced, solved and refined in the chiral monoclinic space- group P21 (a = 7.7804(2) A, b = 10.4193(2) A, c = 11.9464(2) A; a = 90°, p= 90.716(2)°, y = 90°, volume = 968.38(4) A3, Z = 2, Z’ = 1). The final model was built using 18870 (3988 unique) reflections across the 2© range 7.400 to 153.196° returning a R1 (I > (2ol) value of 5.41 % and Flack parameter of -0.007(14) confirming absolute stereochemistry of Anavex3-71 . The asymmetric unit was shown to contain one Anavex3-71 molecule only, exhibiting no disorder. FIG. 1A provides the X-Ray Power Diffraction of the obtained single crystal. Table 1 provides the exemplary peaks. A characteristic XRPD 2© diffractogram was extracted from the data. In orderto understand the stereochemistry of the crystallized Anavex3-71 , the crystallized sample was analyzed by chiral HPLC and compared with enantiomer (AF710A), and racemate. FIGs. 1 B provides the chiral HPLC analysis results, showing retention time of AF710A at around 9.4 and Anavex3-71 at around 12.5, and their areas under the peaks relative to the racemate sample (FIG. 1C). Results indicated stereochemistry of the input Anavex3-71 had not inverted during the single crystal growth study and confirmed the stereochemistry of the desired enantiomer is S. Table 2 provides the crystallographic parameters and refinement indicators of Anavex3-71 crystal.TABLE 1 : Exemplary XRPD Peaks of the Anavex3-71 Crystal (peaks to 50° 20)TABLE 2: Crystallographic parameters and refinement indicators of Anavex3-71M8-S ENANTIOMER: METABOLITE OF ANAVEX3-71

[0101] M8-S enantiomer is the demethylated metabolite of A3-71 and with an optical rotation of -57.7°. FIGs. 2A-2C provide its characterizations of Mass Spectrum,1H NMR and13C NMR, respectively. Both A3-71 and M8-S enantiomer have undergone an extensive series of nonclinical studies to elucidate the pharmacokinetics, metabolism, and toxicity of both compounds prior to the first-in- human study. These studies include single-dose and repeat-dose paradigms lasting 14-28 days in multiple species including mice, rats, and dogs, as well as a series of in vitro investigations.

[0102] The in vivo pharmacokinetic (PK) and toxicokinetic studies of ANAVEXO3-71 revealed that the compound is rapidly absorbed and converted to M8- S enantiomer in rats and dogs, with exposure increasing in a dose-proportional manner without significant accumulation of either the parent or metabolite compounds following single- and multiple-dose administration. For ANAVEXO3-71 , the average protein binding values in plasma were 75.9% ± 0.1 % in rats, 75.5% ± 1.3% in dogs,and 72.3% ± 0.4% in human plasma at a concentration of 2 pM. Additionally, assessments of the blood-plasma ratio (KB / P) of ANAVEX3-71 at a concentration of 1 pM in whole blood revealed a ratio of 0.84 in rats and 0.83 in humans.

[0103] Preliminary nonclinical studies investigating cardiovascular system safety were conducted, demonstrating that the IC50 for the inhibitory effect of ANAVEX3-71 on the human Ether-a-go-go-Related Gene (hERG) potassium channel current was 14.8 pM (Hill coefficient = 1.0). In telemeterized dogs, no changes were noted at single doses of 5, 15, or 30 mg / kg, including no effect on blood pressure parameters (systolic, diastolic, mean arterial, and pulse pressures), heart rate, body temperature, qualitative electrocardiographic parameters ( / .e., waveform abnormalities, arrhythmias), or quantitative electrocardiographic intervals (PR, QRS, QT, and heart rate corrected QT [QTc]) up to 24 hours postdose.

[0104] The in vitro nonclinical safety and toxicology studies included metabolic profiling in rat, dog, and human hepatocytes, as well as Caco-2 permeability assays and studies of potential inhibition of liver transporters (ATP-dependent drug efflux pump P-glycoprotein [P-gp]). ANAVEX3-71 shows high permeability with a Papp coefficient of 7.68 x 10-6 cm / s in the apical to basolateral direction and 20.61 x 10-6 cm / s in the opposite direction, with a slight efflux ratio of 2.68. ANAVEX3-71 also inhibits digoxin driven P-gp mediated efflux with an IC50 value greater than 100 pM. In vitro studies of ANAVEX3-71 and M8-S enantiomer in human liver microsomes demonstrated no significant inhibition or induction of liver enzymes. The metabolism of ANAVEX3-71 in rat, dog, and human hepatocytes revealed that M8-S enantiomer (the N-demethylated metabolite) was by far the most abundant, with 7 other minor metabolites (oxidated or glucuronide conjugated) and no unique metabolites formed in human hepatocytes.

[0105] ln female 3xTg-AD mice, ANAVEX3-71 produced effects previously seen in other S1 R and M1 R agonists, including neuroprotection, improved clearance of pathogenic proteins, and pro-cognitive and pro-memory changes. ANAVEX3-71 is potentially a disease-modifying compound for neurodegenerative disorders, such as AD and FTD, as improvements in cognition remained after a 5-week drug washout period in an aged McGill-R-Thy1-APP transgenic rat model of AD.EXAMPLE 2: CLINICAL STUDY DESIGN

[0106] In the first-in-human study (NCT04442945), single ascending oral doses of 5-200 mg ANAVEX3-71 in healthy adult males demonstrated no serious adverse events and approximately equal rates of mild or moderate adverse events between the placebo and active groups. A cardiodynamic evaluation of ANAVEX3-71 at the previously mentioned doses was performed to assess its effects on ECG parameters. The study was a double-blind, placebo-controlled, randomized single ascending dose (5AD) study in healthy adults, consisting of 4 panels designated 1 , 2a, 2b, and 3. Panels 1 , 2a, and 2b included 6 participants each. The dosing scheme, dose levels, and dose periods are described in FIG. 3. The doses administered were immediate- release capsules.

[0107] Panel 3 (food and sex effects panel) involved the administration of a single 160-mg oral dose of ANAVEX3-71 to a panel of 12 healthy participants (6 males, 6 females) under fed and fasted conditions. The results of the food effect study were described in Fadiran et al, “Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71 , a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease". Clin Pharmacol Drug Dev. 2023; 12(9):888- 901 , which is incorporated by reference in its entirety. Cardiodynamic ECG evaluation occurred prior to drawing PK blood samples in this study. Results from the populationbased characterization of the PK of ANAVEX3-71 in this study were reported in Fadiran et al. above. The cardiodynamic ECG evaluation was performed on panels 1 , 2a, and 2b only. Panels 1 , 2a, and 2b involved the administration of single ascending oral doses of 5, 10, 20, 40, 55, 75, 100, 135, 160, and 200 mg of ANAVEX3-71 or placebo to 6 healthy male participants 18-55 years of age in each dose group, according to a double-blind, placebo-controlled, randomized design. All participants were dosed in the fasted state, and there was a minimum interval of 6 days between each dosing period for an individual participant. The participants in these panels were in-clinic and confined to a phase 1 clinical unit to establish consistent diet and fasting conditions, and for PK sample collection in accordance with the PK schedule.

[0108] The Bellberry Human Research Ethics committee (HREC) provided a scientific and ethical review of the study design and conduct of the study. Bellberry HREC is constituted and operates in accordance with the National Health and Medical Research Council’s National Statement on Ethical Conduct in Human Research (2007,incorporating all updates). All participants provided written informed consent prior to the initiation of the study. The study was performed following the ethical principles that originated in the Declaration of Helsinki and amendments in force at the time of the study. It was also carried out in conformity with the protocol and International Council for Harmonization Good Clinical Practice (ICH-GCP). The ANAVEX3-71-001 study (NCT04442945) was conducted at CMAX Clinical Research Pty Ltd in Adelaide, South Australia.Study Population

[0109] This study enrolled healthy participants 18-55 years of age, inclusive. Only males were included in panels 1 , 2a, and 2b. Inclusion and exclusion criteria are described in the study protocol for AN AVEX3-71-001 (NCT04442945). A total of 18 participants in these 3 panels enrolled and completed the study, with 6 in each panel that underwent cardiodynamic evaluation (panels 1 , 2a, and 2b). Panel 3 did not undergo continuous ECG recordings and was therefore not included in the QT / QTc population.ECG and Pharmacokinetic Sample Collection

[0110] All Holter / ECG data were collected using M12R continuous 12-lead digital recorders and the M12A Enterprise Holter System Client (Global Instrumentation, LLC, Manlius, NY, USA). The equipment was supplied and supported by ERT-Clario.

[0111] A continuous ECG recording on Holter monitors was performed for 25 hours, starting 1 hour pre-dose on day 1 , for all participants in panels 1 , 2a, and 2b. Twelve-lead ECGs were extracted in up to 10 replicates at 3 time points within 1 hour prior to dosing (-50, -40, and -30 minutes) and then paired with PK samples at 0.25, 0.5, 1 , 2, 4, 6, 8, 12, and 24 hours postdose, for a total of 12 time points per period. Participants were supinely resting for at least 10 minutes before and 5 minutes after each time point. When ECG extractions coincided with safety ECGs, vital signs assessment, and blood draws, procedures were carried out in the described order. ECG intervals were measured by the core laboratory in a blinded manner using the Early Precision QT technique (EPQT). The ECG database was locked before any statistical analyses were undertaken.EPQT and TQT Plus ECG Extraction and Measurements

[0112] The central ECG laboratory (ERT-Clario, Philadelphia, PA, USA) used TQT Plus to extract ECGs from the continuous recordings. At the time points described above, up to 10 nonoverlapping 14-second digital 12-lead ECG tracings were extracted from continuous recordings.PK Analytical Method

[0113] ANAVEX3-71 and M8-S enantiomer were quantified in plasma by a validated method using ultra high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS / MS) detection at PPD Laboratory Services, Middleton, Wl, USA. Calibration standards were acceptable if the back-calculated concentrations were within 20.0% of the theoretical concentration at the intended lower limit of quantitation (LLOQ) and within 15.0% of the theoretical concentration for all other levels. Calibration points outside the acceptable limits were excluded from the curve. For an acceptable calibration curve, there must be at least 6 calibration levels represented and a minimum of 75% of the total calibration standards in the run remaining following exclusions.

[0114] For 96-well plate-based sample extraction methods, each plate contained at least 2 quality controls at each concentration level. Each plate was considered acceptable when two-thirds of the quality controls analyzed in the plate met the acceptance criteria. In addition, at least 50% of the quality control results analyzed for each level must be within the acceptance limits for a plate to be acceptable. If a plate failed, the sample results from that plate were unacceptable. For this study, 3 levels of quality controls were analyzed in each run.Statistical Methods

[0115] The planned analyses, as written in the statistical analysis plan, were based on the most recent version of ICH E14 (R3) guidelines, which allow for the assessment of the QTc in early clinical trials using concentration-QTc assessments. All statistical analyses were performed using the statistical software SAS for Windows Version 9.4 (SAS Institute, Inc., Cary, NC, USA). Data collected from all participants enrolled in the study who received at least 1 dose of study treatment (ANAVEX3-71 or placebo) are presented in data listings.

[0116] For descriptive statistics of continuous ECG parameters HR and QTcF, data were summarized for the least square mean (LS mean) and 2-sided 90% confidence interval (Cl), by dose and time point. For all modeling results of the by-time point analysis of change-from-baseline values of continuous ECG parameters, n, LS mean, SE, and 90% Cl were included. Modeling results of the by-time point analysis of placebo-corrected change-from-baseline also included LS mean, SE, and 90% Cl. Mean and median values were rounded to the nearest tenth. SD, SE, and Cl were rounded to the nearest hundredth.Analysis Populations

[0117] All participants who received study treatment had PK samples taken. Participants who had sufficient plasma concentrations for ANAVEX3-71 or its metabolite M8-S enantiomer available were included in the PK analysis dataset. All participants who had ECG measurements at baseline, as well as on-treatment with at least 1 postdose time point within the same treatment period with a valid AQTcF value, were included in the QT / QTc analysis dataset. The QT / QTc population was used for the by-time point, categorical, and method bias sensitivity analyses of the cardiodynamic ECG parameters. All participants who were in both the PK and QT / QTc populations with at least 1 pair of postdose PK and AQTcF data from the same time point, as well as participants in the QT / QTc population who received placebo, were included in the PK / QTc population dataset. The PK / QTc population was used for the concentration-QTc analysis.Baseline ECG

[0118] For all continuous ECG parameters from each period, the baseline was defined as the average of the measured ECG intervals from the 3 predose time points (-50, -40, and -30 minutes) on day 1 for the respective period. For T-wave morphology and U-wave presence from each period, the baseline included findings observed in any of the replicates from the 3 predose time points (-50, -40, and -30 minutes) on day 1 for the respective period. For the arrhythmia analysis, there was only 1 hour of drug- free recording predose on day 1 in each period and not a full 24-hour baseline; arrhythmia findings were compared across doses in a descriptive manner.Heart Rate Correction of the QT Interval and Re-ported QTc

[0119] The QT and preceding RR value for each beat were used for HR correction using Fridericia’s correction (QTcF) method defined as QTcF (ms) = QT (ms) / [RR(in seconds) / 1000]1 / 3. The median QTc value from all beats in each replicate was calculated, and then the mean of all available medians (from a minimum of 3 medians) from a nominal time point was used as the participant’s reportable value at that time point. Change-from-baseline QTcF (AQTcF) was used as the dependent variable in the concentration-QTc analysis and in the by-time point analysis. In the by- time point analysis on the QTcF interval, LS mean, SE, and 2-sided 90% Cl of AQTcF and AAQTcF were calculated for each active dose group, as well as the placebo group for all participants on active treatment as well as on placebo for AQTcF at each postdose time point. In the concentration-QTc analysis, the term placebo-corrected AQTcF (AAQTcF) was used for the model-predicted effect across concentrations on a population level, while the term placebo-adjusted AQTcF (AAQTcF) was used to illustrate the underlying data on both participant and population levels. Table 3 provided the results on AAQTcF.TABLE 3: Placebo-Corrected Change-from-Baseline QTcF (AAQTcF) At Each Time Point with Statistical Modeling (QT / QTc Population)TABLE 3 - Continued with higher concentrationsI §Data was based on a linear mixed-effects model: AQTcF = Time + Treatment + Time x Treatment + Baseline QTcF. An unstructured covariance structure was used to specify the repeated measures (time within period*participant).Analytic Methods

[0120] Concentration-QTc Analysis. The relationship between AQTcF and plasma concentrations of ANAVEX3-71 and its active metabolite M8 were investigated using linear mixed-effects models. The full model had AQTcF as the dependent variable, plasma concentrations of both analytes (ANAVEX3-71 and M8) (without interaction term) as independent variables, with centered baseline QTcF ( / .e., baseline QTcF for individual participants minus the population mean baseline QTcF for all participants within the same treatment period) as a covariate. Fixed effects were study treatment (active = 1 or placebo = 0) and time ( / .e., postdose time point), and random intercepts and slopes were fit per participant. This model was proposed by Garnett et al, and can be applied to both parallel design studies and crossover design studies as described by Schuller et al.

[0121] In all calculations, concentrations in participants who received placebo were set to zero. Plasma concentrations of both analytes below the quantification limit of the assay at all time points were replaced with zero. An unstructured covariance matrix was used for the random effects. The Kenward-Roger method was used to determine estimates of the degrees of freedom (df). From the model and with the 2- sided 90% Cl, the regression parameters for ANAVEX3-71 and M8-S enantiomer concentrations, and the difference between active ANAVEX3-71 treatment and placebo were estimated. The estimates for the time effects were reported with df and SE.

[0122] A total of 3 models were investigated as part of the concentration-QTc analysis. The full model included both analytes (ANAVEX3-71 and M8-S enantiomer), and 2 individual models with each analyte alone. The Akaike Information Criterion(AIC) was used to conduct the model selection, a standard rule for assessing model fit, and the t-value for the treatment effect-specific intercept estimator.

[0123] The selection of the final models was based on models with an absolute t-value for the treatment effect-specific intercept estimate <1.95. In addition, the Pearson correlation coefficient between these 2 analytes (ANAVEX3-71 and M8-S enantiomer) was evaluated to assess collinearity but was not used for model selection. That is, all of the above 3 models were explored regardless of the Pearson correlation coefficient between the 2 analytes. Among these models, the one with the smallest AIC was selected as the primary model. If the AIC differences were small (100*[(largest AIC - smallest AIC) / largest AIC] <6%), the model for ANAVEX3-71 alone was selected. Goodness-of-fit residual plots were created for all 3 models.

[0124] The full model (ANAVEX3-71 and M8-S enantiomer analytes) was used to predict the effect on QT with concentrations from both analytes considered at the same time. In the event that the Tmax values for ANAVEX3-71 and M8-S enantiomer were not the same over the time course of the arithmetic mean plasma concentrations, then the determination of the geometric mean of the individual Cmax values for the ANAVEX3-71 and M8-S enantiomer analytes was conducted as previously described by Schuller et al.

[0125] For each of these 3 models, when applicable, the model-predicted effect and its 2-sided 90% Cl for AAQTcF ( / .e., the sum of slope estimate A concentration for included analytes + treatment effect-specific intercept) at these sets of concentrations were obtained. If the upper bound of the 2-sided 90% Cl

[0126] (equivalent to the upper bound of the 1-sided 95% Cl) of the model- predicted QTc effect (AAQTcF) was below 10 ms at these pairs of concentrations as well as clinically relevant plasma levels, it was concluded that neither ANAVEX3-71 nor M8-S enantiomer causes clinically concerning QTc prolongation within the observed plasma concentration range as stated in ICH E14 (R3) guideline.

[0127] Before the concentration-QTc analysis was performed, the modelindependent checks of assumptions using exploratory plots were explored as described below.

[0128] Assumption 1. No drug effect on HR. In the by-time point analysis, if the LS mean HR was below 10 bpm for all dose levels ofANAVEX3-71 across allpostdose time points, it was concluded that ANAVEX3-71 had no clinically relevant effect on HR.

[0129] Assumption 2. The selected QT correction method should be independent of heart rate. For evaluation of the HR-corrected QT interval, a scatter plot of QTcF and RR intervals for each ANAVEX3-71 dose and pooled placebo in different colors were generated with a simple linear regression line fit to all QTcF-RR pairs across all participants and treatments. A decile plot of QTcF and RR intervals by treatment (pooled ANAVEX3-71 and pooled placebo) with a mean fitted regression line (90% Cl) from a linear mixed-effects model for each treatment was created.

[0130] Assumption 3. No time delay (hysteresis) between drug concentrations and LLQTcF. Hysteresis was assessed by graphical methods based on the LS mean QTcF for each postdose time point from the by-time point analysis and the mean concentrations ofANAVEX3-71 and M8 at the same time points. In addition, hysteresis plots were given for LS mean LLQTcFfrom the by-time point analysis and the mean concentrations ofANAVEX3-71 and M8 at the same time points connected in temporal order by dose.

[0131] Assumption 4. Linear concentration-QTc relationship. A scatter plot of observed LQTcF and concentration for each analyte with a locally weighted scatter plot smoothing (i.e., LOESS) line with 90% Cl and a simple linear regression line were also provided to check the assumption of a linear concentration-QTc relationship.

[0132] After the concentration-QTc analysis was performed, to evaluate the adequacy of model fit with respect to the assumption of linearity, the observed AQTcF values adjusted by population time effect estimated from the model were used. These individual placebo-adjusted AQTcFi.k (AAQTa.k) values equal the observed individual AQTcFi.k for participant i administered with active drug or placebo at time point k minus the estimated population mean placebo effect at time point k (i.e. , time effect). A decile plot of observed drug concentrations and the mean placebo-adjusted AQTcF (AAQTcF) and 90% Cl at the median concentration within each decile was created. The regression line presenting the model-predicted AAQTcF was added to evaluate the fit of a linear model and visualize the concentration-response relationship.

[0133] In addition, to assess the appropriateness of a linear model, normal quantile-quantile (Q-Q) plots for the standardized residuals and the random effects, scatter plots of standardized residuals versus concentration, model-predicted AQTcFand centered baseline QTcF, and box plots of standardized residuals versus nominal time and active treatment were produced for each of the above-performed models, in addition to the decile plot described above. Among these plots, the scatter plots of standardized residuals versus concentration and versus centered baseline QTcF also included the locally weighted scatter plot smoothing lines with optimal smoothing parameters selected by the AIC with a correction. A scatter plot of the observed concentration of each analyte and AAQTcF with a locally estimated scatterplot smoothing (LOESS) line with 90% Cl and a linear regression line was also provided to check the assumption of a linear concentration-QTc relationship. In case a linear model would not fit the data in an acceptable way, additional models were explored, specifically an Emax model.

[0134] As the effect of ANAVEX3-71 on heart rate is apparently small, the use of QTcF is the appropriate correction method and was used accordingly.

[0135] / Wethod Bias Sensitivity Analysis. The purpose of the method bias sensitivity analysis was to ensure that the ECG measurement technique used by the central ECG laboratory, EPQT, did not introduce bias at a level that would significantly affect the results. In this analysis, the fully automated measurements from the iCOMPAS software were compared to the results of the EPQT measurement technique, as described by Ferber et al. In Bland-Altman (BA) plots, QTcF values from fully automated iCOMPAS measurements from the 5-minute time window were subtracted from the QTcF values using EPQT at the same time point for each participant; obtained differences were displayed as a function of the mean of the 2. The relationship between the means and differences between the 2 methods were investigated by robust regression using an M estimator, which reduces the impact of individual outlier values. From the model, the fitted slope (hereafter called the BA slope) and associated 2-sided 95% Cis were given to show the linear trends between the 2 variables. The BA slope indicates whether the observed difference between methods varies with the magnitude of the absolute QTcF value. A negative BA slope would indicate that the central ECG laboratory method (in this case, EPQT) measured relatively shorter QT cF intervals at prolonged levels than the fully automated reference method (iCOMPAS), that is, EPQT introduced a negative bias and could underestimate the QTcF prolongation.

[0136] By-Time Point Analysis. The by-time point analysis for QTcF was based on a linear mixed-effects model with AQTcF as the dependent variable, time( / .e., postdose time point: categorical), treatment (5, 10, 20, 40, 55, 75, 100, 135, and 200 mg of ANAVEX3-71 , and pooled placebo), and time-by-treatment interaction as fixed effects, a participant-specific random effect, and baseline QTcF as a covariate. An unstructured covariance matrix was specified for the repeated measures at postdose time points within the treatment period. When the model with an unstructured covariance matrix failed to converge, other covariance matrices, such as compound symmetry and autoregressive, were considered. The model also included a participant-specific random effect. Participants dosed with placebo were analyzed as a pooled group. From this analysis, the LS mean, SE, and 2-sided 90% Cl were calculated for the contrast “ANAVEX3-71 versus placebo” (AAQTcF) for each dose of ANAVEX3-71 at each postdose time point separately.

[0137] For HR, PR, and QRS interval, the analysis was based on the change from baseline post-dose (AHR, APR, and AQRS). The same (by-time point analysis) model was used as described for QTcF. The LS mean, SE, and 2-sided 90% Cl from the statistical modeling for both change-from-baseline and placebo-corrected change- from-baseline values are listed in tables and graphically displayed.

[0138] Categorical Analysis. Results for categorical outliers, T-wave morphology, and ll-wave presence were summarized in frequency tables with counts and percentages for both the number of participants and the number of time points. Participant data were summarized using the count of distinct participants that fell into the category and the percentage of the total number of participants. Time-point data were summarized using the count of time points at which the assessments fell into the category and the percentage of the total number of time points at which assessments were performed. Counts (either number of participants or the number of time points) for each treatment group were used as the denominator in the calculation of percentages unless otherwise specified.

[0139] A participant or time point was determined as an outlier if any of the criteria (which were assessed separately) was met for the ECG intervals described in the ICH E14 guidance.

[0140] All outliers were summarized for each treatment group on the basis of incidence rates. A participant was counted only once for a particular outlier event if the participant experienced more than 1 episode of that event. The total number of time points was based on the number of observed time points across all participants within a treatment group. For categorical outliers, the number (percentage) of participants,as well as time points that had increases in absolute treatment-emergent QTcF values >450 and <480 ms, >480 and <500 ms, or >500 ms, and changes from pre-dose baseline of >30 and <60 ms, or >60 ms; increase in PR from pre-dose baseline >25% to a PR>200 ms; increase in QRS from predose baseline >25% to a QRS >120 ms; decrease in HR from pre-dose baseline >25% to an HR <50 bpm; and increase in HR from predose baseline >25% to an HR >100 bpm were determined.

[0141] For T-wave morphology and U-wave presence, treatment-emergent changes were assessed, that is, changes did not present at baseline. For each category of T -wave morphology and of U-waves, the category was deemed as present if observed in any replicates at the time point.EXAMPLE 3: RESULTS

[0142] Thirty healthy volunteers enrolled in the study in accordance with the study design and were included in the safety population. Twenty-eight participants from all study panels (1 , 2a, 2b, and 3) were included in the PK population. Only participants in panels 1 , 2a, and 2b underwent continuous ECG recordings on Holter monitors (18 in total). One participant in panel 2b in the 200-mg group had missing or null values in the ECG data and therefore a total of 17 participants from panels 1 , 2a, and 2b were included in the QT / QTc and PK QTc populations.

[0143] The mean (SD) ages of participants in panels 1 , 2a, and 2b were 31.5 (3.73), 28.8 (3.97), and 30.8 (12.83) years, respectively. The mean (SD) ages of participants in panel 3 were 24.3 (4.04) years (3 males fasted then fed), 22.7 (8.08) years (3 males fed than fasted), 28.3 (7.64) years (3 females fasted then fed), and 34.7 (7.09) years (3 females fed than fasted). In each panel, most participants were white; 1 participant in panels 1 , 2a, and 2b, and 4 in panel 3 were Hispanic or Latino.

[0144] The mean (SD) body weight of all male participants was in the range of 70.57 (0.902)-83.15 (10.721 ) kg, and that of female participants was in the range of 58.80 (8.202)-65.90 (8.496) kg. The mean (SD) BMI for all participants was in the range of 22.53 (1.877)-25.55 (2.318) kg / m2.

[0145] Participants were enrolled in the study per the inclusion and exclusion criteria and without relevant disease or medical history. The only concomitant medication taken was paracetamol, which was allowed per protocol.Baseline ECG Parameters

[0146] Baseline ECG parameters were within expectations for a healthy male population across dose groups with mean HR between 53.1 and 64.4 bpm, mean QTcF between 390.4 and 402.9 ms, mean PR between 124.3 and 163.7 ms, and mean QRS between 105.0 and 109.0 ms.Effect on Heart Rate

[0147] ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate. LS mean change-from-baseline HR (AHR) on ANAVEX3-71 generally followed the pattern observed on placebo without an indication of a dosedependent effect (FIG. 4). LS mean placebo-corrected AHR (AAHR) across all postdose time points ranged from -5.4 bpm (at 12 hours postdose in the 75-mg dose group) to 6.7 bpm (at 1 hour postdose in the 100-mg dose group) (FIG. 5 and Table 4). In the highest dose group (200 mg of ANAVEX3-71 ), LS mean AAHR varied between -4.2 bpm (at 12 hours postdose) and 6.0 bpm (at 2 hours postdose). There were no outliers in terms of HR changes.TABLE 4: Placebo-Corrected Change-from-baseline HR (AAHR) at Each Time Point with Statistical Modeling (QT / QTc Population)I025 h Post- ILS Mean I -0.8 I -1.4 I 0.5 I 2.1 I 0.9 IIdoseI|0 5 h Post-dose ILS Mean I -0.4 | -1.2 | 1.9 | 4.6 I 0.5 |I ^90% CI i| (-3.41; 2.54) || (-4.22; 1.72) (-1.13; 484) i (1.63; 7.51) (-2.39; 3.42) JII h Post-dose |LS Mean | 0.4 | -0.2 | 1.6 | 3.4 | -0.2 || ) Il2 h Post-dose |LS Mean | -1.6 | -0.2 | 2.6 2.3 | 0.9 | i14 h Post-dose iLS Mean -0.7 -2.6 | -0.8 ii 1.7 | 0.2 i ii (-4.74; 3.25) ii (-6.61 ; 1.37) i (-4.85; 3 15) i (-2.30; 5.64) i (-3.76; 4.12) i;TABLE 4 - Continued with Higher concentrations 5 5 5 5 5 5Effect on Cardiac Repolarization

[0148] The pattern of LS mean change-from-baseline QTcF (AQTcF) on ANAVEX3-71 and placebo suggested a small dose-dependent shortening with the highest doses (FIG. 6). LS mean placebo-corrected AQTcF (AAQTcF) across postdose time points in the 2 highest dose groups (160 and 200 mg) varied between -7.1 ms (at 2 hours postdose) and -1 .7 ms (at both 0.25 and 0.5 hours postdose) and between - 9.8 ms (at 1 hour postdose) and -0.2 ms (at 0.25 hours postdose), respectively (FIG. 7 and Table 3).Concentration-QTc Results

[0149] Pharmacokinetic Profiles The highest mean plasma concentration of ANAVEX3-71 was observed at 1 , 2, and 3 hour(s) postdose in the 3 highest dose groups (135, 160, and 200 mg; FIG. 7), respectively. The highest mean plasma concentration of M8-S enantiomer was observed at 2, 1 , 1 , 1 , 1 , 2, 1 , 1 , 2, and 1 hour(s) postdose for the 5, 10, 20, 40, 55, 75, 100, 135, 160, and 200 mg dose groups, respectively (FIG. 8).Assessment of Model-Independent Assumptions

[0150] Heart Rate Effect. In the by-time point analysis, LS mean AAHR was below 10 bpm across all postdose time points for all dose levels of ANAVEX3-71 . This data supported that ANAVEX3-71 did not exert a clinically relevant effect on heart rate.[0151 "^Independence ofQTc and HR. Supportive graphs describing the QT cF-RR relationship are provided in FIGs. 9-10. The slopes in the QT-RR relationship forthe pooled ANAVEX3-71 doses and placebo were 0.0068 (P = .0339) and 0.010 (P = .0005), respectively. This indicated that the model assumption of an independent relationship between QTcF and HR was not met either for ANAVEX3-71 or for placebo at the 5% significance level. However, the absolute values of these slopes were <0.06, which was deemed small enough to not impact the concentration-QTc analysis, and additional HR correction methods were not considered based on the lack of an HR effect in the by-time point analysis.

[0152] Assessment of Hysteresis ANAVEX3-71. The time courses of mean ANAVEX3-71 and M8-S enantiomer plasma concentrations and LS mean AAQTcF across postdose time points and hysteresis loops did not produce hysteresis, that is, a delayed effect on the QTc interval.

[0153] Linear Concentration-QTc Relationship The scatter plot of concentrations of ANAVEX3-71 and M8 versus AQTcF with a linear regression line and a LOESS regression line are given in FIG. 11A-B, respectively. The linear regression lines and LOESS regression lines were close across all ranges of observed ANAVEX3-71 and M8-S enantiomer concentrations. This indicated that a linear model for the concentration-QTc relationship appropriately captured the observed data.

[0154] Concentration-QTc Model with ANAVEX3-71 Alone An assessment of the adequacy of the linear mixed-effects model was given by the goodness-of-fit plots for the model with ANAVEX3-71 alone in FIG. 12A, which showed the mean placebo-adjusted AQTcF within each ANAVEX3-71 concentration decile and the model-predicted mean AAQTcF. Metabolite M8 was found to have similar (FIG. 12B). The solid black line with gray shaded area denotes the model-predicted mean AAQTcF with 90% Cl, which is calculated from the equation AAQTcF = -0.66 (ms) - 0.15 (ms per pg / L) x M8-S enantiomer concentration (pg / L). The dashed grey line denotes the 10 ms threshold. The red filled circles with vertical bars denote the estimated mean placebo-adjusted AQTcF (AAQTcF) with 90% Cl displayed at the associated median plasma concentration within each decile for M8-S enantiomer, among which the individually estimated placebo-adjusted AQTcFi.k (AAQTcFi.k) equals the individual AQTcFi.k for participant i administered with M8-S enantiomer attime point k minus the estimation of time effect at time point k. The black circle with vertical bars denotes the mean placebo-adjusted AQTcF with 90% Cl for placebo at a concentration of The plot for ANAVEX3-71 (FIG. 12A) showed that predicted AAQTcF values were close to the estimated placebo-adjusted AQTcF across the plasma concentrations for ANAVEX3-71 . Therefore, it was concluded that the observed data were captured in an acceptable way.

[0155] / Wode / Selection. The Pearson correlation coefficient between ANAVEX3-71 and M8-S enantiomer was 0.80422, that is, less than 0.95, which indicates that these 2 analytes are not highly correlated and therefore can be included in the same concentration-QTc model. Results of the AIC values and the treatment effect-specific intercept estimations for all 3 models from the model selection procedure showed that the treatment effect-specific intercepts for all 3 models were not statistically significant (absolute t-value <1 .95) and that even though the model for ANAVEX3-71 and M8-S enantiomer had the smallest AIC value, the difference in AIC values between the 3 models was small (2803.7 for ANAVEX3-71 and M8-S enantiomer, 2891.9 for ANAVEX3-71 alone, and 2857.5 for M8-S enantiomer alone). Based on this, the model with ANAVEX3-71 alone as the analyte was chosen as the primary model, with the model with M8-S enantiomer alone and the model with both ANAVEX3-71 and M8-S enantiomer as the secondary.

[0156] The estimated population slope of the concentration-QTc relationship for ANAVEX3-71 alone was ~ 0.017 ms per pg / L (P = .0581 ), with a treatment effectspecific intercept of -0.49 ms (P = .3445). The slope for ANAVEX3-71 concentrations was statistically significant at the 10% level, while the treatment effect-specific intercept was not. Using this model, the effect on AAQTcF can be predicted to -4.4 and -4.8 ms at the geometric mean Cmax of ANAVEX3-71 in the 160 mg (232.1 pg / L) and 200 mg (251.1 pg / L) dose groups, respectively.

[0157] This analysis concluded that a QTc effect exceeding 10 ms can be excluded within the full observed plasma concentration ranges of ANAVEX3-71 up to -996 pg / L.

[0158] Based on ANAVEX3-71 and M8-S enantiomer, it can be concluded that the QTc effect exceeding 10 ms can be excluded within the full observed plasma concentration ranges of ANAVEX3-71 and M8 up to ~ 996 and ~ 58 pg / L, respectively.Method Bias Sensitivity Results

[0159] The mean difference in QTcF between the fully automated background QT / RR data using iCOMPAS and the EPQT measurement technique was small across all dose levels, ranging from ~ 1 .28 ms in the 160-mg dose group to ~ 0.27 ms in the 20-mg dose group and was not dose-dependent. The Bland-Altman (BA) slopes were generally small, with all values within ±0.03, except for 0.08 in the 200 mg dose group. When all active drug data were pooled, the BA slope was 0.02. When all active and placebo data were combined, the BA slope was 0.01 . These results demonstrated that the bias was minimal and did not negatively impact the result of the concentration-QT analysis.Effect on Cardiac Conduction: PR and QRS Intervals

[0160] ANAVEX3-71 at the studied doses did not have a clinically relevant effect on cardiac conduction, that is, the PR and QRS intervals. LS mean change- from-baseline PR (APR) on ANAVEX3-71 across postdose time points appeared to vary without relation to dose level (FIG. 13A). LS mean placebo-corrected APR (AAPR) varied between -8.2 ms (at 0.25 hours post-dose in the 55-mg dose group) and 9.1 ms (at 8 hours postdose in the 75-mg dose group). LS mean change-from-baseline QRS (AQRS) was small (FIG. 13B), and LS mean placebo-corrected AQRS (AAQRS) was within ±2.9 ms across all postdose time points. There were no PR or QRS outliers.EXAMPLE 4: RESULTS AND DISCUSSIONS ON PHASE 1 STUDIES

[0161] This study was a phase 1 , first-in-human, double-blind, randomized, single-site, SAD, placebo-controlled, safety tolerability, and PK study of ANAVEX3-71 in healthy adults. The primary objective of this study was to evaluate the effect of ANAVEX371 on the QTc interval and other ECG parameters at the studied doses of 5 - 200 mg in healthy participants. Based on plasma concentration-QTc analyses, ANAVEX3-71 and its metabolite M8-S enantiomer did not demonstrate a clinically relevant QTc prolongation in healthy individuals. Models including the parent drug alone, the metabolite alone, or both parent drug and metabolite showed only small differences in the fit parameter AIC (2803.7 for ANAVEX3-71 and M8-S enantiomer,2891.9 for ANAVEX3-71 alone, and 2857.5 for M8-S enantiomer alone). Thus, the model with ANAVEX3-71 alone was selected as the primary model.

[0162] The estimated population slopes of the concentration-QTcF relationship for ANAVEX3-71 alone and M8-S enantiomer alone were negative and statistically significant at the 10% level. Across all models, a QTc effect exceeding 10 ms can be excluded within the full observed plasma concentration ranges of ANAVEX3-71 and M8-S enantiomer (up to -996 and -58 pg / L, respectively), therefore it was concluded that, at the studied doses, neither ANAVEX3-71 nor its metabolite increase QT length.

[0163] Arrhythmia analysis was performed on the 24-hour Holter recordings on day 1. Besides a few bradycardia events, there were 2 participants in the 55-mg dose group in whom a nonsustained ventricular tachycardia of 3 and 4 beats was observed. One participant in the placebo dose group experienced a 4-beat run of premature ventricular beats. Since such events can be seen in healthy participants and no events were observed in higher dose groups, the data showed that it is unlikely that ANAVEX3-71 will cause episodes of arrhythmia.

[0164] Previous experimental studies of S1 R agonists reported beneficial cardiodynamic effects. The selective serotonin reuptake inhibitor (SSRI) fluvoxamine demonstrated the ability to attenuate QT prolongation and vulnerability to ventricular arrhythmias via S1 R activation in a chronic mild unpredictable stress (CMUS) mouse model. In rats, the S1 R agonist cutamesine (SA4503) ameliorated atrial autonomic nerve function and myocardial inflammation after chronic mild stress via regulation of transforming growth factor- / ? (TGF- / ?) signaling. The antiarrhythmic effects of fluvoxamine supported its use in elderly individuals with delirium, including those with AD. A growing body of evidence surrounding S1 R agonists corroborated the findings of cardiovascular safety from the instant evaluation of ANAVEX3-71 and from another S1 R agonist, ANAVEX2-73, which was currently in development for Rett syndrome, Alzheimer’s Disease (AD), and Parkinson’s disease dementia.

[0165] Thus, in its first-in-human study (NCT04442945), ANAVEX3-71 met its safety objectives at prespecified doses of 5 to 200 mg. These findings confirmed the ANAVEX3-71 preclinical cardiovascular safety findings.

[0166] The results from the cardiodynamic evaluation of the ANAVEX3-71-001 study demonstrated that ANAVEX3-71 and its metabolite (M8-S enantiomer) had no clinically relevant effect on heart rate or cardiac conduction (PR and QRS intervals) or prolongation of the QTc interval. Specifically, the study provided cardiodynamicevaluation of a single ascending dose study in healthy participants with the primary objective of assessing the effect of ANAVEX3-71 , formerly AF710B, on ECG parameters. Twelve-lead ECGs were obtained at 3 time points within 1 hour prior to dosing to establish a baseline and then serially postdose. Concentration-QTc analysis of plasma concentrations of ANAVEX3-71 and metabolite M8-S enantiomer was conducted. ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate or on the PR and QRS intervals. ANAVEX3-71 alone was retained in the primary model due to small fit differences between models which included the metabolite M8-S enantiomer. The estimated population slope of the concentration- QTcF relationship was small and slightly negative: -0.017 ms per pg / L, with a small treatment effect-specific intercept of -0.49 ms. An effect on the placebo-corrected, change-from-baseline QTc exceeding 10 ms can be excluded within the full observed ranges of plasma concentrations of ANAVEX3-71 and M8-S enantiomer up to -996 and -58 pg / L, respectively. The results from this cardiodynamic evaluation demonstrated that ANAVEX3-71 at single ascending doses of 5-200 mg had no clinically relevant effects on any of the studied ECG parameters.EXAMPLE 5: PHASE 1 B STUDIES ON ORAL DOSAGE FORMS

[0167] Anavex is developing ANAVEX®3-71 as a treatment for neurodegenerative and neurophyschiatric disorders, such as schizophrenia, Alzheimer’s disease and frontotemporal dementia. ANAVEX®3-71 is an orally available drug candidate that is believed to restore cellular homeostasis and neural plasticity by targeting S1 Rs and the M1 type of muscarinic receptors, which are especially relevant to CNS disorders. Pre-clinical data indicates ANAVEX®3-71 is a potent S1 R and M1 agonist. Such a combination represents a unique approach to neurodegenerative disease, with the potential to impact major clinical manifestations by addressing the underlying pathophysiology.

[0168] ln addition to the immediate release (IR) capsules used in the above Phase 1 study, modified release (MR) compositions (such as MR tablets) comprising ANAVEX®3-71 as the active ingredient were studied to reduce dosing frequency from three times daily ("ter in die" or TID) to twice daily (“bis in die" or BID), or preferably once daily ("quaque die" or QD) to achieve maximum pharmacological effects. A phase 1 b study was conducted, entitled “Single-Centre, Open-Label, 1-Part Study Designed to Assess the Pharmacokinetic Profiles of ANAVEX3-71 and its MetaboliteM8 [M8-S enantiomer] Following Administration of Modified Release Formulation Prototypes and an Immediate Release (IR) Reference Formulation in Healthy Male and Female Participants”. The study was designed to investigate the PK, relative bioavailability and safety of ANAVEX3-71 MR prototype tablets and ANAVEX3-71 IR oral capsules (reference formulation) across 5 treatment periods (Regimens A to E). A formulation design space was crafted with two strengths of A3-71 (150 mg and 300 mg) as shown in FIG. 14.

[0169] Due to the short apparent half-life of ANAVEX3-71 (median T1 / 22.64 h), it was anticipated that TID dosing would be required to achieve and maintain therapeutic exposure. At the time of study initiation, the potential therapeutic dose strength for the ANAVEX3-71 IR Oral formulation was 125 mg administered up to TID. Exploratory physiologically based pharmacokinetic modelling and simulation analysis showed that TID dosing of ANAVEX3-71 may result in minimal accumulation (-1.17 fold). This was not unexpected since the drug and its M8 metabolite were rapidly cleared from the body. A MR matrix tablet formulation of ANAVEX3-71 was developed to reduce the dosing frequency and enable BID or preferred QD dosing, thereby improving patient compliance and to support successive clinical dosing. GastroPlus® modeling software was used and dissolution data of T80% @ 14 h was the starting MR formulation for testing in the Phase IB clinical trial. This study was an open-label, two-period, non-randomized sequential bioavailability assessment in which an ANAVEX3-71 MR tablet formulation was optimized by using the design space to enable BID or preferably QD dosing. The study utilized a 2-dimensional design space based on dose (150 to 300 mg) and the drug release rate (targeting 80% drug release at approximately 6 to 20 h). The design space parameters were modified during the study based on emerging safety, tolerability and PK data in order to achieve the 125 mg IR TID target product profile (TPP). The study periods explored IR reference (Period 1 ) and the slow (in vitro T80% at 14 h) MR prototype tablet (Period 2) to understand the effect of drug release rate kinetics on the drug absorption. It was planned that successive flexible study periods were then to be used to either optimize the MR tablet dose and / or release rate to map the desired TPP, with the potential to also test a previously dosed formulation in the fed state. Each participant was planned to receive 5 single-dose regimens with a minimum of 7 days between dosing each regimen. However, the study was stopped after 2 treatment periods (Regimens A and B) as the objective of achieving a tablet formation of ANAVEX3-71 with the potentialfor suitable PK performance to support once daily (QD) dosing had been met and the exposure limits outlined in the clinical protocol were exceeded. Therefore, no further formulation development in Periods 3 to 5 was implemented.

[0170] This was a single dose study of the PK profiles of ANAVEX3-71 and its metabolite M8 following administration of an MR formulation prototype and an IR reference formulation. The study was open-labelled, but no randomization was required. Specifically in the case of the immediate-release (IR) capsule, the formulation consisted of ANAVEX3-71 drug substance in a gelatin capsule. Three strengths of 1 , 5, and 20 mg / capsule were prepared, but only used the 5 and 20 mg strengths in clinical trials to date. As for the modified-release (MR) tablets, a formulation design space was crafted with two strengths (150 mg and 300 mg; vs. Fast / Slow dissolution, corresponding to ca. 80% release in 6 hrs or 20-24 hrs, respectively) as shown in FIG. 14 and Table 5 below. ANAVEX3-71 in the dose strength of about 200 mg was used in the Phase 1 B trial.TABLE 5: Formulations of MR TabletsFPA Formulation Prototype A (Low Dose, Fast Release); FPB Formulation Prototype B (High Dose, Fast Release) FPC Formulation Prototype C (Low Dose, Slow Release); FPD Formulation Prototype D (High Dose, Slow Release)

[0171] The overall aim of this study was to assist in the development of an MR formulation for AN AVEX3-71 , with the goal of achieving ideally QD dosing and at least BID dosing. At the time of study initiation, the therapeutic dose was predicted from PK-pharmacodynamic (PD) modelling to be between 50 and 125 mg TID i.e. total daily dose of 150 to 375 mg. The doses selected in this study were based on the benefitrisk balance in healthy volunteers, informed by the exposure parameters observed from the ANAVEX3-71-001 first-in-human (FIH) study detailed in the Examples 1-4. A single 125 mg dose fasted of ANAVEX3-71 I R oral capsules was used as the reference in this study because this dose and single doses up to 200 mg IR have been shown to be safe and well tolerated in the single ascending dose (SAD) portion of the FIH study. The quotient clinical trial was designed such that the formulations (within the design space as shown in FIG. 18) were modified to achieve the optimal blood PK profile, so that QD dosing was possible. Guided by GastroPlus modeling, QD dosing of the MR tablets was achieved as shown in Tables 6-8. Based solely upon GastroPlus modeling, the feasibility for BID dosing was confirmed. However, the Phase 1 B clinical results were superior to that predicted by GastroPlus, demonstrating that QD dosing was achieved with the MR tablets.Table 6: ANAVEX3-71 MR Prototype TabletsTable 7: Characterizations of ANAVEX3-71 MR Prototype TabletsTable 8: Properties of ANAVEX3-71 MR Prototype Tablets

[0172] Due to the nature of MR formulations, including prolonged release and passage over the lower gastrointestinal (Gl) tract where the absorption of most medicines was reduced, the bioavailability of the MR tablets / formulations was expected to be lower than of the IR and so the new MR formulation was expected to require a dose higher than 375 mg to achieve the target profile. However, a cautious approach was adopted for Period 2 and a dose level of about 200 mg was used for the first MR prototype (Period 2), as this dose level was shown to be safe and well tolerated as an IR in the SAD portion of the FIH study and was expected to provide sufficient measurable PK data to allow subsequent formulation and dose selection decisions to be made. This was to help assess both the in vivo performance and the potential risk of dose dumping from the MR prototype tablet before moving into subsequent periods. Based on the relative bioavailability of the MR Prototype and the IR reference formulation from Periods 1 and 2, it was planned for the ANAVEX3-71 dose and the release rates tested in subsequent periods to be adjusted accordingly within the design space. Different doses could have been assessed to investigate the exposure of MR formulation prototypes. It was not expected for the exposures obtained at 200 mg IR dose in the FIH study to be exceeded. However, the highest individual Cmax and AUC(o- iast) values both exceeded the exposure limits outlined in the protocol, which in part lead to the decision for the study to be stopped after Period 2. A second reason for the decision to stop the study was that the ability to dose QD was demonstrated during Period 2, meaning further optimization of dosage or release rate was not required. As this was a Phase 1 study assessing the PK, relative bioavailability and safety of ANAVEX3-71 , the most relevant population was healthy volunteers, as recommendedby the US Food and Drug Administration (FDA) and the European Medicines Agency. Participants who were non-smokers without a history of alcohol or drug abuse or regular co-medication (except hormone replacement therapy [HRT]) were proposed to avoid interaction on drug metabolism and to avoid non-compliance. ANAVEX3-71 is not genotoxic. No reproductive or developmental toxicology or fertility studies have been conducted on ANAVEX3-71 , meaning the effects on fertility and fetal development are not known. Therefore, women of childbearing potential were not permitted to participate in this study. Only women of non-childbearing potential and men were allowed to participate in the study, as long as they complied with the contraception requirements detailed in Section 8.7 of the clinical protocol. Based on the above considerations and target population, healthy male and female participants of non-childbearing potential, aged 18 to 55 years were considered suitable for this study.

[0173] ANAVEX3-71 MR prototype tablets were selected from a two- dimensional design space allowing adjustment of dose level and the drug release rate to enable twice daily or the preferred QD dosing. Participants were admitted to the clinical unit on the morning of Day -1 for both regimens and were dosed in the morning of Day 1 in the fasted state. Exposure to ANAVEX3-71 was assessed by PK sampling up to 48 h post-dose. Urine samples were only collected in Period 1 for the ANAVEX3- 71 IR Oral Capsules (reference formulation). An interim review of safety, tolerability, and PK data up to 48 h post-dose took place after Periods 1 and 2. The decision was made to stop the study after Period 2. There were 11 subjects / participants enrolled, with 10 completed and one discontinued. All 11 participants were included in the safety and PK populations and the Period 1 safety and PK analysis sets. Ten participants were included in the Period 2 safety analysis set and PK analysis set and subset. Healthy male and female participants between 18 and 55 years of age with a body mass index between 18.0 and 30.0 kg / m2. Table 9 provides the test products, dose and mode of administration.Table 9: Test products, dose and mode of administration*A total of 240 ml_ of water was given immediately following oral administration.

[0174] Briefly, a single oral 125 mg dose of ANAVEX3-71 IR Oral Capsule was administered on a single occasion, followed by a minimum of 7 days washout. A single oral 200 mg dose of ANAVEX3-71 MR Prototype Tablet was also dosed on a single occasion. A follow-up phone call was planned to take place 7 to 9 days after the final dose. PK parameters for ANAVEX3-71 and its metabolite M8-S enantiomer (Period 1 only) following a single oral dose of each IMP were obtained. Assessment of adverse events (AEs), vital signs, electrocardiograms (ECGs), physical examinations, body weight, Columbia-Suicide Severity Rating Scale (C-SSRS) and laboratory safety tests. Formal statistical analysis was performed on the ANAVEX3-71 PK parameters Cmax, Ctau, AUC(0-24) and AUC(O-inf), to assess relative bioavailability. The PK parameters underwent a natural logarithmic transformation and were analyzed using mixed effect modelling techniques. The model included terms for treatment fitted as a fixed effect and participant fitted as a random effect.EXAMPLE 6: RESULTS AND DISCUSSION ON PHASE 1B STUDIES

[0175] All plasma specimens, calibration and QC samples were analyzed within 31 days of sample collection and stored at approximately -80°C prior to analysis using a validated bioanalytical method for ANAVEX 3-71 and ANAVEX 3-71 metabolite M8-S enantiomer in human plasma. Plasma samples were analyzed in accordance with the validated method. A total of 924 samples were received, including back-ups, 462 have been analyzed and there are no samples in irreconcilable discrepancy. Human PK data was obtained from SAD and food effect evaluation study. Doses administered in the SAD study were 5, 10, 20, 40, 55, 75, 100, 135, 160 and 200 mg (n= 4 for each dose). The food effect study utilized a crossover study design with a dose of 160 mg administered under fasted and fed conditions (n=12). In the fed arm a high fat - high calories meal was given). ANAVEX®3-71 was administered as an IR capsule in these studies. The average Cp-t profile wascalculated for each study / dose group and used in GastroPlus during PBPK model development. Individual plasma Cp-t data was imported into Phoenix WinNonlin. Prior to calculation of the mean profile, the first value reported as BLQ post-Tmax was replaced with % of the value of the LLOQ. Any values reported as BLQ after that, were considered as zero. Where fewer than half of the subjects had quantifiable levels, mean data points were reviewed for correction bias, and eliminated where stated. Nominal time-points (rather than actual time-points) were used. For AUG calculation, linear trapezoidal linear interpolation calculation method was used; as this may differ from the methods used in production of study reports, the reported AUC values may differ slightly. A PBPK model was developed for ANAVEX® 3-71 using SAD data; dose range 5 to 200 mg, fasted and fed data was also evaluated. The PBPK model was built based on IR capsule SAD data (5 to 200 mg). The model was used to predict the Cp-t profile and PK parameters of a 125 mg IR TID administration at SS. These PK parameters (Cmax SS, AUC0-24h SS, Cmin SS) were used as targets for the development of a MR formulation. A 200 mg MR formulation achieving 80% release in 14 h was predicted to be the most informative formulation to start clinical evaluation with, due to its capacity to explore colonic absorption. FIG. 15 shows the observed and predicted Cp-t profiles. The shape of the profile, Cmax, AUCO-inf, Tmax and C24h are well predicted by the PBPK model. In addition, the 200 mg MR dose falls within the existing IR SAD dose range and therefore minimized any risks associated with failure of the MR prototype formulations (dose dumping). Test results were shown in FIG. 16 and Tables 10-11. FIG. 17 provided the in vitro dissolution profile of MR prototype dosed in the clinic, 80% dissolved at 14 h. For the MR formulation, CLint.u was decreased from the 650 L / h / 70kg (used to simulate the IR arm of the QS study) to 400 L / h / 70kg. This was a surrogate for the reduced intestinal metabolism or efflux that are likely to occur with the MR formulation. Also, as the MR formulation is not disintegrating in stomach, it might behave more like an integral tablet than a rapidly dispersing IR dosage form, which in turn may lead to a longer transit time in stomach Dosing the MR formulation QD between 200 and 300 mg, and releasing 80 % in 14 h would achieve the TPP, which was defined based on TID dosing of the IR reference formulation at 125 mg. This could be due to the presence of gut metabolism that the MR formulation was bypassing, as enzyme expression may vary throughout h the Gl tract. Also, intestinal P-gp may be inhibited by higher concentrations in the lower Gl tract following MR dosing.TABLE 10: PK parameters (observed and predicted) after the administration of a single ANAVEX® 3-71 PO as 200 mg MR formulation to healthy subjectsTABLE 11 : PK parameters after the administration of ANAVEX® 3-71 PO as 125 mg IR and 200 mg MR**Values were geometric mean, except Tmax which was median level.

[0176] Human urine samples were also analyzed. A total of 128 samples were received, including back-ups, 65 have been analyzed and there are no samples in irreconcilable discrepancy. FIG. 18 provides representative chromatograms of ANAVEX 3-71 near the ULOQ, in a treated subject with ANAVEX 3-71 IS & ANAVEX 3-71 metabolite M8-S enantiomer IS (internal standard). FIG. 19 provides the Geometric Mean (x / Geometric SD) Plasma ANAVEX3-71 Concentrations Following Administration of ANAVEX3-71 IR Oral Capsules and ANAVEX3-71 MR Prototype 1 Tablet (Log10 / Linear): Pharmacokinetic Analysis Set.

[0177] Summaries of test results were given in TABLE 12, which provided key geometric mean PK parameters for plasma ANAVEX3-71 and M8-S enantiomer. An average of 0.413% of the 125 mg IR dose administered was excreted as ANAVEX3- 71 in urine by the end of the sampling period. An average of 1.115% of the unadjusted parent dose administered was excreted as M8-S enantiomer in urine by the end of the sampling period. For the comparison of the 200 mg ANAVEX3-71 MR Prototype 1 Tablet vs 125 mg ANAVEX3-71 IR Oral Reference Capsules, the GMRs (90% confidence intervals) relating to ANAVEX3-71 non-dose adjusted peak exposure (Cmax), Ctau and overall exposure (AUC(0-24) and AUC(O-inf)) were 57.67%(42.70%, 77.87%), 219.68% (148.25%, 325.52%), 204.41 % (165.95%, 251.80%) and 226.91 % (174.66%, 294.80%), respectively. Peak exposure of the ANAVEX3-71 MR Prototype 1 Tablet was on average 42% lower than that of the ANAVEX3-71 IR Oral Reference Capsules, while Ctau and overall exposure were in the region of 104% to 127% higher.TABLE 12: PK parameters for plasma ANAVEX3-71 and M8-S enantiomerNA not applicable "Median (range)

[0178] For metabolite M8, following a single oral administration of ANAVEX3- 71 to healthy male and female participants as 125 mg ANAVEX3-71 IR Oral Reference Capsules, plasma concentrations of M8-S enantiomer were evident from between 0.25 h and 0.5 h post-dose in all participants. Maximum plasma concentrations occurred between 1.00 h and 2.00 h post-dose. Following Cmax, plasma concentrations then declined in a biphasic manner and remained quantifiable until between 36 h and 72 hpost-dose. Terminal slopes and AUC(O-inf) estimates were reliably determined for all participants. Resultant elimination half-lives ranged between 6.88 h and 19.16 h. The geometric mean half-life was 10.136 h. An average of 1.115% of the unadjusted parent dose administered was excreted as M8-S enantiomer in urine by the end of the 48h sampling period. Formation of the metabolite M8-S enantiomer following administration of the 125 mg ANAVEX3-71 IR Oral Capsules was rapid with median Tmax occurring at approximately 1.5 h post-dose. Overall exposure of metabolite M8- S enantiomer, based on geometric mean metabolite ratios for AUC accounted for approximately 20% of that estimated for the parent. The geometric mean half-life was longer than those for ANAVEX3-71 at 10.1 h, suggesting elimination of M8-S enantiomer was not formation rate limited.

[0179] In terms of side effects, both the 125 mg dose of ANAVEX3-71 IR Oral Capsules and the 200 mg dose of ANAVEX3-71 MR Prototype 1 Tablet were well tolerated when administered to healthy male and female participants in the fasted state, with no severe treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse drug reactions or deaths reported during the study. Following dosing with 125 mg ANAVEX3-71 IR Oral Capsules in Period 1 , the number of TEAEs participants reported was low, with only 4 (36.4%) participants reporting a total of 5 TEAES, which were all mild in severity and assessed by the investigator as not related to IMP. No subjects were withdrawn from the study due to TEAEs. The most commonly reported TEAE was headache which was reported by 3 (27.3%) participants. All headaches occurred more than 24 h after dosing with 125 mg ANAVEX3-71 IR Oral Capsules and were assessed by the investigator as not related to IMP. There were no TEAEs reported following dosing with 200 mg ANAVEX3-71 MR Prototype 1 Tablet. Five TEAEs were reported in participants receiving ANAVEX3-71 IR Oral Capsules (4 [36.4%] participants) while there were no TEAEs reported in participants receiving ANAVEX3-71 MR Prototype 1 Tablet. Three (27.3%) participants reported a TEAE of headache following administration of ANAVEX3-71 IR Oral Capsules. TEAEs of vessel puncture site bruise and dysphonia were reported by 1 (9.1 %) participant each. All TEAEs were mild in severity, and none were assessed by the investigator to be related to IMP. There were no clinically important changes in mean haematology and clinical chemistry values from baseline (Day -1 , admission for each study period) to 48 h post-dose for either treatment group. Shifts from within the reference range at baseline to outside the reference range after dosing with ANAVEX3-71 IR OralCapsules and ANAVEX3-71 MR Prototype 1 Tablet were recorded for no more than 25.0% of participant. No participants experienced AEs associated with out-of-range haematology or clinical chemistry values following administration of ANAVEX3-71 IR Oral Capsules or ANAVEX3-71 MR Prototype 1 Tablet. No individual urinalysis results were considered clinically significant and reported as AEs. There were no notable differences between ANAVEX3-71 IR Oral Capsules or ANAVEX3-71 MR Prototype 1 Tablet for any vital sign parameter. There were no clinically relevant mean changes from baseline (Day 1 , pre-dose for each study period) for any ECG parameter measured and no notable differences between ANAVEX3-71 IR Oral Capsules or ANAVEX3-71 MR Prototype 1 Tablet for any ECG parameter. All participants recorded QTcF values that were <450 msec at all time points, and there were no increases in QTcF from baseline (Day 1 , pre-dose for each study period) that were >30 msec. No individual ECG results were reported as AE. Therefore, no clinically significant AEs were observed in clinical laboratory evaluations, vital signs, ECGs or C-SSRS and no physical examination findings that were assessed by the investigator to be related to the studied formulation. In conclusion, no new potential safety signals were recorded during this study, and 125 mg ANAVEX3-71 IR Oral Capsules and the 200 mg MR Prototype 1 Tablets appeared to be well tolerated in healthy male and female study participants.

[0180] In summary, following single oral administration of the ANAVEX3-71 IR Oral Capsules, absorption of ANAVEX3-71 was rapid (median Tmax 1 h) compared to administration of the ANAVEX3-71 MR Prototype 1 Tablet (median Tmax 5.5 h). Peak exposure for the ANAVEX3-71 MR Prototype 1 Tablet, in terms of Cmax, was lower than for the ANAVEX3-71 I R Oral Capsules. However, both Ctau and overall exposure (in terms of AUC(o-24) and AUC(o-inf» were greater for the ANAVEX3-71 MR Prototype 1 Tablet. The inter-participant variability associated with peak and overall exposure was lower at 33.6% to 48.9% following administration of the ANAVEX3-71 MR Prototype 1 Tablet compared to the ANAVEX3-71 I R Oral Capsules (55.6% to 63.0%). The elimination phase of ANAVEX3-71 appeared similar for the ANAVEX3-71 IR Oral Capsules and 200 mg ANAVEX3-71 MR Prototype 1 Tablet with geometric mean T1 / 2 of 4.13 h and 5.06 h, respectively. Following administration of the ANAVEX3-71 IR Oral Capsules, metabolism of AN AVEX3-71 was rapid, with median Tmax for M8-S enantiomer at 1.5 h post-dose. Following administration of the ANAVEX3-71 IR Oral Capsules, overall exposure for metabolite M8-S enantiomer, based on geometricmean metabolite ratios for AUC accounted for approximately 20% of that for the parent. The elimination phase of metabolite M8-S enantiomer appeared longer than that of the parent, with a geometric mean T1 / 2 of 10.1 h. Following administration of the ANAVEX3-71 IR Oral Capsules, an average of 0.413% and 1.12% of the dose of ANAVEX3-71 administered was excreted as ANAVEX3-71 and M8-S enantiomer in urine, respectively, at the end of the 48 h sampling period. The 125 mg ANAVEX3-71 IR Oral Capsules appeared to be well tolerated when administered to healthy male and female participants in the fasted state, with a low incidence of TEAEs. All TEAEs were assessed as mild and not related to IMP, and none lead to the withdrawal of any participant. The 200 mg ANAVEX3-71 MR Prototype 1 Tablet appeared to be well tolerated when administered to healthy male and female participants in the fasted state, with no TEAEs reported following dosing. Owing to observed PK and safety results following administration of the 200 mg ANAVEX3-71 MR Prototype 1 Tablet in the fasted state, the study objectives were met and further formulation development in Periods 3 to 5 was not required to be pursued. ANAVEX3-71 MR Prototype 1 Tablet demonstrated the ability to dose QD.EXAMPLE 7: PHASE 2 STUDY DESIGN

[0181] This was a study to evaluate the safety, tolerability, efficacy, pharmacokinetics, and electrophysiology of ANAVEX3-71 in patients with Schizophrenia. ANAVEX3-71-SZ-001 is a two-part study. The first part was Part A: Multiple Ascending Dose, PK, safety, and dose selection. The second part was Part B: Double Blind, Placebo Controlled for exploratory efficacy and continued repeatdose safety. This was an in-patient study investigating the effects of ANAVEX3-71 in patients with Schizophrenia for the first time. Participants underwent either 10 days or 28 days of dosing (Part A and Part B, respectively). Participants were assessed for clinical outcome measures used in the clinic as well as novel fluid and electrophysiological biomarkers. Table 13 provides a summary of testing arms and procedure when ANAVEX3-71 oral capsules are used. ANAVEX3-71 MR Tablets are similarly suitable for the study design. Table 14 provides the primary and secondary outcome measures. Table 15 provides eligibility and other inclusion / exclusion criteria. Additionally, after the conclusion on testing with IR capsules, it is planned to switch the formulation to the MR tablets, whose doses may be established based on the results from the IR capsules. The MR tablets have the potential to lower daily dosesfrom those of the IR capsules, as demonstrated in the Phase 1 B studies presented in Example 6.TABLE 13: ARMS and TREATMENTActive Comparator: Drug: ANAVEX3-71 oral capsules ANAVEX3-71 30 mg TID (Part A) ANAVEXO3-71 (formerly AF710B) is a dual SIGMAR1 receptor agonist and M1 positive allosteric modulatorThe first active treatment with agonistic effects. This novel mechanism of action arm of the study during offers the potential to treat all symptom domains Part A (multiple (positive, negative, and cognitive) of schizophrenia ascending doses). without the side effects of standard of care antipsychotics.Active Comparator: Drug: ANAVEX3-71 oral capsules ANAVEX3-71 60 mg TID (Part A) ANAVEXO3-71 (formerly AF710B) is a dual SIGMAR1 receptor agonist and M1 positive allosteric modulatorThe second active with agonistic effects. This novel mechanism of action treatment arm of the offers the potential to treat all symptom domains study during Part A (positive, negative, and cognitive) of schizophrenia (multiple ascending without the side effects of standard of care doses). antipsychotics.Placebo Comparator: Drug: Placebo oral capsulesANAVEXX3-71 PlaceboTID (Part A) The placebo comparator for the study.The placebo arm of Part A (multiple ascending doses).Active Comparator: Drug: ANAVEX3-71 oral capsules ANAVEX3-71 TBD mg TID (Part B) ANAVEXO3-71 (formerly AF710B) is a dual SIGMAR1 receptor agonist and M1 positive allosteric modulatorThe active arm of Part B with agonistic effects. This novel mechanism of action of the study. The dose will offers the potential to treat all symptom domains be determined based on (positive, negative, and cognitive) of schizophrenia data obtained in Part A. without the side effects of standard of care antipsychotics.TABLE 14: PRIMARY AND SECONDARY OUTCOME MEASURES• Single Dose Maximum Observed Plasma Concentration (Cmax) [ Time Frame: [Part A] Day 1 ]Pharmacokinetic blood measurements of ANAVEX3-71 and metabolite M8 [M8-S enantiomer] at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8-hours post-dose.• Multiple Dose Maximum Observed Plasma Concentration (Cmax) [ Time Frame: [Part A] Day 1 and Day 9 ]Pharmacokinetic blood measurements of ANAVEX3-71 and metabolite M8 [M8-S enantiomer] at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8-hours post-dose.• Cmax (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ]The maximum plasma concentration of ANAVEX3-71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8- hours post-dose on Days 1 and 9.• Tmax (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ]The time to maximum plasma concentration of ANAVEX3-71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8- hours post-dose on Days 1 and 9.• AUC (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ]The area under the curve of the plasma concentration of ANAVEX3- 71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8-hours post-dose on Days 1 and 9.• AUC (single state) [ Time Frame: [Part A] Day 1 and Day 9 ]The area under the curve of the plasma concentration of ANAVEX3- 71 and metabolite M8 [M8-S enantiomer] after a single day of dosing. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8-hours post-dose on Days 1 and 9.CL / F (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ] he oral clearance of ANAVEX3-71 and metabolite M8 after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8-hours post-dose on Days 1 and 9. Vz / F (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ] he volume of distribution based on the terminal elimination phase following administration ANAVEX3-71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8-hours post-dose on Days 1 and 9. T1 / 2 (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ] he time to elimination of half the quantity of ANAVEX3-71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8- hours post-dose on Days 1 and 9. Rac (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ] he observed accumulation rate of ANAVEX3-71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8-hours post-dose on Days 1 and 9. Rac, Cmax (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ] he observed accumulation ratio for Cmax of ANAVEX3-71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8- hours post-dose on Days 1 and 9. PTR (steady state) [ Time Frame: [Part A] Day 1 and Day 9 ] he peak-to-trough ratio at steady state for ANAVEX3-71 and metabolite M8 [M8-S enantiomer] after reaching a steady state. With measurements taken at pre-dose, 0.5, 1 , 2-, 3-, 4-, and 8- hours post-dose on Days 1 and 9. Adverse Events [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ] afety as measured by the number of participants with treatment- related adverse events and the number of treatment-related adverse events, as assessed by CTCAE v4.0. Vital Signs [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ] afety as measured by changes in vital signs including heart rate (beats per minute), blood pressure (mmHg), respiration rate (breaths per minute), and body temperature (degrees centigrade). These measurements will be reported together for the investigatorto assess their clinical relevance and relation to potential treatment emergent adverse events.• 12-lead ECG (RR interval) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the time elapsed between two successive R-waves of the QRS signal on the electrocardiogram (in seconds).• 12-lead ECG (P wave) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the electrical depolarization of the atria of the heart (in milliseconds).• 12-lead ECG (PR interval) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the conduction between the atria and ventricles (in milliseconds).• 12-lead ECG (PR segment) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the portion of the ECG from the end of the P wave to the beginning of the QRS complex as measured by the electrocardiogram.• 12-lead ECG (QRS complex) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in ventricular depolarization as measured by the Q, R, and S waves on the electrocardiogram.• 12-lead ECG (ST segment) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the interval between ventricular depolarization and repolarization as represented by the end of the S wave and beginning of the T wave on the electrocardiogram.• 12-lead ECG (T wave) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in ventricular repolarization (in milliseconds).12-lead ECG (QT interval) [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ] afety as measured by changes in ventricular depolarization and repolarization as represented by the interval between the QRS complex to the end of the T wave. Clinical Safety Labs - Renal Panel [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ] afety as measured by changes in clinical safety laboratory parameters including glucose, calcium, phosphorus, blood urea nitrogen, creatinine, sodium, potassium, chloride, and bicarbonate. These measurements will be combined to report whether clinical safety labs are abnormal and / or clinically significant by the investigator. Clinical Safety Labs - Hepatic Panel [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ] afety as measured by changes in clinical safety laboratory parameters including albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, total protein, lactate dehydrogenase, and gamma-glutamyl transferase. These measurements will be combined to report whether clinical safety labs are abnormal and / or clinically significant by the investigator. Clinical Safety Labs - Lipid Panel [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ] afety as measured by changes in clinical safety laboratory parameters including triglycerides, cholesterol (low-density lipoprotein [LDL], high-density lipoprotein [HDL]), and creatine phosphokinase. These measurements will be combined to report whether clinical safety labs are abnormal and / or clinically significant by the investigator. Clinical Safety Labs - Hematology Panel [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ] afety as measured by changes in clinical safety laboratory parameters including Red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell counts with differential, platelet count, RBC indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], and mean corpuscular hemoglobin concentration [MCHC]) and if RBC indices are abnormal, and reflex to RBC morphology if indices are abnormal. Thesemeasurements will be combined to report whether clinical safety labs are abnormal and / or clinically significant by the investigator.• Clinical Safety Labs - Urinalysis Panel [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 1 14 days (Part B) ]Safety as measured by changes in clinical safety laboratory parameters including Protein, glucose, pH, blood, leukocytes, leukocyte esterase, urobilinogen, bilirubin, ketones, and nitrite. These measurements will be combined to report whether clinical safety labs are abnormal and / or clinically significant by the investigator.• Clinical Safety Labs - Coagulation Panel [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 1 14 days (Part B) ]Safety as measured by changes in clinical safety laboratory parameters including activated partial thromboplastin time, prothrombin time, and international normalized ratio. These measurements will be combined to report whether clinical safety labs are abnormal and / or clinically significant by the investigator.• Brief Physical Examination [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the general appearance of nails, skin, hair, body habitus, movement coordination, odors, breathing pattern, eyes, ears, nose, mouth, face, salivary glands, lymph nodes, thyroid, anterior and posterior torso, proximal / distal motor strength, and distal pulses. These measurements are combined to assess the general neurological status of the participant to report abnormalities and / or clinical significance by the investigator.• Brief Neurological Examination [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the participant's mental status, gait, truncal stability, motor function, and visual capabilities. These measurements are combined to assess the general neurological status of the participant to report abnormalities and / or clinical significance by the investigator.• AIMS [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the Abnormal Involuntary Movement Scale (AIMS). This is a rating scale that was designed to measure involuntary movements known as tardive dyskinesia (TD), which sometimes develops as a side effect of long-termtreatment with neuroleptic (anti-psychotic) medications. The test, which can be completed in about 5 minutes, has a total of twelve items rating involuntary movements of various areas of the patient's body. Items are scored on a 0 (none) to 4 (severe) basis; the scale provides a total score (items 1 through 7) or item 8 can be used in isolation as an indication of overall severity of symptoms.• SAS [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]Safety as measured by changes in the Simpson-Angus Scale (SAS), administered typically within 5 minutes, it is a performance scale that measures anti-psychotic-induced parkinsonism symptoms. The rater asks the patient to perform 10 tasks and rates responses on a scale of 0-4 (normal to severe).• BARS [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]The Brief Adherence Rating Scale (BARS), administered typically within 5 minutes, is a 4-item questionnaire to assess a patient's adherence with their currently prescribed medication regimen. Medication non-adherence is common in patients with psychiatric conditions and associated with worse clinical outcomes. The BARS assesses a patient's compliance with their prescribed medication regimen. The tool is administered by a clinician and includes 4 items: 3 questions and an overall visual analog rating scale to estimate the proportion of doses taken by the patient in the past month (0-100%). The three questions probe patients' knowledge about their medication regimen: number of prescribed doses per day, number of days the patient did not take the prescribe dose, and number of days the patient took less than the prescribed dose.• CDSS [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]The Calgary Depression Scale for Schizophrenia (CDSS) is a 9-item clinician-rated outcome measure that assesses the level of depression in people with schizophrenia spectrum disorder, including attenuated psychosis syndrome. It distinguishes depressive symptoms from negative, positive, and extrapyramidal symptoms. The scales take approximately 10 minutes to administer and has a lookback period of 2-weeks. Each item is rated on a scale of 0-3 (absent to severe).• C-SSRS [ Time Frame: [Part A and Part B Screening to Safety Follow Up Visit] Up to 78 days (Part A) and Up to 114 days (Part B) ]The Columbia Suicide Severity Rating Scale (C-SSRS) is a suicidal ideation rating scale. The scale identifies behaviors and thoughts that are associated with an increased risk of suicidal actions in the future. The C-SSRS baseline / screening version will be conducted at screening. The C-SSRS Since Last Visit version will be conducted for all visits after screening. Answers are "Yes" or "No" with the opportunity for the participant to explain their answers further.• EEG-ERP - Passive, Duration Deviant, Oddball ERP[ Time Frame: [Part A and Part B] Up to 12 days (Part A) and Up to 30 days (Part B) ]Electroencephalography (EEG) and event-related potential (ERP) measures of the duration deviant mismatch negativity paradigm. In this paradigm, 2 tones of the same frequency and sound intensity, one short duration (Standard) and one longer duration (Deviant), are sequentially presented to the patient through inserted earphones. Standard stimuli are presented more often than Deviant stimuli. While the auditory stimuli are being played, the patient is instructed to perform a picture-word matching task where they press a button on the COGNISON® handset when they see a picture and a word on a monitor positioned in front of them that do not match.• EEG-ERP - Active, Auditory, Oddball ERP [ Time Frame: [Part A and Part B] Up to 12 days (Part A) and Up to 30 days (Part B) ]Electroencephalography (EEG) and event-related potential (ERP) measures. In this paradigm, 2 tones of the same sound intensity, one low frequency (Standard) and one higher frequency (Target) are sequentially presented to the patient through inserted earphones. The Standard stimuli are presented more often than the T arget stimuli. The patient is told to listen for the high- frequency stimuli (Target) and press a button on the COGNISION® handset as fast as they can.• EEG-ERP - Auditory Steady State Response [ Time Frame: [Part A and Part B] Up to 12 days (Part A) and Up to 30 days (Part B) ]Electroencephalography (EEG) and event-related potential (ERP) measures. In this paradigm, a short stream of clicks is repeatedly presented to the patient through inserted earphones. While the click-streams are being presented, the patient is instructed to fix their gaze on a white cross displayed on a computer monitor positioned in front of them.• EEG-ERP - Resting EEG [ Time Frame: [Part A and Part B] Up to 12 days (Part A) and Up to 30 days (Part B) ]Electroencephalography (EEG) and event-related potential (ERP) measures. In this paradigm, the patient is asked to close their eyes and relax for 5 minutes while EEGs are recorded.Current Positive and Negative Syndrome Scale (PANSS)Secondary [ Time Frame: [Part A and Part B] Up to 12 days (Part A) and UpOutcome to 30 days (Part B) ]The Positive and Negative Syndrome Scale (PANSS) is an approximate 30-minute structured interview scale used for measuring the symptom severity of patients with schizophrenia. It is widely used in the study of antipsychotic therapy.Brief Assessment of Cognition in Schizophrenia (BAGS) [ Time Frame: [Part A and Part B] Up to 12 days (Part A) and Up to 30 days (Part B) ]The Brief Assessment of Cognition in Schizophrenia (BACS) assesses the aspects of cognition found to be most impaired and most strongly correlated with outcomes in patients with schizophrenia. The BACS requires less than 35 min to complete.Clinical Global Impressions Scale Schizophrenia (CGI-SCH) [ Time Frame: [Part A and Part B] Up to 12 days (Part A) and Up to 30 days (Part B) ]The Clinical Global Impression-Schizophrenia Scale (CGI-SCH) assesses the positive, negative, depressive, cognitive symptoms, and overall severity of schizophrenia. The (CGI-SCH) scale is a brief assessment instrument which is originally adapted from the Clinical Global Impression (CGI) scale and the CGI Bipolar Patients (CGI-BP) scale. It was developed to study the outcome of antipsychotic treatment in schizophrenia in an observational study (Schizophrenia Outpatient Health Outcomes (SOHO) Study. The CGI-SCH has shown strong validity, and it has slightly higher interrater reliability than the PANSS (Kumari et al., 2017).Virtual Reality Functional Capacity Assessment Tool (VRFCAT) [ Time Frame: [Part A and Part B] Up to 12 days (Part A) and Up to 30 days (Part B) ]The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a computerized measure that was developed to be a reliable, valid, and sensitive measure of functional capacity, with the potential to demonstrate real-world functional improvements associated with cognitive change. The VRFCAT, typically administered within 15 minutes, presents patients with a realistic simulated environment to re-create routine activities of daily living, including, e.g., exploring a kitchen, catching a bus to a grocery store, finding / purchasing food in a grocery store, and returning home on a bus. To permit repeated testing while avoiding learning effects, 6 alternate forms were created that vary the ingredients stored in the cabinets, items on the recipe and grocery list, cost of the bus rides, cost of groceries, and money available in a wallet.• Blood measurements of chitinase-3-like protein 1 (YKL-40)[ Time Frame: [Part B] Baseline to End of Treatment (Day -2 to Day 28) ]Previous studies have identified genetic variants of the chitinase- 3-like protein 1 gene (which expresses YKL-40) and elevated serum YKL-40 with an increased risk for schizophrenia in certain populations (Ohi et al., 2010). Subsequent studies in broader populations demonstrated monocyte activation and elevated YKL-40 in the plasma and cerebrospinal fluid of patients experiencing first-episode psychosis (Orhan et al., 2018). This study seeks to explore blood levels of YKL-40 before and after treatment with ANAVEX3-71 to investigate the immune calming effects associated with Sigma-1 receptor activation in patients with schizophrenia. The expected effect of Sigma-1 activation on inflammation may be an upstream effect by attenuating disease- related, chronic pro-inflammatory signaling by monocytes and glia, to prevent downstream injury due to inflammation (Zhang et al., 2023).• Blood measurements of glial fibrillary acidic protein (GFAP)[ Time Frame: [Part B] Baseline to End of Treatment (Day -2 to Day 28) ]Immune dysfunction theories of schizophrenia include glial- related dysfunction and assume that initial disturbances in glial cells can lead or contribute to neuronal abnormalities that drive symptoms of schizophrenia. Glial perturbations in schizophrenia are associated with a neuroinflammatory response and elevated levels of glial fibrillary acidic protein (GFAP) (Wang et al., 2015).• Blood measurements of circulating amino acid metabolites[ Time Frame: [Part B] Baseline to End of Treatment (Day -2 to Day 28) ]Changes in the metabolomic profile of circulating amino acids and related metabolites are implicated in the etiology of numerous neurological and neuropsychiatric disorders (Donatti et al., 2020). Metabolomics studies of patients with schizophrenia demonstrate numerous metabolite signatures of schizophrenia including elevated glutamate (Davison et al., 2018). Changes in these metabolite levels may result from treatment, based on previous research into the treatment of other central nervous system disorders with Sigma-1 receptor agonists such as ANAVEX3-71.• Exploratory DNA / RNA, including whole genome analysis and whole transcriptome mRNA [ Time Frame: [Part B] Baseline to End of Treatment (Day -2 to Day 28)]Exploratory DNA / RNA, including whole genome analysis and whole transcriptome mRNA. Assessed in whole blood via next generation sequencing (NGS) method. Whole genomesequencing (WGS) with 30x read depth. These measurements will be used to understand the potential effects of genetic variation on treatment response and the potential effect oftreatment on changes in gene expression which may be relevant to the etiology of schizophrenia.TABLE 15: ELIGIBILITY AND OTHER CRITERIA FOR PHASE 2 STUDYEligibility Inclusion Criteria: Criteria 1 . Male and female volunteers 18-50 years of age, inclusive at screening.2. Has a primary diagnosis of schizophrenia, for > 1 year3. Stable schizophrenia psychiatric symptoms for at least 6 weeks prior to screening.4. Schizophrenia clinical symptom severity defined by meeting ALL of the following per the Positive and Negative Syndrome Scale (PANSS) item scores at screening: a. Delusions (P1 ) < 4 b. Hallucinatory behavior (P3) < 4 c. Unusual thought content (G9) < 4 d. Hostility (P7) < 45. Patient has a PANSS total score < 80 at screening and baseline visits and no worsening in PANSS total score between screening and baseline, of more than 20%.6. Has a Brief Assessment of Cognition (BAGS) score < 50 at the screening visit.7. On a stable regimen of at least one and up to a maximum of two second-generation ("atypical") antipsychotic medications for at least 6 weeks prior to screening and agree to stay on this regimen for their entire study participation, with the following exceptions: a. Clozapine use is not permitted b. Quetiapine for sleep at doses less than 300 mg are permitted. c. Day time (including morning) quetiapine use as the background antipsychotic is not permitted.8. Able to understand the requirements of the study and able and willing to provide written informed consent and to abide by the study procedures, in the judgment of the Investigator, including able and willing to remain in an in-patient setting during the study.9. If of childbearing potential, using adequate contraceptive methods for the duration of the study.10. Body mass index of 18.5 to 40.0 kg / m2 (inclusive) and total body weight >50 kg (110 lbs.) for males and >40 kg (88 lbs.) for females.11. Has a negative urine screen for drugs of abuse and negative alcohol breath test at screening and check-in.12. Patient resides in a stable living situation and is anticipated to return to that same stable living situation.Exclusion Criteria:1 . Participation in a schizophrenia study in which the patient has received any investigational medications within 60 days prior to the baseline visit.2. History or presence of a clinically significant, poorly treated, or unstable conditions that would jeopardize the safety of the patient or the validity of the study results.3. Clinically significant abnormal findings on the physical examination, medical history, ECG, or clinical laboratory results at screening.4. Calgary Depression Scale for schizophrenia (CDSS) score >6 at the screening or baseline visits.5. Simpson Angus Scale (SAS) total score >5 at the screening and baseline visits at the screening or baseline visits.6. Abnormal Involuntary Movement (AIMS) score of 2 for two or more movements or a score of 3 or 4 for any single movement on this scale at the screening or baseline visits.7. Any primary the DSM-5-TR (American Psychiatric Association 2022) disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening).8. Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not allowed for 90 days after the final dose of study drug.9. Risk for suicidal behavior during the study.10. Inability to detect a 1000 Hz tone at 40 dB in both ears at screening.11. Has psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening.Sexes Eligible for All : Study:Ages i 18 Years to 50 Years (Adult)EXAMPLE 8: PHASE 2A RESULTS AND DISCUSSIONS

[0182] Part A of the Phase 2 study ANAVEX03-71-SZ-001 (NCT06245213), was a multiple ascending dose study in 16 participants treated with either oral placebo, oral ANAVEX®3-71 90 mg daily, or oral ANAVEX®3-71 180 mg daily for 10 days. Preliminary results demonstrated a dose-dependent effect of ANAVEX®3-71 on two key EEG biomarkers in patients with schizophrenia. Treatment with ANAVEX®3-71 compared to placebo resulted in improvements in 40 Hz Auditory Steady-State Response (ASSR) Inter Trial Coherence (ITC) and Resting State Alpha Power, both of which were increased. These effects were most pronounced in the higher dose group demonstrating a dose-dependent pharmacodynamic effect. These results provided evidence of CNS target engagement and potential therapeutic effects of ANAVEX®3-71 in schizophrenia. The observed changes reversed known EEG and ERP biomarker abnormalities associated with schizophrenia. These EEG biomarkers correlated with positive, negative, and cognitive symptoms of schizophrenia. Individuals with schizophrenia typically have reduced neural synchrony as measured by 40 Hz ASSR ITC. Improvements in 40 Hz ASSR ITC indicated enhanced neural synchronization, potentially leading to reduced auditory hallucinations (positive symptom), improved executive function, and working memory (cognitive symptoms). Individuals with schizophrenia also typically have decreased resting state alpha power correlating with sensory and behavioral problems. Increases in Resting State Alpha Power reflected improvements in thalamocortical circuits and sensory gating, potentially resulting in reduced irritability and anxiety (negative symptoms). The observed initial effects on biomarkers indicated the oral M1 / SIGMAR1 therapy ANAVEX®3-71 may help patients address both positive, negative, and cognitive symptoms of schizophrenia. These results were encouraging for further development of ANAVEX®3-71 for people with schizophrenia. Meanwhile, ANAVEX®3-71 was well tolerated, with no serious adverse events reported.REFERENCES1. S. A. Peters, “Physiologically-Based Pharmacokinetic (PBPK) Modeling and Simulations Principles, Methods, and Applications in the Pharmaceutical Industry,” Wiley, 2012.2. C. Hall, “Interspecies scaling in pharmacokinetics: A novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo,” Journal of pharmaceutical sciences, vol. 101 , no. 3, 2012.3. Quotient Sciences, “Pharmaceutical Development and Control Strategy Report for ANAVEX3-71 Modified Release Tablet Formulation,” Nottingham, 2023.4. S. Davis, J. Hardy and J. Para, “Transit of pharmaceutical dosage forms through the small intestine,” Gut, vol. 27, no. 8, pp. 886-892, 19865. Sheldrick, G.M. “A Short History of SHELX,” Acta Crystallog raphica, A64, 112- 122 (2008). http: / / dx.doi.org / 10.1107 / S01087673070439306. Le Page, Y. J. “Single-crystal structure validation with the program PLATON,” J Appl. Cryst. 20, 264 (1987).7. Le Page, Y. “PLATON / ADDSYM,” J of Appl. Cryst. 21 , 983(1988).8. Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K., Puschmann, H. “OLEX2: A Complete Structure Solution, Refinement and Analysis Program,” J Appl. Cryst. 42, 339-341 (2009).9. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Hu-man Use Good Clinical Practice (GCP) Guidelines approved by the Committee for Me-dicinal Products for Human Use (CHMP) on 17 Jul 1996, which came into force on 17 Jan 1997, updated Jul 2002, Integrated Addendum E6 (R2) dated 09 Nov 2016.10. The Medicines for Human Use (Clinical Trials) (Amendment) (EU Exit) Regulations. Statutory Instruments 2019 No. 744.11. The Medicines for Human Use (Clinical Trials) Regulations. Statutory Instruments 2004 No. 1031.12. The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory Instruments 2006 No. 1928.The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations. Statutory Instruments 2006 No. 2984. The Medicines for Human Use (Clinical Trials) Amendment Regulations. Statutory Instruments 2008 No. 941. World Medical Association, Declaration of Helsinki. Ethical Principles for Medical Research In-volving Human Subjects (and all subsequent amendments). Investigator’s Brochure for ANAVEX3-71 . Anavex Life Sciences Corp. Edition 2.0. Release Date: 06 Oct 2022. Maurice T, Su T P. The pharmacology of sigma-1 receptors. Pharmacol Therapeut. 2009. 124:195-206. Weng T-Y, Anne Tsai S-Y, Su T-P. Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases. J Biomed Sci. 2017. 24:74-88. Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases. Cell Death Diff. 2006. 13:385-392. Su T P, Su T C, Nakamura Y, Tsai S Y. The sigma-1 receptor as a pluripotent modulator in living systems. Trend Pharmacol Sci. 2016. 37:262-278. Christ M G, Clement A M, Behl C. The Sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. Feb 2020. 43(2):78-81. Schmidt H R, Kruse A C. The molecular function of sigma receptors: Past, Present and Future. Trends Pharmacol Sci. Sep 2019. 40:636-654. Bradley S J, Bourgognon J M, Sanger H E, et al. M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss. The Journal of clinical investigation. 2017. 127(2):487-499. FDA Guidance: Assessing the Effects of Food on Drugs in INDs and NDAs- Clinical Pharmacology Considerations. June 2022. EMA - Guidance on the investigation of bioequivalence. 20 January 2010. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011. 168:1266-1277. Brown and Prescott. Repeated measures data. In: Brown H and Prescott R, 3rd edition. Applied Mixed Models in Medicine. Chichester, UK: John Wiley & Sons, Ltd: 2015: 242-243.

Claims

We claim:

1. A method for treating a neuropsychiatric disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sigma-1 receptor agonist selected from:1-[2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan- 1-one (AF710);1-[(2R)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (AF710A);1-[(2S)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (ANAVEX 3-71 , AF710B); a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof; wherein the therapeutically effective amount is the amount effective in controlling one or more symptoms associated with the neuropsychiatric disorder.

2. The method of claim 1 , wherein the neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid Personality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder.

3. The method of claim 1 or claim 2, wherein the one or more symptoms comprises hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, or any combination thereof.

4. The method of claim 2, wherein the Schizotypal Personality Disorder is schizophrenia or bipolar disorder.

5. The method of claim 4, wherein the schizophrenia is selected from paranoid type, disorganized type, catatonic type, and undifferentiated type.

6. The method of claim 4, wherein the bipolar disorder comprises bipolar I, bipolar II, cyclothymic disorder, or rapid cycling bipolar.

7. The method of any one of claims 1-6, wherein the polymorph of ANAVEX 3-71 is characterized by PXRD of FIG. 1 B.

8. The method of any one of claims 1-6, wherein the metabolite is M8-S enantiomer and has the structure of Formula (II):Formula (II)9. The method of any one of claims 1-8, wherein the administration is once per day, twice per daily, or three times per day.

10. The method of any one of claims 1-9, wherein the therapeutically effective amount is from about 10 mg / day to about 600 mg / day.11 . The method of any one of claims 1 -10, wherein the therapeutically effective amount is delivered orally or intravenously.

12. The method of any one of claims 1-1 1 , wherein the therapeutically effective amount is from about 15 mg / day to about 600 mg / day when administered orally.

13. The method of any one of claims 1-12, wherein the therapeutically effective amount is from about 10 mg / day to about 50 mg / day when administered intravenously.

14. A method for treating a neurodegenerative disorder, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a sigma-1 receptor agonist selected from:1 -[2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan- 1-one (AF710);1-[(2R)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (AF710A);1 -[(2S)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (ANAVEX 3-71 , AF710B), a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof; wherein the therapeutically effective amount is the amount effective in controlling one or more symptoms associated with the neurodegenerative disorder.

15. The method of claim 14, wherein the one or more symptoms of the neurodegenerative disorder comprises dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof.

16. The method of claim 15, wherein the dementia is associated with a disorder selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections.

17. The method of claim 15 or claim 16, wherein the dementia is selected from AIDS related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, Fronto-temporal dementia (FTD), and idiopathic dementia.

18. The method of any one of claims 15-17, wherein the dementia is associated with Alzheimer’s disease or Parkinson disease.

19. The method of any one of claims 14-18, wherein the polymorph of ANAVEX 3-71 is characterized by PXRD of FIG. 1 B.

20. The method of any one of claims 14-18, wherein the metabolite is M8-S enantiomer and has the structure of Formula (II):Formula (II)21 . The method of claims 14-20, wherein the administration comprises once per day, twice per day, or three times per day.

22. The method of any one of claims 14-21 , wherein the therapeutically effective amount is from about 10 mg / day to about 600 mg / day.

23. The method of any one of claims 14-22, wherein the therapeutically effective amount is delivered orally or intravenously.

24. The method of any one of claims 14-23, wherein the therapeutically effective is from about 15 mg / day to about 600 mg / day when administered orally.

25. The method of any one of claims 14-23, wherein the therapeutically effective amount is from about 10 mg / day to about 50 mg / day when administered intravenously.

26. The method of any one of claims 1-25, wherein the therapeutically effective amount does not impact cardiodynamic functions of the subject.

27. A pharmaceutical composition comprising(i) a sigma-1 receptor agonist selected from one or more of1 -[2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan-1-one (AF710);1-[(2R)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (AF710A);1-[(2S)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (ANAVEX 3-71 , AF710B); a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof; and(ii) an excipient; wherein the sigma-1 receptor agonist is in an amount effective in controlling one or more symptoms associated with a neuropsychiatric or neurodegenerative disorder.

28. The pharmaceutical composition of claim 27, wherein the sigma-1 receptor agonist is ANAVEX 3-71 .

29. The pharmaceutical composition of claim 27 or claim 28, wherein the polymorph of ANAVEX 3-71 is characterized by PXRD of FIG. 1 B.

30. The pharmaceutical composition of claim 27, wherein the metabolite is M8-S enantiomer and has the structure of Formula (II):Formula (II)31 . The pharmaceutical composition of any one of claims 27-30, wherein the composition is an oral composition or an injectable composition.

32. The pharmaceutical composition of any one of claims 27-31 , wherein the composition comprises a tablet, a capsule, or an oral liquid.

33. The pharmaceutical composition of any one of claims 27-32, wherein the composition is for immediate release, modified release, or extended release.

34. The pharmaceutical composition of any one of claims 27-33, wherein the composition releases the sigma-1 receptor agonist over a period of about 9 hours, about 10 hours, about 1 1 hours, about 12 hours, about 13 hours or about 14 hours.

35. The pharmaceutical composition of any one of claims 27-34, wherein the excipient comprises a release-controlling agent, a filler, a glidant, a lubricant, a pH modifier, water for injection, or any combination thereof.

36. The pharmaceutical composition of any one of claims 27-35, wherein the excipient comprises one or more of hypromellose K100 LV, hypromellose K15M, lactose monohydrate, microcrystalline cellulose, fumaric acid, silica colloidal anhydrous, or magnesium stearate.

37. The pharmaceutical composition of any one of claims 27-36, wherein the amount is from about 2 mg to about 300 mg.

38. The pharmaceutical composition of any one of claims 27-37, wherein the amount is from about 5 mg to about 300 mg in an oral composition.

39. The pharmaceutical composition of any one of claims 27-37, wherein the amount is from about 2 mg to about 20 mg in an injectable composition.

40. The pharmaceutical composition of any one of claims 27-38, wherein the composition is an immediate release capsule, and the amount is selected from about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 55 mg, about 75 mg, about100 mg, about 125 mg, about 135 mg, about 160 mg, about 180 mg, and about 200 mg.41 . The pharmaceutical composition of any one of claims 27-38, wherein the composition is a modified release tablet, and the amount is selected from about 150 mg, about 180 mg, about 200 mg, and about 300 mg.

42. The pharmaceutical composition of claim 41 , wherein the pharmaceutically active agent is the polymorph of ANAVEX 3-71 characterized by PXRD of FIG. 1 B, and wherein the excipient comprises one or more of:(i). hypromellose K100 LV in the amount of about 0 mg to about 150 mg;(ii). hypromellose K15M in the amount of about 0 mg to about 225 mg;(iii). microcrystalline cellulose in the amount of about 103 mg to about 329 mg;(iv). lactose monohydrate in the amount of about 75 mg;(v). fumaric acid in the amount of about 37.5 mg;(vi). silica colloidal anhydrous in the amount of about 1 .5 mg; and(vii). magnesium stearate in the amount of about 7.5 mg.

43. The pharmaceutical composition of any one of claims 27-42, wherein the neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid Personality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder; or wherein the one or more symptoms of the neuropsychiatric disorder comprises hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, or any combination thereof.

44. The pharmaceutical composition of any one of claims 27-42,wherein the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections, and any combination thereof; or wherein one or more symptoms of neurodegenerative disorder comprises dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof.

45. A dosage form comprising(i) a sigma-1 receptor agonist selected from one or more of1-[2,8-dimethyl-1 -thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3-yl)propan- 1-one (AF710);1-[(2R)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (AF710A);1-[(2S)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]decan-3-yl]-3-(1 H-indol-3- yl)propan-1-one (ANAVEX 3-71 , AF710B); a polymorph, a metabolite, a pharmaceutically acceptable salt thereof, a polymorph of a pharmaceutically acceptable salt, and any combination thereof; and(ii) an excipient; wherein the sigma-1 receptor agonist is in an amount effective in controlling one or more symptoms associated with a neuropsychiatric or neurodegenerative disorder.

46. The dosage form of claim 45, wherein the sigma-1 receptor agonist is ANAVEX 3-71.

47. The dosage form of claim 45 or claim 46, wherein ANAVEX 3-71 is a polymorph characterized by PXRD of FIG. 1 B.

48. The dosage form of claim 45, wherein the metabolite is M8-S enantiomer and has the structure of Formula (II):

49. The dosage form of any one of claims 45-49, wherein the dosage form is an oral dosage form or an injectable dosage form.

50. The dosage form of any one of claims 45-49, wherein the dosage form comprises a tablet, a capsule, or an oral liquid.51 . The dosage form of any one of claims 45-50, wherein the dosage form is for immediate release, modified release, or extended release.

52. The dosage form of any one of claims 45-51 , wherein the dosage form releases the sigma-1 receptor agonist over a period of about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours or about 14 hours.

53. The dosage form of any one of claims 45-52, wherein the excipient comprises a release-controlling agent, a filler, a glidant, a lubricant, a pH modifier, water for injection, or any combination thereof.

54. The dosage form of any one of claims 45-53, wherein the excipient comprises one or more of hypromellose K100 LV, hypromellose K15M, lactose monohydrate, microcrystalline cellulose, fumaric acid, silica colloidal anhydrous, or magnesium stearate.

55. The dosage form of any one of claims 45-54, wherein the amount is from about 2 mg to about 300 mg.

56. The dosage form of any one of claims 45-55, wherein the amount is from about 5 mg to about 300 mg in an oral dosage form.

57. The dosage form of any one of claims 45-55, wherein the amount is from about 2 mg to about 20 mg in an injectable dosage form.

58. The dosage form of any one of claims 45-57, wherein the dosage form is an immediate release capsule, and the amount is selected from about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 55 mg, about 75 mg, about 100 mg, about 125 mg, about 135 mg, about 160 mg, about 180 mg, and about 200 mg.

59. The dosage form of any one of claims 45-57, wherein the dosage form is a modified release tablet, and the amount is selected from about 150 mg, about 180 mg, about 200 mg, and about 300 mg.

60. The dosage form of claim 45, wherein the pharmaceutically active agent is the polymorph of ANAVEX 3-71 characterized by PXRD of FIG. 1 B, and wherein the excipient comprises one or more of:(i). hypromellose K100 LV in the amount of about 0 mg to about 150 mg;(ii). hypromellose K15M in the amount of about 0 mg to about 225 mg;(iii). microcrystalline cellulose in the amount of about 103 mg to about 329 mg;(iv). lactose monohydrate in the amount of about 75 mg;(v). fumaric acid in the amount of about 37.5 mg;(vi). silica colloidal anhydrous in the amount of about 1 .5 mg; and(vii). magnesium stearate in the amount of about 7.5 mg.61 . The dosage form of any one of claims 45-60, wherein the neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid PersonalityDisorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder; or wherein the one or more symptoms of the neuropsychiatric disorder comprises hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, or any combination thereof.

62. The dosage form of any one of claims 45-60, wherein the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections, and any combination thereof; or wherein one or more symptoms of neurodegenerative disorder comprises dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof.

63. A compound of Formula (I), Formula (II), Formula (III), an enantiomer, a diastereomer, an isomer, a crystal, or a pharmaceutically acceptable salt thereof.Formula (III)64. A compound of FORMULA (II), a diastereomer, an isomer, a crystal, or a pharmaceutically acceptable salt thereof.

65. A dosage form comprising the compound of claim 63 or claim 64, and a pharmaceutically acceptable carrier.

66. A composition comprising the compound of claim 63 or claim 64, and a carrier.

67. Use of the compound of claim 63 or claim 64, the dosage form of claim 64, or the composition of claim 65, in treating a neuropsychiatric disorder, or a neurodegenerative disorder, or one or more symptoms thereof.

68. The use of claim 67, wherein neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, Paranoid Personality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder.

69. The use of claim 67, wherein the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections, and any combination thereof.

70. The use of claim 67, wherein the one or more symptoms comprises hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof.

71. A method of treating a neuropsychiatric disorder, or a neurodegenerative disorder, or one or more symptoms thereof, comprising administering a therapeutically effective amount of claim 63 or claim 64.

72. The method of claim 71 , wherein neuropsychiatric disorder is selected from the group consisting of Antisocial Personality Disorder, Borderline Personality Disorder, Compulsive Personality Disorder, Dependent Personality Disorder, Histrionic Personality Disorder, Hysteria, Narcissistic Personality Disorder, ParanoidPersonality Disorder, Passive-Aggressive Personality Disorder, Schizoid Personality Disorder, and Schizotypal Personality Disorder.

72. The method of claim 71 , wherein the neurodegenerative disorder is selected from Alzheimer’s disease, Parkinson disease, Huntington disease, Brain injury, Multiple sclerosis, Pick disease, Progressive supranuclear palsy and infections, and any combination thereof.

73. The method of claim 72, wherein the one or more symptoms comprises hallucination, delusion, psychosis, cognitive difficulty, disorganized thinking, dementia, memory loss, loss of language, confusion, impaired thinking ability, declined social skills, or any combination thereof.

74. The method of any one of claims 71-73, wherein the therapeutically effective amount is about 2 mg to about 300 mg.

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