WO2024073794A1

WO2024073794A1 - SUBJECT SELECTION FOR 11β-HSD1 INHIBITOR TREATMENT

Info

Publication number: WO2024073794A1
Application number: PCT/AU2023/050878
Authority: WO
Inventors: Steven Geoffrey GOURLAY; Jack Dylan TAYLOR
Original assignee: Actinogen Medical Limited
Priority date: 2022-10-07
Filing date: 2023-09-12
Publication date: 2024-04-11

Abstract

The present disclosure generally relates to the surprising discovery that subjects likely to respond to treatment with an 11β-HSD1 inhibitor can be selected for treatment based on a comparison between a baseline level of a tau protein in the subject, and a reference level of the tau protein.

Description

SUBJECT SELECTION FOR 11β-HSD1 INHIBITOR TREATMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority from Australian Provisional Patent Application No. 2022902939 filed on 7 October 2022, the contents of which are herein incorporated by reference in their entirety.

FIELD

The present disclosure generally relates to the therapeutic field of selecting subjects for treatment with an 11β-HSDl inhibitor. The present disclosure also relates to the identification and selection of subjects for responsiveness to treatment with an 11β-HSDl inhibitor, which may include improving cognitive functioning or impairment in subjects.

BACKGROUND 11β-Hydroxy steroid dehydrogenase ( 11β-HSDl) is an enzyme that catalyzes the conversion of cortisone to active cortisol, and is of great significance to biological basal metabolism. Cortisol is a steroid hormone known to have physiological effects on, for example, development, neurobiology, inflammation, blood pressure, metabolism, and programmed cell death. Therefore, inhibition of 11β-HSDl and associated reduction of cortisol, has been proposed as a treatment for a range of disease pathologies.

Whilst clinical phenotyping may incline a practitioner towards one treatment plan or another, there is no evidence-driven approach available to determine the suitability of an individual subject for treatment with an 11β-HSDl inhibitor. Finding a solution to the present difficulty of determining the suitability of an individual subject for treatment with an 11β- HSDl inhibitor promises to bring a marked improvement in the likelihood of patient responsiveness to treatment, and will aid in avoiding the cost, burden, and physiological detriment associated with unnecessary treatment, where it can be determined that a patient is likely to be non-responsive to that treatment.

The benefits of such a method extend beyond the mere determination of suitability for treatment with an 11β-HSDl inhibitor, as it may also assist in determining the likely nature and extent of that response, the likely duration of that response, the optimal dose or amount of the treatment to effect that response, as well as other factors such as the likelihood of an adverse event. Determination of these factors strongly correlates to patient outcome, which at present is difficult to determine to the extent of desired certainty. Given the financial, physical, and psychological burden to the individual and society associated with the treatment of diseases wherein 11β-HSD 1 is pathologically implicated, there are large benefits to be reaped through informed and accurate patient selection. Thus, there is a need for an empirical approach to determining the suitability of treating a patient with an 1 lp- HSD1 inhibitor to improve patient outcomes.

Alzheimer’s Disease (AD) is one example of a disease whose treatment stands to benefit from an approach to determining the suitability for treating a patient with an 11β-HSD 1 inhibitor. AD is typically diagnosed on the basis of clinical presentation of syndromic change. Yet, a definitive diagnosis of AD is confirmed only by autopsy confirmation of the presence of plaques consisting of aggregated amyloid-P peptide and intracellular neurofibrillary tangles of abnormally phosphorylated tau. AD develops years before the symptoms of dementia appear. Indeed, it is believed that brain pathology begins up to 15 years before the appearance of mild cognitive impairment or clinical dementia. Complicating matters further, not all clinical presentations are found post-mortem to be accompanied with AD-associated neuropathological changes. Thus, it has become increasingly clear that clinical presentation alone is an insufficient basis for the accurate diagnosis of AD, and that consideration of biomarkers for diagnosis and treatment is critical to improving patient outcomes.

Given the burden of cognitive diseases like AD to the individual and society, further investigation is warranted concerning the utility of AD-associated neuropathological biomarkers and cognitive tests towards informing treatment options. Improved treatment through the judicious selection of suitable patients for 11β-HSD 1 inhibitor treatment is an important development to effecting a significant reduction in the burden of this disease.

SUMMARY

The present disclosure is predicated in part on the surprising discovery that tau protein can be used to select subjects more likely to respond to treatment with an 11β-HSD 1 inhibitor. Treatment with an 11β-HSD 1 inhibitor can include improving cognitive functioning or impairment in subjects, for example healthy subjects or subjects suffering from neurodegenerative diseases such as Alzheimer’s Disease (AD). Treatment with an 11β-HSDl inhibitor may also delay or halt progression of cognitive impairment in subjects.

In one aspect, there is provided a method of determining whether a human subject suffering, or suspected of suffering, from a neurodegenerative disease is likely to respond to treatment with an 11β-HSDl inhibitor, the method comprising:

(a) obtaining data on a baseline level of a tau protein in the human subject; and

(b) determining whether the human subject is likely to respond to treatment with an 11β-HSD 1 inhibitor based on the baseline level of the tau protein, wherein the baseline level of the tan protein, being equal to or greater than a reference level of the tan protein associated with the neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSD 1 inhibitor.

In one aspect, there is provided a method of identifying or selecting a subject for receiving treatment with an 11β-HSD 1 inhibitor for responsiveness to the treatment, the method comprising determining the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided a method of determining an increased probability of responsiveness to a treatment of a subject with an 11β-HSD 1 inhibitor, the method comprising determining the baseline level of a tau protein in the subject, wherein the increased probability of responsiveness is determined where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided a method of treating a subject with an 11β-HSDl inhibitor, the method comprising administering an 11β-HSDl inhibitor to the subject, wherein the subject has previously been identified or selected for receiving treatment with an 11β-HSD 1 inhibitor for responsiveness to the treatment, by determining the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In an embodiment, the method comprises identifying and selecting a subject for receiving treatment with the 11β-HSD 1 inhibitor for responsiveness to the treatment based on determining the baseline level of a tau protein in the subject, and administering the 11β-HSD 1 inhibitor to the subject.

In another embodiment, the treatment of the 11β-HSD 1 inhibitor provides an improvement of cognitive functioning in the treated subject relative to a non-treated subject, an improvement of cognitive impairment in the treated subject relative to a non-treated subject, and/or a prophylactic treatment for preventing cognitive decline in a subject predisposed to a disorder or disease associated with cognitive decline.

In another embodiment, the treatment is for a neurodegenerative disease selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple system atrophy, Frontal lobe dementia, vascular dementia, and prion diseases. In one example, the treatment is for Alzheimer’ s disease. In another embodiment, the treatment of the 11β-HSDl inhibitor provides a delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability, of the treated subject relative to a non-treated subject using one or more testing criteria methods selected from Cogstate Neuropyschological Testing criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests, CDR-SB, MMSE, ADAS-Cog, CogState Cognition Test Battery, CANTAB test battery, and Amsterdam instrumental activities of daily living.

In another aspect, there is provided a method of determining whether a human subject suffering, or suspected of suffering, from a neurodegenerative disease is likely to respond to treatment with an 11β-HSDl inhibitor, the method comprising:

(a) obtaining data on a baseline level of cognitive function of the human subject as assessed by the Mini-Mental State Exam (MMSE); and

(b) determining whether the human subject is likely to respond to treatment with an 11β-HSDl inhibitor based on the baseline level of cognitive function, wherein the baseline level of cognitive function, being equal to or greater than a reference level of cognitive function described by an MMSE score that is less 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

In another aspect, there is provided a use of a tau protein or a tau protein for use in identifying or selecting a subject for responsiveness in receiving a treatment of an 11β-HSDl inhibitor by determination of the baseline level of the tau protein in the subject.

In another aspect, there is provided an 11β-HSDl inhibitor for use in treatment of a subject identified or selected for responsiveness in receiving the treatment by determination of the baseline level of a tau protein in the subject.

In another aspect, there is provided an 11β-HSDl inhibitor for use in increasing the probability of responsiveness to a treatment in a subject by determination of the baseline level of a tau protein in the subject.

In another aspect, there is provided a use of an 11β-HSDl inhibitor in the manufacture of a medicament for treatment of a subject identified or selected for responsiveness in receiving the treatment by determination of the baseline level of a tau protein in the subject.

In another aspect, there is provided a use of an 11β-HSDl inhibitor in the manufacture of a medicament for increasing the probability of responsiveness to a treatment in a subject by determination of the baseline level of a tau protein in the subject. In another aspect, there is provided a use of a tan protein or a tan protein for use in identifying or selecting a subject for responsiveness in receiving a treatment of an 11β-HSDl inhibitor by determination of the baseline level of the tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided an 11β-HSD1 inhibitor for use in treatment of a subject identified or selected for responsiveness in receiving the treatment by determination of the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided an 11β-HSDl inhibitor for use in increasing the probability of responsiveness to a treatment in a subject by determination of the baseline level of a tau protein in the subject, wherein the increased probability of responsiveness is determined where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided a use of an 11β-HSDl inhibitor in the manufacture of a medicament for treatment of a subject identified or selected for responsiveness in receiving the treatment by determination of the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided a use of an 11β-HSDl inhibitor in the manufacture of a medicament for increasing the probability of responsiveness to a treatment in a subject by determination of the baseline level of a tau protein in the subject, wherein the increased probability of responsiveness is determined where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided software or hardware programmed to implement an algorithm that processes data related to tau protein levels obtained by performing the method of the disclosure via an univariable or multivariable analysis to provide a disease/condition index value and provide or permit a determination that a human subject suffering, or suspected of suffering from, a neurodegenerative disease will respond to treatment with an 11β-HSDl inhibitor.

Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise. For the avoidance of any doubt, it will be understood that any embodiment herein referring to the administration of an 11β-HSDl inhibitor, or treatment step or method comprised thereof, that provides some improvement or benefit to a subject, applies mutatis mutandis to any aspect or embodiment described herein, including but not limited to, methods of determining whether the subject is likely to be provided with that improvement or benefit by treatment with the 11β-HSDl inhibitor, and vice versa.

The present application is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally- equivalent products, compositions and methods are clearly within the scope of the application, as described herein.

Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

DETAILED DESCRIPTION

General Definitions

Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, medicinal chemistry, microbiology and the like).

As used herein, the term “and/or”, e g., “X and/or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning, e.g. A and/or B includes the options i) A, ii) B or iii) A and B..

As used herein, the term about, unless stated to the contrary, refers to +/- 20%, typically +/- 10%, typically +/- 5%, of the designated value.

As used herein, the terms “a”, “an” and “the” include both singular and plural aspects, unless the context clearly indicates otherwise.

It is to be appreciated that certain features that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

Throughout the present specification, various aspects and components of the application can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the application. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification.

Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

As used herein, the term “treating” (or “treat”, “treatment” etc.) includes an improvement in cognitive functioning and/or reduction, alleviation and/or elimination of one or more symptoms associated with a specific disorder or condition. Such symptoms may be correlated with cognitive decline or impairment in subjects suffering from neurodegenerative diseases such as AD. For example, as used herein, the phrase “treating cognitive impairment” includes improving, reducing, alleviating and/or eliminating symptoms associated with cognitive impairment, relative to the symptoms prior to treatment and/or with respect to subjects determined less likely to respond to treatment. Similarly, “respond to treatment” will include any improvement, reduction, alleviation, or elimination of one or more symptoms associated with the specific disorder or condition, that is provided in the subject following the treatment. It also may include a slowing of the rate of worsening or progression of the symptoms and/or disorder. In the context of neurodegenerative disease, such symptoms (and likewise, any improvement, reduction, alleviation, or elimination thereof) include those relating to cognition and/or function, and may be acute, subacute, or chronic. In some cases, the response may be experienced by the subject for a particular period of time, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks or more. In some cases, the response may be experienced by the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more. In some cases, the response may be experienced by the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 years or more. Over the period in which the subject responds to treatment, the extent of the response may remain stable, decrease, or increase, for example, improvement to the subject’s cognition and/or functioning may increase as the treatment continues.

As used herein, the term “preventing” (or “prevention”) includes prophylaxis of the specific disorder or condition. For example, as used herein, the phrase “preventing cognitive impairment” refers to preventing the onset or duration of the symptoms associated with cognitive impairment in subjects. In some embodiments, the phrase “preventing cognitive impairment” refers to slowing or halting the progression of cognitive impairment. In some embodiments, the phrase “preventing cognitive impairment” refers to delaying or preventing the onset of the symptoms of the cognitive impairment. Prevention may be absolute (such that no cognitive impairment occurs), or may be effective only in some individuals, to some extent, or for a limited amount of time.

As used herein, the term “subject” may be used interchangeably with the terms “patient” and “individual”. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

As used herein, the term “halogen” means fluorine, chlorine, bromine, or iodine.

As used herein, the term “alkyl” encompasses both straight-chain (i.e., linear) and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec -butyl, pentyl, and hexyl groups. In one example, the alkyl group is of one to six carbon atoms (i.e. C1-6alkyl).

As used herein, the term “alkoxy” refers to the group -O-alkyl, where “alkyl” is as described above. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy groups. In one example, the alkoxy group is of one to six carbon atoms (i.e. -O- C1-6alkyl).

As used herein, the term “alkenyl” refers to both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl groups. In one example, the alkenyl group is of two to six carbon atoms (i.e. C2-6alkenyl).

As used herein, the term “alkynyl” refers to both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon triple bond. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl groups. In one example, the alkynyl group is of two to six carbon atoms (i.e. C2- 6alkynyl).

As used herein, the term “haloalkyl” refers to an alkyl group having at least one halogen substituent, where “alkyl” and “halogen” are as described above. Similarly, the term “dihaloalkyl” means an alkyl group having two halogen substituents, and the term “trihaloalkyl” means an alkyl group having three halogen substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, fluoropropyl, and fluorobutyl groups. Examples of dihaloalkyl groups include difluoromethyl and difluoroethyl groups. Examples of trihaloalkyl groups include trifluoromethyl and trifluoroethyl groups. In one example, the haloalkyl group is of one to six carbon atoms (i.e. C1-6haloalkyl).

As used herein, the term “oxyhaloalkyl” refers to the group -O-haloalkyl, where “haloalkyl” is as described above Examples of -O-haloalkoxy groups include -O-fluoromethyl, -O-chloromethyl, -O-bromomethyl, -O-iodomethyl, -O-fluoropropyl, and -Ofluorobutyl groups. In one example, the oxyhaloalkyl group is of one to six carbon atoms (i.e. -O-C1- 6haloalkyl).

As used herein, the term “carbocyclyl” refers to an aromatic or non-aromatic cyclic group of carbon atoms. A carbocyclyl group may, for example, be monocyclic or polycyclic (i.e. bicyclic, tricyclic). A polycyclic carbocyclyl group may contain fused rings. In one example, the carbocyclyl group is of three to ten carbon atoms (i.e. C3-10carbocyclyl). In one example, the carbocyclyl group is of three to seven carbon atoms (i.e. C3-7carbocyclyl). Examples of monocyclic non-aromatic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl groups. Aromatic carbocyclyl groups include phenyl and napthalenyl.

As used herein, the term “heterocyclyl” refers to an aromatic or non-aromatic cyclic group which is analogous to a carbocyclic group, but in which from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. A heterocyclyl group may, for example, be monocyclic or polycyclic (e.g. bicyclic). A polycyclic heterocyclyl may for example contain fused rings. In a bicyclic heterocyclyl group there may be one or more heteroatoms in each ring, or heteroatoms only in one of the rings. A heteroatom may be N, O, or S. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides. In one example, the heterocyclyl group is of three to ten atoms (i.e. 3- 10-membered heterocyclyl) . In one example, the heterocyclyl group is of three to seven atoms (i.e. 3-7-membered heterocyclyl). Examples of monocyclic non- aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl. Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranyl, indanyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzoazepanyl. Examples of monocyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl. Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, isoquinolinyl, and benzohydroxazole.

Subject Selection and Treatment

The subject matter of the present disclosure is predicated in part on the surprising discovery that Tau protein can be used to select subjects more likely to respond to treatment with an 11β-HSDl inhibitor. Treatment with an 11β-HSDl inhibitor can include improving cognitive functioning or impairment in subjects, for example healthy subjects or subjects suffering from neurodegenerative diseases such as Alzheimer’s disease (AD). Treatment with an 11β-HSDl inhibitor may also delay or halt progression of cognitive impairment in subjects, for example subjects suffering from neurodegenerative diseases such as Alzheimer’s disease (AD).

(b) determining whether the human subject is likely to respond to treatment with an 11β-HSDl inhibitor based on the baseline level of the tau protein, wherein the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with the neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

In some embodiments, the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple system atrophy, and prion diseases. In one example, the neurodegenerative disease is Alzheimer’s Disease (AD). In one example, the neurodegenerative disease is mild or moderate Alzheimer’s Disease (AD). In one example, the neurodegenerative disease is mild Alzheimer’s Disease (AD). In one example, the neurodegenerative disease is moderate Alzheimer’s Disease (AD). In some embodiments, the human subject does not have, or is not suspected of having, mild cognitive impairment. In some embodiments, the baseline level of the tan protein, being equal to or greater than the reference level of the tan protein associated with the neurodegenerative disease is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of cognitive functioning in the treated subject relative to a non-treated subject, an improvement of cognitive impairment in the treated subject relative to a non-treated subject, and/or a prophylactic treatment for preventing cognitive decline in a subject predisposed to a disorder or disease associated with cognitive decline.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with the neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide a delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability and/or function, of the treated subject relative to a non-treated subject assessed according to one or more testing criteria methods selected from Cogstate Neuropyschological Testing criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests, CDR-SB, MMSE, ADAS-Cog, CogState Cognition Test Battery, CANTAB test battery, and Amsterdam instrumental activities of daily living. In some examples, the cognitive impairment and/or improvement in a subject may be determined using Cogstate Neuropyschological Testing Battery criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests. In some examples, the cognitive impairment and/or improvement in a subject may be determined using CDR-SB. In some examples, the improvement is by showing a change in baseline in Executive Function and/or Episodic Memory.

In some embodiments, the human subject has an Mini-Mental State Exam (MMSE) score of less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10. In another embodiment, the neurodegenerative disease is Alzheimer’s disease, and the human subject has an MMSE score of less than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10.

In some embodiments, wherein the human subject is suffering, or suspected of suffering, from a neurological disease characterised by a Mini-Mental State Exam (MMSE) score of less than 20, and the baseline level of the tau protein being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease is indicative that treatment with the 11β-HSD1 inhibitor is likely to delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability, of the treated subject relative to a non-treated subject assessed according to one or more testing criteria methods selected from Cogstate Neuropyschological Testing criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests, CDR-SB, MMSE, ADAS- Cog, CogState Cognition Test Battery, CANTAB test battery, and Amsterdam instrumental activities of daily living.

In some embodiments, the method further comprises treating the human subject with an 11β-HSD 1 inhibitor if it is determined that the human subject is likely to respond to treatment thereto, or if it is determined that there is an increased probability of responsiveness to treatment. In some embodiments, the method further comprises treating the human subject with an 11β-HSD 1 inhibitor if it is determined that the human subject is likely to respond to treatment thereto.

In one aspect, there is provided a method of identifying or selecting a subject for receiving treatment with an 11β-HSDl inhibitor for responsiveness to the treatment, the method comprising determining the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided a method of determining an increased probability of responsiveness to a treatment of a subject with an 11β-HSDl inhibitor, the method comprising determining the baseline level of a tau protein in the subject, wherein the increased probability of responsiveness is determined where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided a method of treating a subject with an 11β-HSDl inhibitor, the method comprising administering an 11β-HSDl inhibitor to the subject, wherein the subject has previously been identified or selected for receiving treatment with an 11β-HSD 1 inhibitor for responsiveness to the treatment by determining the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided a method of treating a neurodegenerative disease in a subject, the method comprising administering an 11β-HSD 1 inhibitor to the subject, wherein the subject has been determined as being likely to respond treatment with an 11β-HSD 1 inhibitor based on a level of a tau protein in the subject.

In some embodiments, the subject has been determined as being likely to respond treatment with an 11β-HSDl inhibitor by performing the method of as disclosed herein.

Wherein the subject has been determined as being likely to respond treatment with an 11β-HSD 1 inhibitor by performing the method of any one of the methods as disclosed herein. In an embodiment, the method comprises identifying and selecting a subject for receiving treatment with the 11β-HSDl inhibitor for responsiveness to the treatment based on determining the baseline level of a tau protein in the subject, and administering the 11β-HSDl inhibitor to the subject.

In another embodiment, the treatment of the 11β-HSDl inhibitor provides an improvement of cognitive functioning in the treated subject relative to a non-treated subject, an improvement of cognitive impairment in the treated subject relative to a non-treated subject, and/or a prophylactic treatment for preventing cognitive decline in a subject predisposed to a disorder or disease associated with cognitive decline. In another embodiment, the treatment is for a neurodegenerative disease selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple system atrophy, and prion diseases.

In one example the treatment is for Alzheimer’s disease. In one example, the treatment is for moderate Alzheimer’s disease. In one example the treatment is for mild Alzheimer’s disease. In one example the treatment is for mild or moderate Alzheimer’s disease.

In another embodiment, the treatment of the 11β-HSDl inhibitor provides a delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability, of the treated subject relative to a non-treated subject using one or more testing criteria methods selected from Cogstate Neuropyschological Testing criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests, CDR-SB, MMSE, ADAS-Cog, CogState Cognition Test Battery, CANTAB test battery, and Amsterdam instrumental activities of daily living.

In another embodiment, the subject has an MMSE score of less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10. In another embodiment, the treatment is for Alzheimer’s disease and the subject has an MMSE score of less than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10.

(b) determining whether the human subject is likely to respond to treatment with an 11β-HSDl inhibitor based on the baseline level of cognitive function, wherein the baseline level of cognitive function being equal to or greater than a reference level of cognitive function described by an MMSE score that is less 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

In one embodiment, the reference level of cognitive function is described by an MMSE score that is less than 20.

In another aspect, there is provided use of an 11β-HSDl inhibitor in the manufacture of a medicament for increasing the probability of responsiveness to a treatment in a subject by determination of the baseline level of a tau protein in the subject.

In another aspect, there is provided use of a tau protein or a tau protein for use in identifying or selecting a subject for responsiveness in receiving a treatment of an 11β-HSDl inhibitor by determination of the baseline level of the tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided an 11β-HSDl inhibitor for use in treatment of a subject identified or selected for responsiveness in receiving the treatment by determination of the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

In another aspect, there is provided an 11β-HSDl inhibitor for use in increasing the probability of responsiveness to a treatment in a subject by determination of the baseline level of a tau protein in the subject, wherein the increased probability of responsiveness is determined where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease. In another aspect, there is provided a use of an 11β-HSDl inhibitor in the manufacture of a medicament for treatment of a subject identified or selected for responsiveness in receiving the treatment by determination of the baseline level of a tau protein in the subject, wherein the subject is identified or selected where the baseline level of the tau protein is equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease.

At least according to some embodiments as described herein, tau proteins have been found not to be modulated by the use of 11β-HSDl inhibitors, and therefore provide an independent predictor for improved responsiveness in treatment using 11β-HSDl inhibitors. 11β-HSDl inhibitors have also been found not to modulate amyloid beta protein, such as AB 42/40 ratios.

Tau Proteins

Tubulin associated unit (tau) proteins are a group of protein isoforms produced by alternative splicing from the gene MAPT (microtubule-associated protein tau). Tau proteins are more abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance.

The person skilled in the art will appreciate that tau proteins undergo a variety of in vivo post-translational modifications, such as acetylation and/or phosphorylation. In some embodiments, the tau protein is total tau protein, which refers to all detectable tau protein species, including all tau protein isoforms and tau proteins with one or more post-translational modifications, for example (but not limited to) phosphorylation and/or acetylation. In some embodiments, the tau protein is an acetylated tau protein (acTau) or a phosphorylated tau protein (pTau). In one example, the tau protein is an aggregated tau protein. In one example, the tau protein is a non-phosphorylated tau protein. In another embodiment, the tau protein is a phosphorylated tau (pTau) protein. For example, the tau protein may be a phosphorylated tau (pTau) protein having any one or more phosphorylated threonines at position 181, 50, 69, 111, 153, 175, 205, 212, 217, 231 of the tau protein and/or one or more phosphorylated serines at position 46, 199, 202, 235, 262, 293, 324, 356, 396, 404. In one example, the tau protein may be a phosphorylated tau (pTau) having one or more phosphorylated threonines at position 181, 50, 69, 111, 153, 175, 205, 212, 217, and/or 231 of the tau protein. In one example, the tau protein may be a phosphoraylated Tau (pTau) protein having one or more phosphorylated serines at position 46, 199, 202, 235, 262, 293, 324, 356, 396, and/or 404. In one example, the tau protein is pTau-181, pTau-217, pTau-231, pTau-205 or MTBR-243. In one example, the tau protein is pTau-181, pTau-217 or pTau-231. In one example, the tau protein is pTau-181 or pTau-217. In one example, the tau protein is pTau-217. In one example, the tau protein is pTau-181. Accordingly, the present disclosure also provides for a method of determining whether a human subject suffering, or suspected of suffering, from a neurodegenerative disease is likely to respond to treatment with an 11β-HSDl inhibitor, the method comprising:

(a) obtaining data on a baseline level of pTau-181 in the human subject; and

(b) determining whether the human subject is likely to respond to treatment with an 11β-HSDl inhibitor based on the baseline level of pTau-181, wherein the baseline level of pTau-181, being equal to or greater than a reference level of pTau-181 associated with a neurodegenerative disease is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

The baseline level of the tau protein may be determined by various methods known in the field, for example imaging or sample analysis. As used herein “baseline level of a/the tau protein”, will be understood to refer to a level of a/the tau protein that is ultimately derived or determined from a sample, scan, image, test, and the like, which is derived or obtained from the human subject, prior to step (b) of the method according to any aspect or embodiment described herein. Thus, in some embodiments, the baseline level of a tau protein in the human is a level of the tau protein: (i) in a biological sample obtained from the human subject, or (ii) derived from a measured value obtained from an image obtained from a tau-positron emission tomography (PET) scan of a brain region of the human subject. In some embodiments, the baseline level of a tau protein in the human subject is a level of the tau protein in a biological sample obtained from the human subject. In some embodiments, the baseline level of a tau protein in the human subject is a level of the tau protein derived from a measured value obtained from an image obtained from a tau-positron emission tomography (PET) scan of a brain region of the human subject.

In some embodiments, the method further comprises determining the level of the tau protein: (i) in the biological sample obtained from the human subject; or (ii) from the brain image of the human subject. In some embodiments, the method further comprises determining the level of the tau protein in the biological sample obtained from the human subject. In some embodiments, the method further comprises determining the level of the tau protein from the image obtained from a tau-positron emission tomography (PET) scan of a brain region of the human subject. In some embodiments, the method further comprises performing a tau-positron emission tomography (PET) scan of the human subject to obtain an image of the human subject or brain region thereof.

Biological Samples

In some embodiments, the sample is a biological sample. In some embodiments, the biological sample is obtained from the human subject. The sample or biological sample may be a body fluid, for example blood, blood plasma, or cerebrospinal fluid. Thus, in some embodiments, the biological sample is whole blood, blood serum, blood plasma, or cerebrospinal fluid. In some embodiments, the biological sample is blood. In some embodiments, the biological sample is blood plasma. In some embodiments, the biological sample is cerebrospinal fluid. In some embodiments, the biological sample is blood or plasma, and the tau protein is pTau-181 or pTau-217. In some embodiments, the biological sample is blood plasma, and the tau protein is pTau-181. The person skilled in the art will appreciate that there are various methods known in the art for the quantification of tau protein, including particular tau proteins, in a biological sample. Examples of such methods include, but are not limited to, ELISA using or combined with an antigen-antibody reaction and liquid chromatography (for example, HPLC). In one embodiment, the tau protein is measured by ELISA. Assay kits for determining the amount of tau protein (including for pTau-181) in a sample including a biological sample are readily available, see for example, Simoa® pTau-181 V2 Advantage kit 2020 as published from Quanterix. which is herein incorporated by reference thereto. Further examples of assays suitable for the present application include those described in Janelidze et al., Brain (2023) 146(4): 1592-1601, the contents of which is herein incorporated by reference in its entirety.

In some embodiments, the method further comprises performing one or more assays on the biological sample obtained from the human subject to determine the level of the tau protein therein.

In some embodiments, determining the level of the tau protein in the biological sample comprises:

(i) contacting the biological sample obtained from the subject with one or more binding proteins capable of binding to the tau protein; and

(ii) determining the level of the tau protein by quantifying the level of binding protein complexed with or bound to the tau protein. In some embodiments, the binding protein is an antibody or a fragment thereof.

It will be understood that the method of the present application involves a comparison of the baseline level of the tau protein to a reference level of the tau protein. It will be understood that the reference level is a minimum level of the tau protein carrying an association with and/or is indicative of a neurodegenerative disease. In some embodiments, the reference level is a minimum level of the tau protein carrying an association with and/or is indicative of a neurodegenerative disease. In some embodiments, the reference level is a minimum level of the tau protein carrying an associated with and/or is indicative of clinical Alzheimer’s disease (AD).

The person skilled in the art will appreciate, that a level of a tau protein may be quantified differently depending on the sample from which it is derived. For example, a level of a tau protein in a biological sample (for example, blood plasma) may be quantified in terms of concentration (for example, pg/mL).

In some embodiments, the baseline level of the tau protein (in pg/mL) being equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor. In some embodiments, the baseline level of the tau protein being equal to or greater than 6 pg/mL (for example 6.74 pg/mL) is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor. In some embodiments, the baseline level of the tau protein being equal to or greater than 10 pg/mL (for example, 10.2 pg/mL) is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

The baseline level of the tau protein (in pg/ml) may be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In one embodiment, the baseline level of the tau protein (in pg/ml) may be at least 6. In another embodiment, the baseline level of the tau protein (in pg/ml) may be at least 10.

PET Imaging

The imaging may be tau positron emission tomography (tau-PET) imaging. Tau-PET imaging has been described in various reviews, for example in Lowe et al., ‘Tau-positron emission tomography correlates with neuropathology findings’, Alzheimer ’s & Dementia (2020) 16(3): pp561-571. A person skilled in the art will appreciate that a variety of tau- specific ligands and/or tracers exist for tau PET, for example those described in Leuzy et al., Molecular Psychiatry (2019) 24: 1112-1134. Tau PET may be conducted by injection of suitable tau-PET tracers, such as 18F-labeled arylquinoline derivatives and 11C-labeled phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums, 5H-pyrio[4,3-b] indole. Further suitable tau-PET tracers include [18F]flortaucipir, [18F]RO948 (RO6958948), [11C]PBB3, [18F]MK-6240, [18F]Pl-2620, [18F]GTP1, [18F]JNJ311 (JNJ64349311), [18F] JNJ067 (INJ64326067), [18F]APN-1607 (PM-PBB3) and combinations thereof, (see, Bao et al., Aging Neurosci. 2021, 13:624330). PET images are obtained using commercially available PET/computer tomography scanners such as Biograph mCT (Siemens), Biograph 6 Truepoint (Siemens), Discovery 690 (GE Healthcare). Magnetic resonance imaging (MRI) is conducted by MRI images are obtained using commercially available scanners such as 3.0-T Discovery MR750 (GE Healthcare), 3.0- T Tim Trio (Siemens), 3.0-T Prisma (Siemens), and 1.5-T Magnetom® Avanto (Siemens).

It will be appreciated by persons skilled in the art that the baseline level of the tau protein may be derived or inferred from a measured value that is obtained from an image obtained from a tau PET scan. In some embodiments, the tau PET scan is of the brain (or region thereof) of the human subject. There is no particular limitation on the method of derivation or inference of the baseline level of the tau protein from the measured value obtained from the image obtained from the tau PET scan, nor is there any particular limitation on the measured value obtained from the image obtained from the tau PET scan. The measured value obtained from image may refer to a measured value obtained from a particular region of the image (and therefore, region of the brain). In one embodiment, the measured value of the image is the volume of the brain region whose structure is considered to change as a neurodegenerative disease (for example, AD) progresses or the area of a region that reflects the change in the accumulated amount of a particular substance (for example, tau protein). Examples of the volume of the brain region are the volume of a particular structure (for example, the medial temporal region and the entorhinal cortex) or the volume of the whole brain obtained from the image. Any region of the brain is suitable for tau-PET analysis. Particularly suitable brain regions include the central region, frontal lobe, temporal lobe, parietal lobe, occipital lobe, limbic lobe, insula, and sub cortical gray nuclei. In some embodiments, the image of the whole brain region (global tau-PET) is used to derive the baseline level of the tau protein. In some embodiments, the image is of the inferior temporal brain region, middle brain region, superior temporal brain region, lateral parietal brain region, bilateral entorhinal cortex brain region, fusiform brain region, parahippocampal brain region, inferior brain region, or inferior temporal brain region. Tau-PET images are processed to obtain uniform image size and voxel dimensions. Examples of the method for calculating the measurement (i.e., baseline level of the the tau protein) from an image include use of a software for automated volumetry (for example, FreeSurfer (http://surfer.nmr.mgh.harvard.edu)) and a software for the measured value of cerebral atrophy (for example, Voxel-based Specific Regional analysis system for Alzheimer's Disease: VSRAD (R)).

A baseline level of the tau protein may be derived from a measured value obtained from an image obtained from a tau PET scan, for example in terms of a standard uptake value ratio (SUVR), which is the ratio of the image-derived radioactivity concentration and the whole body concentration of the injected radioactivity. SUVR images are produced using cerebellar gray matter and white matter as the reference regions. To determine low tau, intermediate tau, and high tau, white matter is particularly suitable for use as the reference region. SUVR is calculated using automated anatomical labeling atlas (AAL) or data driven volumes if interest for brain regions.

In some embodiments, the baseline level of the tau protein (in SUVR) being equal to or greater than about 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.70, 1.80, 1.90 or 2.00 is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor. In some embodiments, the baseline level of the tau protein (in SUVR) being between about 1.00 to about 1.60, about 1.05 to about 1.45, about 1.10 to about 1.45, or about 1.35 and about 1.45, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

While a level of tau protein may be in relation to the entire brain region (global tau- PET), the person skilled in the art will appreciate that a level of the tau protein that is indicative that the subject is likely to respond to treatment with an 11β-HSDl inhibitor, may vary depending on the region of the brain that is analysed. For example, in one embodiment, the baseline level of the tau protein (in SUVR) in relation to the inferior temporal brain region ranging from about 1.05 to 1.45 is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (viz. the reference level of the tau protein is a range from about 1.05 to about 1.45). In another embodiment, the baseline level of the tau protein (in SUVR) in relation to the inferior temporal brain region being about 1.45 is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (viz. the reference level of the tau protein is about 1.45). Similarly, when the brain region is the lateral temporal brain region, the reference level of the tau protein (in SUVR) may range from about 1.35 to about 1.45. When the brain region is the middle and superior temporal brain region, the reference level of the tau protein (in SUVR) may range from about 1.35 to about 1.45. When the brain region is the lateral parietal brain region, the reference level of the tau protein (in SUVR) may range from about 1.10 to about 1.45. When the brain region is the bilateral entorhinal cortex, the reference level of the tau protein (in SUVR) may range from about 1.05 to about 1.45. When the brain region is the fusiform, the reference level of the tau protein (in SUVR) may range from about 1.05 to about 1.45. When the brain region is the parahippocampal, the reference level of the tau protein (in SUVR) may range from about 1.05 to about 1.45. In some circumstances, it may be possible to correlate tau imaging data to a blood plasma tau level.

The method can comprise selecting a subject as being suitable for receiving treatment with an 11β-HSDl inhibitor to increase the probability of responsiveness to the treatment by determining the baseline level of a tau protein in a sample obtained from the subject. In one example, if a baseline level of the tau protein (in pg/ml) is at least 6, then the subject is selected for the treatment.

Cognitive Testing

The present disclosure is predicated in part on the surprising discovery that tau protein can be used to select subjects more likely to respond to treatment with an 11β-HSDl inhibitor. Treatment with an 11β-HSDl inhibitor can include improving cognitive functioning impaired in subjects suffering from neurodegenerative diseases such as Alzheimer’s disease (AD).

As used herein, the term “cognitive function” or “cognitive functioning” will be understood to encompass both cognitive ability (or cognition) and function, which in the context of neurodegenerative diseases, are terms that will be understood by the person skilled in the art.

The cognitive impairment and/or improvement in a subject may be determined using the Wechsler Adult Intelligence Scale (WAIS) scale, for example WAIS-IV released in 2008. WAIS-IV is composed of 10 core subtests and five supplemental subtests, with the 10 core subtests comprising the Full Scale IQ. With the new WAIS-IV, the verbal/performance subscales from previous versions were removed and replaced by the index scores. The General Ability Index (GAI) was included, which consists of the Similarities, Vocabulary and Information subtests from the Verbal Comprehension Index and the Block Design, Matrix Reasoning and Visual Puzzles subtests from the Perceptual Reasoning Index. The GAI is clinically useful because it can be used as a measure of cognitive abilities that are less vulnerable to impairment. Wechsler, David (1939) entitled “The measurement of adult intelligence. Baltimore: Williams & Wilkins. P. 229. “Wechsler Adult Intelligence Scale- Revised”. http;//www.cps.nova.edu/~cpphelp/WAIS-R.html . There are four index scores representing major components of intelligence:

( 1 ) V erbal Comprehension Index (V CI) ;

(2) Perceptual Reasoning Index (PRI);

(3) Working Memory Index (WMI); and

(4) Processing Speed Index (PSI).

In some examples, the subject has at least 0.1, 0.5, 1, 2, or 5, SD impairment on WAIS Coding Test relative to age, education and gender.

In other examples, the cognitive impairment and/or improvement in a subject may be determined using Cogstate Neuropyschological Testing Battery criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests. In some examples, the improvement is by showing a change in baseline in Executive Function and/or Episodic Memory.

In one example, the cognitive impairment and/or improvement in a subject may be determined using Cogstate Neuropyschological Testing Battery criteria.

As used herein, “cognitive impairment” refers to the deterioration, or loss, of cognitive ability and/or function relative to the subject. Such deterioration, or loss, of cognitive ability, may be evident in an otherwise cognitively healthy subject.

Other medical conditions that may be associated with cognitive impairment or decline include medical conditions that primarily affect, or are highly associated with, the central nervous system (CNS). In some embodiments, the subject is suffering from a medical condition that is associated with the central nervous system (CNS), for example Alzheimer’s disease (AD).

In some embodiments, the subject has a disorder associated with a substantially elevated level of cortisol, such as dementia. Dementias include, but are not limited to Alzheimer’s disease, multi-infarct dementia, dementia with Lewy bodies, fronto-temporal dementia (including Pick’s disease), progressive supranuclear palsy, Korsakoff’s syndrome, Biswanger’s disease, HIV-associated dementia, Creutzfeldt-Jakob disease (CJD), multiple sclerosis, motor neurone disease, Parkinson’s disease, Huntington’s disease, Niemann-Pick disease type C, normal pressure hydrocephalus, and Down’s syndrome.

Age and gender of subjects

It is understood that cognitive decline varies amongst different subjects. In some embodiments, the age (in years) of the subject is at least about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100. In some embodiments, the age of the subject (in years) is less than about 90, 80, 70, 60, 50, 40, 30, 20, or 10. The age of the subject may be in a range between any two of these upper and/or lower values, for example between 15 to 70 years of age.

Enhancement of cognitive ability

It will also be understood that the method disclosed herein may be beneficial in treating or preventing cognitive impairment in a subject. As used herein, “treating” refers to an increase in cognitive ability compared to a subject’s previous ability (i.e., before being administered an 11β-HSDl inhibitor). The enhancement of cognitive ability may be experienced in relation to one or more facets of cognition including, for example, psychomotor function, visual attention, learning and memory, working memory, and visual associate memory. Such cognitive abilities may be measured using various techniques known in the field, such as those described below (e.g. Cogstate Battery Tests). In some embodiments, a subject experiences enhanced psychomotor function. In some embodiments, a subject experiences enhanced visual attention. In some embodiments, a subject experiences enhanced learning and memory. In some embodiments, a subject experiences enhanced working memory. In some embodiments, a subject experiences enhanced visual associate memory.

Methods of assessing cognitive ability and/or function

There are several tests through which the cognitive ability and/or function of a subject may be assessed. Accordingly, based on the results of these tests, it is possible to assess a subject’s cognitive functioning including improvement thereof. The person skilled in the art will appreciate that there exists a variety of tests that can be employed to accurately assess the cognitive state of a subject. Such tests include, but are not limited to, Cogstate Battery Tests, Cambridge Neuropsychological Test Automated Battery (CANTAB), Intelligence Quotient (IQ) Test, Kohs Block Design Test, Miller Analogies Test, Otis-Lennon School Ability Test (OLSAT), Raven’s Progressive Matrices, Stanford-Binet Intelligence Scales, Wechsler Intelligence Scale for Children (WISC), Wonderlic Test, Porteus Maze Test, Pimsleur Language Aptitude Battery, Knox Cubes, Draw-a-Person Test, Mini-Mental State Exam (MMSE), the Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog, ADCOMs, Rey Auditory Visual Learning Test (RAVLT), NTB and NPI), Clinical Dementia Scale sum of Boxes (CDR-SB), and CDR Computerized Assessment System. Cogstate Battery Tests include, for example, Detection test, Identification test, One Card Learning test, One Back Working Memory test, and the Continuous Paired Associate Learning test. Each test is designed to assess various parameters that may be attributed to the cognitive ability of a subject. Accordingly, in some embodiments the administration of an 11β-HSDI inhibitor provides improved cognitive testing (Cogstate Test Battery) of the treated subject relative to a nontreated subject. An improvement in cognitive testing, as determined by the Cogstate Test Battery results, may also be considered from a summation of each individual test results (e.g., Detection test, Identification test, One Card Learning test, One Back Working Memory test, and the Continuous Paired Associate Learning test).

In some examples, any one or more cognitive tests measuring reaction time improvement may provide an improvement of at least about (loglO, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, any one or more cognitive tests may provide a “p value” probability measurement from a treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002, or 0.001. In some examples, the cognitive testing may provide a Cohen’s “d-value” standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some examples, the cognitive testing may provide a “p-value” and “d-value” according to any combination of individual embodiments thereof as described herein. In some embodiments, the baseline level of the tan protein, being equal to or greater than the reference level of the tan protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSD 1 inhibitor is likely to provide an improvement of psychomotor function of the treated subject relative to a non-treated subject. In some embodiments, where the method further comprises treatment, the administration of the 1 lp- HSD1 inhibitor provides an improvement of psychomotor function of the treated subject relative to a non-treated subject. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of psychomotor function of the treated subject relative to a non-treated subject. Psychomotor function is evidenced by an improvement in simple reaction time, and is measured in speed of performance (Logic milliseconds). As will be appreciated by the person skilled in the art, psychomotor function is critical in a subject’s ability to execute both gross and fine motor skills. Accordingly, psychomotor function is an essential component of physical skills including, for example, movement, coordination, manipulation, dexterity, grace, strength, and speed. It is therefore foreseeable that the method described herein may find particular application in improving psychomotor function in a cognitively healthy subject. In some embodiments, the administration of an 11β-HSD 1 inhibitor is likely to provide and/or provides an improvement of psychomotor function in a cognitively healthy subject. In some embodiments, the administration of an 11β-HSD 1 inhibitor is likely to provide and/or provides an improvement in physical skill of a cognitively healthy subject. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of gross motor skills in a cognitively healthy subject. In some embodiments, the administration of an 1 lp- HSD1 inhibitor is likely to provide and/or provides an improvement of fine motor skills in a cognitively healthy subject.

The methods described herein may also find particular application in assisting a subject in regaining psychomotor function. A loss of psychomotor function may result for any number of reasons including, but not limited to, accident and/or injury, a stroke, or other medical condition. Such a loss of psychomotor skills may affect any one or more areas of the subject’s body including, but not limited to, the limbs. Accordingly, the administration of an 11β-HSD 1 inhibitor may assist to restore psychomotor function The term “restore psychomotor function” is used herein to mean a return, to some extent, of previous motor function.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSD 1 inhibitor is likely to provide an improvement of psychomotor function speed of performance. In some embodiments, where the method further comprises treatment, the administration of the 11β-HSD 1 inhibitor provides an improvement of psychomotor function speed of performance. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of psychomotor function speed of performance. The psychomotor function speed improvement may be measured between the treated subjects relative to non-treated subjects. In some examples, a psychomotor function speed improvement may be provided by a log 10 reaction time (milliseconds) of less than about 2.60. 2.59, 2.58, 2.57, 2.56, 2.55, 2.54, 2.53, 2.52, 2.51, or 2.50. In some examples, a psychomotor function speed improvement may be at least about (log10, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, the psychomotor function testing has a p value probability measurement from a treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09. In some examples, the psychomotor function testing may provide a Cohen’ s d-value standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, or 0.7. In some examples, the psychomotor function testing may provide a “p-value” and “d-value” according to any combination of individual embodiments thereof, such as a p-value less than about 0.09 with a d-value effect size of greater than about 0.7.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of visual attention of the treated subject relative to a non-treated subject. In some embodiments, where the method further comprises treatment, the administration of the 11β-HSDl inhibitor provides an improvement of visual attention of the treated subject relative to a non-treated subject. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of visual attention of the treated subject relative to a nontreated subject. Visual attention is evidenced by an improvement in choice retention time, and is measured in speed of performance (Logio milliseconds). In some embodiments, the improvement in visual attention is evidenced by an improvement in choice retention time. In some embodiments, the improvement in visual attention is assessed by the Cogstate Identification Test. In some embodiments, the administration of an 11β-HSDl inhibitor provides an improvement of visual attention speed of performance of the treated subject relative to a non-treated subject. The visual attention speed improvement may be measured between the treated subjects relative to non-treated subjects. In some examples, a visual attention speed improvement may be provided by a log 10 reaction time (milliseconds) of less than about 2.80, 2.79, 2.78, 2.77, 2.76, 2.75, 2.74, 2.73, 2.72, 2.71, or 2.70. In some examples, a visual attention speed improvement may be at least about (loglO, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, the visual attention testing has a p value probability measurement from a treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09, 0.08, 0.07, 0.06, or 0.05. In some examples, the visual attention may provide a Cohen’s d-value standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, or 0.6. In some examples, the visual attention testing may provide a “p-value” and “d- value” according to any combination of individual embodiments thereof, such as a p-value less than about 0.05 with a d-value effect size of greater than about 0.6.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of learning and memory of the treated subject relative to a non-treated subject. In some embodiments, where the method further comprises treatment, the administration of the 1 lp- HSD1 inhibitor provides an improvement of learning and memory of the treated subject relative to a non-treated subject. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of learning and memory of the treated subject relative to a non-treated subject. Learning and memory is evidenced by an improvement in visual recognition learning, and is measured in accuracy of performance (arcsine proportion correct). In some embodiments, the improvement in learning and memory is evidenced by an improvement in visual recognition learning. In some embodiments, the improvement in learning and memory is assessed by the Cogstate One Card Learning Test. In some embodiments, the administration of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is likely to provide and/or provides an improvement of learning and memory accuracy of proportion (i.e., arcsine proportion correct) of at least about X% of the treated subject relative to a non-treated subject. The learning and memory accuracy improvement may be measured between the treated subjects relative to non-treated subjects. In some examples, a learning and memory accuracy testing may be provided by an arcsine accuracy of at least about 1.0, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09. or 1.10. In some examples, the learning and memory accuracy testing has a p value probability measurement from a treated subject group of less than about 0.9. In some examples, the visual attention may provide a Cohen’s d-value standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.15, or 0.19. In some examples, the visual attention testing may provide a “p-value” and “d-value” according to any combination of individual embodiments thereof, such as a p-value less than about 0.9 with a d-value effect size of greater than about 0.15.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of working memory of the treated subject relative to a non-treated subject. In some embodiments, where the method further comprises treatment, the administration of the 11β-HSDl inhibitor provides an improvement of working memory of the treated subject relative to a non-treated subject. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of working memory of the treated subject relative to a non- treated subject. In some embodiments, the improvement in working memory is assessed by the Cogstate One Back Working Memory Test, and is measured in number of errors. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of working memory number of errors of at least about X% of the treated subject relative to a non-treated subject. The working memory improvement may be measured between the treated subjects relative to non-treated subjects. In some examples, a working memory test may be provided by a loglO reaction time of less than about 2.90, 2.89, 2.88, 2.87, 2.86, 2.85, 2.84, 2.83, 2.82, 2.81, or 2.80. In some examples, a working memory test improvement may be at least about (loglO, milliseconds) 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20. In some examples, the working memory testing has a p value probability measurement from a treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01. In some examples, the working memory testing may provide a Cohen’s d-value standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some examples, the visual attention testing may provide a “p-value” and “d-value” according to any combination of individual embodiments thereof, such as a p-value less than about 0.01 with a d-value effect size of greater than about 0.8.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSD1 inhibitor is likely to provide an improvement of visual associate memory of the treated subject relative to a non-treated subject. In some embodiments, where the method further comprises treatment, the administration of the 11β- HSD1 inhibitor provides an improvement of visual associate memory of the treated subject relative to a non-treated subject. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of visual associate memory of the treated subject relative to a non-treated subject. In some embodiments, visual associate memory is assessed by the Cogstate Continuous Paired Associate Learning Test, and is measured in number of errors. The visual associate memory improvement may be measured between the treated subjects relative to non-treated subjects. In some examples, a visual associate memory testing may be provided by an error score out of 30 of less than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10. In some examples, a visual associate memory testing may be provided by an improvement in error score of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In some examples, the visual associate memory testing has a p value probability measurement from a treated subject group of less than about 0.5. In some examples, the visual associate memory testing may provide a Cohen’s d-value standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.2, 0.3, or 0.4. In some examples, the visual associate memory testing may provide a “p-value” and “d-value” according to any combination of individual embodiments thereof, such as a p-value less than about 0.5 with a d-value effect size of greater than about 0.4.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of cognitive function as assessed by the MMSE Test. In some embodiments, where the method further comprises treatment, the administration of the 11β-HSDl inhibitor provides an improvement of cognitive function as assessed by the MMSE Test.

In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of cognitive function as assessed by the MMSE Test. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement in MMSE test score of the treated subject relative to a non-treated subject. In some examples, an MMSE test score is less than about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10. In some examples, an MMSE test score is in a range provided by any two of the previously described values. In some examples, an MMSE test score improvement is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, or 3.0. In some examples, the MMSE testing has a p value probability measurement from a treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01. In some examples, the MMSE testing may provide a Cohen’s d-value standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some examples, the MMSE testing may provide a “p-value” and “d-value” according to any combination of individual embodiments thereof, such as a p-value less than about 0.1 with a d-value effect size of greater than about 0.6.

In some embodiments, the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of cognitive function as assessed by the CDR-SB test. In some embodiments, where the method further comprises treatment, the administration of the 11β-HSDl inhibitor provides an improvement of cognitive function as assessed by the CDR-SB test.

In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement of cognitive function as assessed by the CDR-SB test. In some embodiments, the administration of an 11β-HSDl inhibitor is likely to provide and/or provides an improvement in CDR-SB test score of the treated subject relative to a non-treated subject. In some examples, a CDR-SB test score is less than about 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5. In some examples, a CDR-SB test score is in a range provided by any two of the previously described values. In some examples, a CDR-SB test score improvement is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0. In some examples, a CDR-SB test score improvement is in a range between about 0.1 and about 2.0, about 0.1 and about 1.0, about 0.2 and about 1.0, about 0.3 and about 1.0, about 0.4 and about 1.0, about 0.5 and about 1.0, about 0.5 and about 0.9, or about 0.6 and about 0.9. In some examples, a CDR-SB test score improvement is an improvement relative to the CDR-SB test score of the subject prior to the subject receiving treatment with the 11β-HSDl inhibitor, wherein the improvement is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1, or in a range between about 0.1 and about 2.0, about 0.1 and about 1.0, about 0.2 and about 1.0, about 0.3 and about 1.0, about 0.4 and about 1.0, about 0.5 and about 1.0, about 0.5 and about 0.9, or about 0.6 and about 0.9. Thus, in some embodiments, the baseline level of the tau protein being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 1 1 p-HSDl inhibitor is likely to provide a delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability and/or function, of the treated subject relative to a non-treated subject assessed according to CDR-SB, wherein the CDR-SB test score improvement relative to a non-treated subject is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0, or in a range between about 0.1 and 2.0, 0.1 and 1.0, 0.2 and 1.0, 0.3 and 1.0, 0.4 and 1.0, 0.5 and 1.0, 0.5 and 0.9, and 0.6 and 0.9.

In some examples, a CDR-SB test score improvement is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1, or in a range between about 0.1 and about 2.0, about 0.1 and about 1.0, about 0.2 and about 1.0, about 0.3 and about 1.0, about 0.4 and about 1.0, about 0.5 and about 1.0, about 0.5 and about 0.9, or about 0.6 and about 0.9, and wherein the baseline level of the tau protein in the human subject is equal to or greater than 10.2 about pg/mL.

In some examples, a CDR-SB test score improvement is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1, or in a range between about 0.1 and about 2.0, about 0.1 and about 1.0, about 0.2 and about 1.0, about 0.3 and about 1.0, about 0.4 and about 1.0, about 0.5 and about 1.0, about 0.5 and about 0.9, or about 0.6 and about 0.9, and wherein the baseline level of the tau protein in the human subject is equal to or greater than 6.74 about pg/mL.

In some examples, a CDR-SB test score improvement is an improvement relative to the CDR-SB test score of the subject prior to the subject receiving treatment with the 11β-HSDl inhibitor, wherein the improvement at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1, or in a range between about 0.1 and about 2.0, about 0.1 and about 1.0, about 0.2 and about 1.0, about 0.3 and about 1.0, about 0.4 and about 1.0, about 0.5 and about 1.0, about 0.5 and about 0.9, or about 0.6 and about 0.9, and wherein the baseline level of the tau protein in the human subject is equal to or greater than 10.2 about pg/mL. In one example, the improvement is at least about 0.1. In one example, the improvement is at least about 0.3.

In some examples, a CDR-SB test score improvement is an improvement relative to the CDR-SB test score of the subject prior to the subject receiving treatment with the 11β-HSDl inhibitor, wherein the improvement is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1, or in a range between about 0.1 and about 2.0, about 0.1 and about 1.0, about 0.2 and about 1.0, about 0.3 and about 1.0, about 0.4 and about 1.0, about 0.5 and about 1.0, about 0.5 and about 0.9, or about 0.6 and about 0.9, and wherein the baseline level of the tau protein in the human subject is equal to or greater than 6.74 about pg/mL.

In some examples, the CDR-SB testing has a p value probability measurement from a treated subject group of less than about 0.5, 0.4, 0.3, 0.2, 0.1, or 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01. In some examples, the CDR-SB testing may provide a Cohen’s d- value standardised difference between two means (i.e. treated and untreated subject) of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8. In some examples, the CDR-SB testing may provide a “p-value” and “d-value” according to any combination of individual embodiments thereof, such as a p-value less than about 0.1 with a d-value effect size of greater than about 0.6. lip-HSDl Inhibitors

The present disclosure is predicated in part on the surprising discovery that plasma levels of phosphorylated tau protein can be used to select subjects more likely to respond to treatment with an 11β-HSDl inhibitor. Treatment with an 11β-HSDl inhibitor can include improving cognitive functioning impaired in subjects suffering from neurodegenerative diseases such as Alzheimer’s disease (AD).

An 11β-HSDl inhibitor may be selected from one or more of the following: ABT384, AZD4017, ABT305, INCB-13739, BVT.3498, BVT 116429, bezafibrate; CRx-401 , diflunisal; BMS-823778; UE2343; and carbenoxolone. Various examples of 11β-HSDl inhibitors are described in WO2019/186171, which is incorporated by reference thereto.

An 11β-HSDl inhibitor may be selected from a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

As used herein, a compound of Formula I has the following chemical structure:

Formula I; wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -CN, -CF3, -OR³, -SR³, - NR³R⁴, -COR³, -CO2R³, -CONR³R⁴, -NR³COR⁴, -SO2R³, -SO₂NR³R⁴, and -NR³SO₂R⁴.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is halogen. In some embodiments, R¹ is chlorine. In some embodiments, R¹ is fluorine. In some embodiments, R¹ is bromine. In some embodiments, R¹ is iodine. In some embodiments, R¹ is C1-6alkyl. In some embodiments, R¹ is -O-C1-6alkyl. In some embodiments, R¹ is C1-6haloalkyl. In some embodiments, R¹ is -O-C1-6haloalkyl. In some embodiments, R¹ is C2-6alkenyl. In some embodiments, R¹ is C2-6alkynyl. In some embodiments, R¹ is 3-10-membered carbocyclyl. In some embodiments, R¹ is a 6-membered carbocyclyl. In some embodiments, R¹ is a 5- membered carbocyclyl. In some embodiments, R¹ is 3-10-membered heterocyclyl. In some embodiments, R¹ is a 6-membered heterocyclyl. In some embodiments, R¹ is a 5-membered heterocyclyl. In some embodiments, R¹ is -CN. In some embodiments, R¹ is -CF3. In some embodiments, R¹ is -OR³. In some embodiments, R¹ is -SR³. In some embodiments, R¹ is - NR³R⁴. In some embodiments, R¹ is -COR³. In some embodiments, R¹ is -CO2R³. In some embodiments, R¹ is -CONR³R⁴. In some embodiments, R¹ is -NR³COR⁴. In some embodiments, R¹ is -SO2R³. In some embodiments, R¹ is -SO2NR³R⁴. In some embodiments, R¹ is -NR³SO₂R⁴.

In some embodiments, R² is hydrogen. In some embodiments, R² is halogen. In some embodiments, R² is chlorine. In some embodiments, R² is fluorine. In some embodiments, R² is bromine. In some embodiments, R² is iodine. In some embodiments, R² is C1-6alkyl. In some embodiments, R² is -O-C1-6alkyl. In some embodiments, R² is C1-6haloalkyl. In some embodiments, R² is -O-C1-6haloalkyl. In some embodiments, R² is C2-6alkcnyl. In some embodiments, R² is C2-6alkynyl. In some embodiments, R² is 3-10-membered carbocyclyl. In some embodiments, R² is a 6-membered carbocyclyl. In some embodiments, R² is a 5- membered carbocyclyl. In some embodiments, R² is 3-10-membered heterocyclyl. In some embodiments, R² is a 6-membered heterocyclyl. In some embodiments, R² is a 5-membered heterocyclyl. In some embodiments, R² is -CN. In some embodiments, R² is -CF3. In some embodiments, R² is -OR³. In some embodiments, R² is -SR³. In some embodiments, R² is - NR³R⁴. In some embodiments, R² is -COR³. In some embodiments, R² is -CO2R³. In some embodiments, R² is -CONR³R⁴. In some embodiments, R² is -NR³COR⁴. In some embodiments, R² is -SO2R³. In some embodiments, R² is -SO2NR³R⁴. In some embodiments, R² is -NR³SO₂R⁴.

If present, each 3-10-membered carbocyclyl and 3-10-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkcnyl, C2- 6alkynyl, -CN, -CF₃, -OR⁵, -SR⁵, -NR⁵R⁶, -COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, - SO2NR⁵R⁶, and -NR⁵SO₂R⁶

In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more C1-6alkyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -O-C1-6alkyl substituents. In some embodiments, the 3-10- membered carbocyclyl is substituted with one or more C1-6haloalkyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -O-C1-6haloalkyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more C2-6alkenyl substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more C2-6alkynyl substituents. In some embodiments, the 3-10- membered carbocyclyl is substituted with one or more -CN substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -CF3 substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -OR⁵ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -SR⁵ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -COR⁵ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10- membered carbocyclyl is substituted with one or more -CO2R⁵ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -CONR⁵R⁶ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -NR⁵COR⁶ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -SO2R⁵ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -SChNR⁵R⁶ substituents. In some embodiments, the 3-10-membered carbocyclyl is substituted with one or more -NR⁵SO2R⁶ substituents.

In some embodiments, R¹ is a 6-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1- 6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -CF3, -OR⁵, -SR⁵, - NR⁵R⁶, -COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, -SO₂NR⁵R⁶, and -NR⁵SO₂R⁶. In some embodiments, R¹ is a 5-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-C1-6 ialoalkyl, C₂-6alkenyl, C₂-6alkynyl, -CN, -CF3, -OR⁵, -SR⁵, -NR⁵R⁶, - COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, -SO₂NR⁵R⁶, and -NR⁵SO₂R⁶.

In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more C1-6alkyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -O-C1-6alkyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more C1-6haloalkyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -O-Ci- ehaloalkyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more C2-6alkenyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more C2-6alkynyl substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -CN substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -CF3 substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -OR⁵ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -SR⁵ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -COR⁵ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more halogen substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -CO2R⁵ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -CONR⁵R⁶ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -NR⁵COR⁶ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -SO2R⁵ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -SO2NR⁵R⁶ substituents. In some embodiments, the 3-10-membered heterocyclyl is substituted with one or more -NR⁵SO2R⁶ substituents.

In some embodiments, R² is a 6-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1- 6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -CF3, -OR⁵, -SR⁵, - NR⁵R⁶, -COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, -SO₂NR⁵R⁶, and -NR⁵SO₂R⁶. In some embodiments, R² is a 5-membered carbocyclyl and is substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -CF3, -OR⁵, -SR⁵, -NR⁵R⁶, - COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, -SO₂NR⁵R⁶, and -NR⁵SO₂R⁶.

If present, each R³ and R⁴ are independently selected from the group consisting of hydrogen, C1-6alkyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl.

In some embodiments, R³ is hydrogen. In some embodiments, R³ is C1-6alkyl. In some embodiments, R³ is 3-7-membered carbocyclyl. In some embodiments, R³ is 3-7-membered carbocyclyl. In some embodiments, R³ is a 5-membered carbocyclyl. In some embodiments R³ is a 6-membered carbocyclyl.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is C1-6alkyl. In some embodiments, R⁴ is 3-7-membered carbocyclyl. In some embodiments, R⁴ is 3-7-membered carbocyclyl. In some embodiments, R⁴ is a 5-membered carbocyclyl. In some embodiments R⁴ is a 6-membered carbocyclyl.

If present, each R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C1-6alkyl.

In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is C1-6alkyl.

In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is C1-6alkyl.

In some embodiments, R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -OH, -CN, and -NH2. If present, each 3-10-membered carbocyclyl and 3-10- membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl.

In some embodiments, R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, 6-membered carbocyclyl, 6-membered heterocyclyl, -OH, - CN, and -NH2. If present, each 6-membered carbocyclyl and 6-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NHz, and C1-6alkyl.

In some embodiments, R¹ is selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl, and R² is independently selected from the group consisting of:

In some embodiments, R¹ is hydrogen and R² is independently selected from the group consisting of:

In some embodiments, R¹ is halogen and R² is independentinvly selected from the group consisting of:

In some embodiments, R¹ is -OH and R² is independently selected from the group consisting of:

In some embodiments, R¹ is -CN and R² is independently selected from the group consisting of:

In some embodiments, R¹ is -CF3 and R² is independently selected from the group consisting of:

In some embodiments, R¹ is -NH2 and R² is independently selected from the group consisting of:

and

In some embodiments, R¹ is C1-6alkyl and R² is independently selected from the group consisting of:

In some embodiments, R¹ is chlorine and R² is independently selected from the group onsisting of:

and In some embodiments, R¹ is bromine and R² is independently selected from the group consisting of:

and

In some embodiments, R¹ is fluorine and R² is independently selected from the group consisting of:

In some embodiments, R¹ is iodine and R² is independently selected from the group consisting of:

In some embodiments, R² is selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl, and R¹ is independently selected from the group consisting of:

In some embodiments, R² is hydrogen and R¹ is independently selected from the group consisting of:

In some embodiments, R² is halogen and R¹ is independently selected from the group consisting of:

In some embodiments, R² is -OH and R¹ is independently selected from the group consisting of:

and

In some embodiments, R² is -CN and R¹ is independently selected from the group consisting of:

In some embodiments, R² is -CF3 and R¹ is independently selected from the group consisting of:

and

In some embodiments, R² is -NH2 and R¹ is independently selected from the group consisting of:

In some embodiments, R² is C1-6alkyl and R¹ is independently selected from the group consisting of:

and In some embodiments, R² is chlorine and R¹ is independently selected from the group consisting of:

and

In some embodiments, R² is bromine and R¹ is independently selected from the group consisting of:

and In some embodiments, R² is fluorine and R¹ is independently selected from the group consisting of:

and

In some embodiments, R² is iodine and R¹ is independently selected from the group consisting of:

In some embodiments, R¹ and R² are each independently selected from the group consisting of:

and

In some embodiments, the compound of Formula I is selected from the group consisting of:

In some embodiments, the compound of Formula I is:

In some embodiments, the compound of Formula I is:

In some embodiments, the compound of Formula I is:

In some embodiments, the compound of Formula I is:

In some embodiments, the compound of Formula I is:

In some embodiments, the compound of Formula I is:

In some embodiments, the compound of Formula I is:

In some embodiments, the compound of Formula I is:

As would be understood by the person skilled in the art, the compound of Formula I includes any stereoisomers of the depicted structure. That is, the compound of Formula I includes a racemic mixture.

As used herein, a compound of Formula la has the following chemical structure:

Formula la

The definitions of R¹ and R² are the same as those provided for a compound of Formula I. That is, the difference between a compound of Formula I and a compound of Formula la is that the stereochemistry in a compound of Formula la has been resolved.

In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, has a particular stereochemistry as depicted in the following chemical structure:

Formula la.

The compound of Formula la, when having such particular stereochemistry, is also referred to as “UE2343” or “Xanamem”, and has CAS No.: 1346013-80-6. The chemical name (i.e., IUPAC name) of Formula la is (5-(lH-Pyrazol-4-yl)thiophen-3-yl)(3-hydroxy-3- (pyrimidin-2-yl)-8-azabicyclo[3.2.1] octan-8-yl)methanone.

A compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be prepared by any suitable method as would be understood by the person skilled in the art. A compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, may be prepared in accordance with the procedure described in WO2011/135276, which is herein incorporated by reference thereto.

Salts

It may be convenient or desirable to prepare, purify and/or handle a corresponding salt of the compound, such as, for example, a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable organic or inorganic salts. Examples of pharmaceutically acceptable salts are discussed in Berge el al., 1977, “Pharmaceutically Acceptable Salts,” J. Pharm. Sci., vol. 66, pl-19.

For example, if the compound is anionic, or has a functional group that may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earth cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4⁺) and substituted ammonium ions (e.g., NH3R⁺, NH2R2⁺, NHR3⁺, NRA). Examples of suitable substituted ammonium ions include, but are not limited to, those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4⁺.

If the compound is cationic, or has a functional group that may be cationic (e.g., -NHz may be -NH3⁺), then a salt may be formed with a suitable anion. Examples of suitable inorganic cations include, but are not limited to, those derived from the inorganic acids including hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the organic acids including 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphor sulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxy maleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicyclic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from polymeric acids including tannic acid and carboxy methyl cellulose.

A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilises the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterion. It will also be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport. Unless otherwise specified herein, reference to a particular compound also includes salts thereof.

Solvates and hydrates

It may be convenient or desirable to prepare, purify and/or handle a corresponding solvate of the compound. Those skilled in the art of organic chemistry and/or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallised. Such complexes are referred to as “solvates”, and as used herein, the term “solvate” refers to such a complex of solute (e.g., a compound, salt of a compound) and solvent. Examples of solvents that may form pharmaceutically acceptable solvates include, but are not limited to, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine. If the solvate is water, the solvate may be conventionally referred to as a “hydrate”. In some embodiments, the pharmaceutically acceptable solvate is a pharmaceutically acceptable hydrate. The hydrate may be, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified herein, reference to a particular compound also includes solvates thereof.

Prodrugs

It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term “prodrug”, as used herein, pertains to compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active that the desired active compound, but may provide advantageous handling, administration, or metabolic properties.

Also, as would be understood by a person skilled in the art of organic chemistry and/or medicinal chemistry, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Dosage Regimen

It will be appreciated that the dosage regimens and compositions as described herein may apply to any of the embodiments or examples of the methods as described herein.

As used herein, “therapeutically effective amount” refers to an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) being administered in an amount sufficient to improve cognitive functioning and/or alleviate or prevent to some extent one or more of the symptoms of the disorder or condition being treated, typically without undue adverse side effects or to achieve a desired pharmacological effect or therapeutic improvement with a reduced side effect profile. The results can include the reduction and/or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. Therapeutically effective amounts may, for example, be determined by routine experimentation, including but not limited to a dose escalation clinical trial. The phrase “therapeutically effective amount” includes, for example, a prophylactically effective amount. In some embodiments, a prophylactically effective amount is an amount sufficient to prevent further cognitive impairment or decline. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound and any of age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. An appropriate an effective amount” or “a therapeutically effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

The amount of an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) that will be effective in the treatment and/or prevention of a particular function, disorder or condition disclosed herein will depend on the nature of the function, disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. Such techniques are known to the person skilled in the art.

In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor administered in an amount so as to deliver a total daily dosage (in mg) of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150, or 200. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor administered in an amount so as to deliver a total daily dosage (in mg) of less than 200, 150, 100, 75, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor administered in an amount so as to deliver a total daily dosage (in mg) in a range provided by any of the previously described upper and/or lower amounts, for example, a total daily dosage of between about 1 and 100 mg, about 5 and 75 mg, about 10 and 50 mg, about 15 and 45 mg, or about 20 and 40 mg.

In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor administered in an amount, in a particular form, or according to a dosage regime as described herein, and the method comprises treating the human subject with the 11β-HSDl inhibitor, wherein the 11β- HSD1 inhibitor is administered in that amount, in that particular form, or according to that dosage regime.

The precise dose to be administered to the subject will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject’s circumstances. For example, suitable dosage ranges for oral administration, are generally from about 0.001 milligram to 1000 milligrams of an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) per kilogram body weight.

In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered in an amount so as to deliver a total daily dosage (in mg) of at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 100, 150, or 200. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered in an amount so as to deliver a total daily dosage (in mg) of less than about 200, 150, 100, 75, 60, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1. The total daily dosage may be provided in a range between at any two of these upper and/or lower amounts. For example, a total daily dosage may be provided in an amount of between about 1 and 100 mg, about 5 and 75 mg, about 10 and 50 mg, about 15 and 45 mg, or about 20 and 40 mg.

In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered once daily, twice daily, three times daily, or four times daily. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered once daily. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSD1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered to the subject according to a dosage regimen in which the 1 l^-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered twice daily. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered to the subject according to a dosage regimen in which the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered three times daily. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered to the subject according to a dosage regimen in which the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered four times daily. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSD1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered to the subject according to a dosage regimen in which the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered multiple times daily. In some examples, the 1 lp- HSD1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered as a once daily dose of between about 10 mg and 30 mg, for example at about 20 mg. In other examples, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered as a twice daily dose of between about 5 mg and 20 mg per dose, for example at about 10 mg per dose. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered as a three-times daily dose of between about 5 mg and 15 mg per dose, for example at about 10 mg per dose.

In some embodiments, a therapeutically effective amount of the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject at a predetermined frequency. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject according to a dosage regimen in which the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered once daily, twice daily, three times daily, or four times daily. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject according to a dosage regimen in which a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered once daily. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject according to a dosage regimen in which the 11β-HSD 1 inhibitor (e .g . a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered twice daily. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject according to a dosage regimen in which the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered three times daily. In some embodiments, the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject according to a dosage regimen in which the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered four times daily. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject according to a dosage regimen in which the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered multiple times daily. In some examples, the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered as a once daily dose of between about 10 mg and 30 mg, for example at about 20 mg. In other examples, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered as a twice daily dose of between about 5 mg and 20 mg per dose, for example at about 10 mg per dose. In some embodiments, the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered as a three-times daily dose of between about 5 mg and 15 mg per dose, for example at about 10 mg per dose.

In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSD 1 inhibitor administered in an amount so as to deliver a total daily dosage of from about 1 to 70 mg of Formula I or from about 5 to 40 mg of Formula I; and if the method comprises treating the human subject, further comprises administering the 11β-HSD 1 inhibitor in an amount so as to deliver a total daily dosage of from about 1 to 70 mg of Formula I or from about 5 to 40 mg of Formula I. Further, in some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor administered as a single once-daily dosage or a twice-daily dosage; and if the method comprises treating the human subject, comprises administering the 11β-HSD 1 inhibitor as a single once-daily dosage or a twice-daily dosage. Further, in some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSD 1 inhibitor administered as a twice-daily dosage of 10 mg per dosage; and if the method comprises treating the human subject, further comprises administering the 11β-HSD 1 inhibitor as a twice-daily dosage of 10 mg per dosage.

In some embodiments, a therapeutically effective amount of the 11β-HSD 1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject at a predetermined frequency and/or duration. For example, administration according to any embodiments (e.g. frequency) as described herein may be for a duration of about, or at least about, 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 2 years, or 5 years. Administration of the therapeutically effective amount of the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) may be ongoing so long as a therapeutic effect is received by the subject.

As used herein, the term “administer” and “administering” are used to mean introducing the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) into a subject. When administration is for the purpose of treatment, the compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is provided at, or after the onset of, a symptom of cognitive decline. The therapeutic administration of this substance serves to attenuate any symptom, or prevent additional symptoms from arising. When administration is for the purposes of preventing or reducing the likelihood cognitive decline, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is provided in advance of any visible or detectable symptom. The prophylactic administration of t the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) serves to attenuate subsequently arising symptoms or prevent or reduce the likelihood of the symptoms from arising altogether.

In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered by any suitable route. Examples include, but are not limited to, oral, topical, transdermal, intranasal, vaginal, rectal, intraarterial, intramuscular, intraosseous, intraperitoneal, epidural and intrathecal. In some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) administered orally or orally with food.

An 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) may be administered by any suitable route. Examples include, but are not limited to, oral, topical, transdermal, intranasal, vaginal, rectal, intraarterial, intramuscular, intraosseous, intraperitoneal, epidural and intrathecal. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered orally. Accordingly, in some embodiments, the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease, is indicative that the subject is likely to respond to treatment with the 11β-HSD1 inhibitor administered orally or administered orally with food; and if the method comprises treating the human subject, further comprises administering the 11β-HSDl inhibitor orally or orally with food.

An 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) may be administered to the subject with respect to the subj ect’ s fasted state, as would be understood by the person skilled in the art. For example, the subject may be administered the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) before, with, or after a meal. In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject before a meal (i.e., the subject being in a fasted state). In some embodiments, the 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) is administered to the subject with a meal. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered at a certain interval (i.e., 30 mins, 1 hour, 2 hours, 3 hours, etc.) following a meal.

Pharmaceutical Compositions

Compositions suitable for use in the methods and uses described herein comprise an 11β-HSDl inhibitor, or a pharmaceutically acceptable salt, solvate or prodrug thereof. In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, is presented as a pharmaceutical composition.

In one example, a pharmaceutical compositions can comprise an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) with one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilisers, or the like. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. Generally, suitable pharmaceutically acceptable carriers are known in the art and are selected based on the end use application. The pharmaceutically acceptable carrier may act as a diluent, dispersant or carrier for the active agents and other optional components of the composition. The pharmaceutically acceptable carrier may also contain materials commonly used in pharmaceutically products and can be in a wide variety of forms. For example, the carrier may be water, liquid or solid emollients, silicone oils, emulsifiers, surfactants, solvents, humectants, thickeners, powders, propellants and the like. In some embodiments, the composition is a pharmaceutical composition, and wherein the composition comprises a pharmaceutically acceptable excipient.

The composition may for example contain a solvent, such as water (e.g. water for injection) or a pharmaceutically acceptable organic solvent.

The compositions may further include diluents, buffers, citrate, trehalose, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants), inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc and other such suitable cations).

The compositions of the present disclosure may also include polymeric excipients/additives or carriers, e.g., polyvinylpyrrolidones, derivatised celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch (HES), dextrates (e.g., cyclodextrins, such as 2- hydroxypropyl-P-cyclodextrin and sulfobutylether-P-cyclodextrin), polyethylene glycols, and pectin.

Other pharmaceutical carriers, excipients, optional ingredients and/or additives suitable for use in the compositions according to the present disclosure are listed in “Remington: The Science & Practice of Pharmacy”, 19. sup. th ed., Williams & Williams, (1995), and in the “Physician’s Desk Reference”, 52. sup. nd ed., Medical Economics, Montvale, N.J. (1998), and in “Handbook of Pharmaceutical Excipients”, Third Ed., Ed. A. H. Kibbe, Pharmaceutical Press, 2000.

An 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) may be formulated in compositions including those suitable for inhalation to the lung, by aerosol, parenteral (including intraperitoneal, intravenous, subcutaneous, or intramuscular injection) or oral administration.

The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) into association with a carrier that constitutes one or more accessory ingredients.

In general, the compositions are prepared by bringing an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) into association with a liquid carrier to form a solution or a suspension, or alternatively, by bringing a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof into association with formulation components suitable for forming a solid, optionally a particulate product, and then, if warranted, shaping the product into a desired delivery form.

In some embodiments, the composition is formulated for oral delivery. Compositions for oral delivery may, for example, be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions may contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in a tablet or pill form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade. The oral compositions described herein may contain from about 1% to about 95% of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof by weight, and the oral compositions may be dosed 1, 2, 3, 4, 5 or more times daily. The oral compositions described herein may contain a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof by weight % in at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, or 90. The oral compositions described herein may contain a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof by weight % in less than about 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5. The oral compositions described herein may contain a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof by weight % in a range provided by any two of these upper and/or lower values, for example between about 5 and 20 wt %.

In some embodiments, the composition is formulated for parenteral delivery. For example, in one embodiment, the composition may be a sterile, lyophilized, crystalized or amorphous composition that is suitable for reconstitution in an aqueous vehicle prior to injection.

In one embodiment, a composition suitable for parenteral administration conveniently comprises a sterile aqueous preparation of a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which may for example be formulated to be isotonic with the blood of the recipient.

Pharmaceutical compositions are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of an 1 lp- HSD1 inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof). The desired formulation may be placed in a small chamber and nebulized. Nebulization may be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof).

As discussed below, an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) of the present disclosure may for example be administered in combination with one or more additional pharmaceutically active agents. Thus, in some embodiments, the composition comprises a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof as defined herein, or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, and one or more additional pharmaceutically active agents.

Generally, the composition comprises an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) in an amount that is therapeutically effective amount. In some embodiments, the therapeutically effective amount is provided by a single dose. In some embodiments, the therapeutically effective amount is provided by one or more doses administered as part of a course of treatment, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or greater than 27 doses.

The person skilled in the art would understand that the amount of an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) present in the composition will vary depending on the other ingredients present in the composition, the desired effect and the like. In some embodiments, the composition comprises an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) in a concentration between about 0.001 to 1000 mg/mL, 0.01 to 500 mg/mL, 0.1 to 50 mg/mL. In some embodiments, the composition comprises an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) in a concentration between about 1 to 99 wt%, 1 to 90wt%, 1 to 85 wt%, 1 to 80 wt%, 1 to 75 wt%, 1 to 70 wt%, 1 to 65 wt%, 1 to 60 wt%, 1 to 55 wt%, 1 to 50 wt%, 1 to 45 wt%, 1 to 40 wt%, 1 to 35 wt%, 1 to 30 wt%, 5 to 99 wt%, 10 to 99 wt%, 15 to 99 wt%, 20 to 99 wt%, 25 to 99 wt%, 30 to 99 wt%, 35 to 99 wt%, 40 to 99 wt%, 45 to 99 wt%, 50 to 99 wt%, 54 to 99 wt%, 60 to 99 wt%, 65 to 99 wt%,

70 to 99 wt%, 75 to 99 wt%, 80 to 99 wt%, 85 to 99 wt%, 90 to 99 wt%, 5 to 90 wt%, 20 to 80 wt%, 30 to 70 wt%, or 40 to 60 wt%.

In some embodiments, an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) may be administered in combination with a further therapeutic agent. In some embodiments, the methods and uses described herein also relate to co-administering one or more substances in addition to a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof to the subject, the term “co-administer” indicates that each of at least two compounds are administered during a time frame wherein the respective periods of biological activity or effects overlap. Thus, the term includes sequential as well as coextensive administration of compounds. Similar to administering compounds, co-administration of more than one substance can be for therapeutic and/or prophylactic purposes. If more than one substance or compound is co-administered, the routes of administration of the two or more substances need not be the same. The scope of the methods and uses described herein are not limited by the identity of the substance or substances which may be co-administered with a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof. For example, compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof may be co-administered with fluids or other substances that are capable of alleviating, attenuating, preventing or removing symptoms in a subject suffering from, exhibiting the symptoms of, or at risk of suffering from cognitive decline. Types of fluid that can be co-administered with a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof should be specific to the circumstances surrounding the particular subject that is suffering from, exhibiting the symptoms of, or at risk of suffering from a bacterial infection. For example, fluids that may be co-administered with a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof include but are not limited to, electrolytes and/or water, salt solutions, such as sodium chloride and sodium bicarbonate, as well as whole blood, plasma, serum, serum albumin and colloid solutions.

The composition may be a food or beverage, or provided into a food or beverage. The composition may be a veterinary product, such as a dog or cat food product. The composition may be a feed additive, a supplement, or a medical food. In some embodiments, an 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) may be incorporated into food products and beverages. An 11β-HSDl inhibitor (e.g. a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof) may be impregnated, mixed, emulsified, sprayed or coated onto carriers such as cellulose, methylcellulose, dextrose, cyclodextrose, cyclodextrin, maltitol, and fibre. Delivery may also be enhanced with a range of surfactants, lipids, complexes, solvents and cosolvent pharmaceutical delivery systems known in the pharmaceutical art to improve bioavailability, absorption and efficacy. As used herein, the term “food” or “food product” includes any edible product for human or non-human consumption, such as but not limited to supplements, snacks (sweet and savory), cocoa-containing foods, flavours, beverages, dietary supplements and formulations including supplements used in animal health and nutrition. Additional ingredients desired in the resulting food product may be added at any point in the process. Knowledge-Based Systems

Knowledge-based computer software and hardware for implementing an algorithm of the disclosure also form part of the present disclosure. Such computer software and/or hardware are useful for performing a method of the disclosure. Thus, the present disclosure also provides software or hardware programmed to implement an algorithm that processes data related to tau protein levels obtained by performing the method of the disclosure via an univariable or multivariable analysis to provide a disease/condition index value and provide or permit a determination that a subject suffering, or suspected of suffering from, a neurodegenerative disease will respond to treatment with an 11β-HSDl inhibitor.

In one example, a method of the disclosure may be used in existing knowledge-based architecture or platforms associated with pathology services. For example, results from a method described herein are transmitted via a communications network (e.g. the internet) to a processing system in which an algorithm is stored and used to generate a predicted posterior probability value, which translates to the index of probability of responsiveness to treatment with an 11β-HSDl inhibitor which is then forwarded to an end user in the form of a predictive report.

The method of the disclosure may, therefore, be in the form of a kit or computer-based system which comprises the reagents necessary to detect the concentration or level of a tau protein in a biological sample and the computer hardware and/or software to facilitate determination and transmission of reports to a clinician.

The methods and assays of the present disclosure permits integration into existing or newly developed pathology architecture or platform systems. For example, the present disclosure contemplates a method of allowing a user to determine likely responsiveness of a subject to treatment with an 11β-HSDl inhibitor, including:

(a) receiving data in the form of levels of a tau protein for a biological test sample;

(b) processing the subject data via univariate and/or multivariate analysis to provide a disease index value;

(c) determining the status of the subject in accordance with the results of the disease index value in comparison with predetermined values; and

(d) transferring an indication of the status of the subject to the user via the communications network reference to the multivariate analysis includes an algorithm which performs the multivariate analysis function.

In one example, the method additionally includes:

(a) having the user determine the data using a remote end station; and (b) transferring the data from the end station to the base station via the communications network.

The base station can include first and second processing systems, in which case the method can include:

(a) transferring the data to the first processing system;

(b) transferring the data to the second processing system; andc) causing the first processing system to perform the univariate or multivariate analysis function to generate the disease index value.

The method may also include:

(a) transferring the results of the univariate or multivariate analysis function to the first processing system; and

(b) causing the first processing system to determine the status of the subject.

In this case, the method also includes at least one of:

(a) transferring the data between the communications network and the first processing system through a first firewall; and

(b) transferring the data between the first and the second processing systems through a second firewall.

The second processing system may be coupled to a database adapted to store predetermined data and/or the univariate or multivariate analysis function, the method include:

(a) querying the database to obtain at least selected predetermined data or access to the multivariate analysis function from the database; and

(b) comparing the selected predetermined data to the subject data or generating a predicted probability index.

The second processing system can be coupled to a database, the method including storing the data in the database.

The method can also include having the user determine the data using a secure array, the secure array of elements capable of determining the level of the tau protein in the subject sample and having a number of features each located at respective position(s) on the respective code. In this case, the method typically includes causing the base station to:

(a) determine the code from the data; (b) determine a layout indicating the position of each feature on the array; and(c) determine the parameter values in accordance with the determined layout, and the data.

The method can also include causing the base station to:

(a) determine payment information, the payment information representing the provision of payment by the user; and

(b) perform the comparison in response to the determination of the payment information.

The present disclosure also provides a base station for determining the status of a subject with respect to likely responsiveness to therapy with an 11β-HSDl inhibitor, the base station including:

(a) a store method;

(b) a processing system, the processing system being adapted to:

(i) receive subject data from the user via a communications network; and

(ii) determining the status of the subject in accordance with the results of the algorithmic function including the comparison; and

(c) output an indication of the status of the subject to the user via the communications network.

The processing system can be adapted to receive data from a remote end station adapted to determine the data.

The processing system may include:

(a) a first processing system adapted to:

(i) receive the data; and

(ii) determine the status of the subject in accordance with the results of the univariate or multivariate analysis function including comparing the data; and

(b) a second processing system adapted to:

(i) receive the data from the processing system;

(ii) perform the univariate or multivariate analysis function including the comparison; and

(iii) transfer the results to the first processing system. The base station typically includes:

(a) a first firewall for coupling the first processing system to the communications network; and

(b) a second firewall for coupling the first and the second processing systems. The processing system can be coupled to a database, the processing system being adapted to store the data in the database.

The present disclosure is now described further in the following non-limiting examples.

EXAMPLE EMBODIMENTS

Example Embodiment 1. A method of identifying or selecting a subject for receiving treatment with an 11β-HSDl inhibitor for responsiveness to the treatment, the method comprising determining the baseline level of a tau protein in the subject.

Example Embodiment 2. A method of determining an increased probability of responsiveness to a treatment of a subject with an 11β-HSDl inhibitor, the method comprising determining the baseline level of a tau protein in the subject.

Example Embodiment 3. A method of treating a subject with an 11β-HSDl inhibitor, the method comprising administering an 11β-HSDl inhibitor to the subject, wherein the subject has previously been identified or selected for receiving treatment with an 11β-HSDl inhibitor for responsiveness to the treatment by determining the baseline level of a tau protein in the subject.

Example Embodiment 4. The method of any one of Example Embodiments 1 to 3, wherein the method comprises identifying and selecting a subject for receiving treatment with the 11β-HSDl inhibitor for responsiveness to the treatment based on determining the baseline level of a tau protein in the subject, and administering the 11β-HSDl inhibitor to the subject.

Example Embodiment 5. The method of any one of Example Embodiments 1 to 4, wherein the treatment of the 11β-HSDl inhibitor provides an improvement of cognitive functioning in the treated subject relative to a non-treated subject, an improvement of cognitive impairment in the treated subject relative to a non-treated subject, and/or a prophylactic treatment for preventing cognitive decline in a subject predisposed to a disorder or disease associated with cognitive decline.

Example Embodiment 6. The method of any one of Example Embodiments 1 to 5, wherein the treatment is for a neurodegenerative disease selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, Alzheimer's disease (AD), Huntington's disease, multiple system atrophy, Frontal lobe dementia, vascular dementia, and prion diseases.

Example Embodiment 7. The method of any one of Example Embodiments 1 to 6, wherein the treatment with the 11β-HSDl inhibitor provides a delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability and/or function, of the treated subject relative to a non-treated subject using one or more testing criteria methods selected from Cogstate Neuropyschological Testing criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests, CDR-SB, MMSE, ADAS-Cog, CogState Cognition Test Battery, CANTAB test battery, and Amsterdam instrumental activities of daily living. Example Embodiment 8. The method of any one of Example Embodiments 1 to 7, wherein the subject has an MMSE score of less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10.

Example Embodiment 9. The method of any one of Example Embodiments 1 to 8, wherein the treatment is for Alzheimer's disease (AD), and wherein the subject has an MMSE score of less than 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10.

Example Embodiment 10. The method of any one of Example Embodiments 1 to 9, wherein the treatment of the 11β-HSDl inhibitor provides an improvement of a change in baseline in Executive Function and/or Episodic Memory.

Example Embodiment 11. The method of any one of Example Embodiments 1 to 10, wherein the baseline level of the tau protein (in pg/ml) is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

Example Embodiment 12. The method of any one of Example Embodiments 1 to 11, wherein the method comprises selecting a subject as being suitable for receiving treatment with an 11β-HSD1 inhibitor in order to increase the probability of responsiveness to the treatment by determining the baseline level of a tau protein in a sample obtained from the subject, wherein if a baseline level of the tau protein (in pg/ml) is at least 1 then the subject is selected for the treatment.

Example Embodiment 13. The method of any one of Example Embodiments 1 to 12, wherein the tau protein is a phosphorylated tau (pTau) protein.

Example Embodiment 14. The method of any one of Example Embodiments 1 to 13, wherein the tau protein is a phosphorylated tau (pTau) protein having any one or more phosphorylated serines of 46, 199, 202, 235, 262, 293, 324, 356, 396, 404, 422 and/or threonines 181, 50, 69, 111, 153, 175, 205, 212, 217, 231 of the Tau protein.

Example Embodiment 15. The method of any one of Example Embodiments 1 to 14, wherein the tau protein is pTau-181.

Example Embodiment 16. The method of any one of Example Embodiments 1 to 15, wherein the level of the tau protein is determined by imaging or sample analysis.

Example Embodiment 17. The method of Example Embodiment 16, wherein the imaging is PET imaging etc.

Example Embodiment 18. The method of Example Embodiment 16, wherein the sample is blood, blood plasma, or cerebrospinal fluid. Example Embodiment 19. The method of any one of Example Embodiments 1 to 18, wherein the 1 lp-HSDl inhibitor is selected from the group consisting of ABT384, AZD4017, ABT305, INCB- 13739, BVT.3498, BVT 116429, bezafibrate; CRx-401, difhinisal; BMS- 823778; UE2343; and carbenoxolone.

Example Embodiment 20. The method of any one of Example Embodiments 1 to 19, wherein the 11β-HSD1 inhibitor is selected from a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

Formula I; wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -CN, -CF3, -OR³, -SR³, - NR³R⁴, -COR³, -CO2R³, -CONR³R⁴, -NR³COR⁴, -SO2R³, -SO₂NR³R⁴, and -NR³SO₂R⁴; wherein R³ and R⁴ are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl; wherein each 3-10- membered carbocyclyl, 3-10-membered heterocyclyl, 3-7-membered carbocyclyl, and 3-7- membered heterocyclyl, is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-Ci- 6haloalkyl, C₂-6alkenyl, C₂-6alkynyl, -CN, -CF3, -OR⁵, -SR⁵, -NR⁵R⁶, -COR⁵, -CO2R⁵, - CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, -SO₂NR⁵R⁶, and -NR⁵SO₂R⁶; and wherein each R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C1-6alkyl.

Example Embodiment 21. The method of Example Embodiment 20, wherein the compound of Formula I is a compound of Formula la, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

Formula la; wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -CN, -CF3, -OR³, -SR³, - NR³R⁴, -COR³, -CO2R³, -CONR³R⁴, -NR³COR⁴, -SO2R³, -SO₂NR³R⁴, and -NR³SO₂R⁴; wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C1-6alkyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl; wherein each 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 3-7- membered carbocyclyl, and 3-7-membered heterocyclyl, is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, - O-C1-6alkyl, C1-6haloalky 1, -O-C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -CF3, -OR⁵, -SR⁵, -NR⁵R⁶, -COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, -SO₂NR⁵R⁶, and -NR⁵SO₂R⁶; and wherein each R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C1-6alkyl.

Example Embodiment 22. The method of Example Embodiment 20 or Example Embodiment 21, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -OH, -CN, and -NH2; and wherein if present, each 3-10-membered carbocyclyl and 3-10-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl.

Example Embodiment 23. The method of any one of Example Embodiments 20 to 22, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, 6-membered carbocyclyl, 6-membered heterocyclyl, -OH, -CN, and -NH2; and wherein if present, each 6-membered carbocyclyl and 6-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl.

Example Embodiment 24. The method of any one of Example Embodiments 20 to 23, wherein R¹ is selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl, and R² is independently selected from the group consisting of:

and

Example Embodiment 25. The method of any one of Example Embodiments 20 to 24, wherein the compound of Formula I is selected from the group consisting of:

Example Embodiment 26. The method of any one of Example Embodiments 20 to 25, wherein the compound of Formula I is:

Example Embodiment 27. The method of any one of Example Embodiments 20 to 26, wherein the compound of Formula I is:

Example Embodiment 28. The method of any one of Example Embodiments 1 to 27, wherein the 11β-HSDl inhibitor is administered in amount so as to deliver a total daily dosage of from about 1 to 70 mg of Formula I or from about 5 to 40 mg of Formula I.

Example Embodiment 29. The method of any one of Example Embodiments 1 to 28, wherein the 11β-HSDl inhibitor is administered as a single once-daily dosage or a twice-daily dosage.

Example Embodiment 30. The method of any one of Example Embodiments 1 to 29, wherein the 11β-HSDl inhibitor is administered as a twice-daily dosage of 10 mg per dosage.

Example Embodiment 31. The method of any one of Example Embodiments 1 to 30, wherein the 11β-HSDl inhibitor is administered orally or is administered orally with food.

EXAMPLES

General: Materials and Methods

Formulations comprising an 11β-HSD1 inhibitor were tested on human subjects to evaluate selection and treatment suitability for the subjects. The 11β-HSDl inhibitor selected was a compound of Formula 1 , as described herein, which was synthesized and characterized according to the procedure described in WO2011135276, which is herein incorporated by reference thereto. The compound of Formula 1 that was selected is also known as UE2343 or (5-(lH-pyrazol-4-yl)thiophen-3-yl)(3-hydroxy-3-(pyrimidin-2-yl)-8-azabicyclo[3.2.1]octan- 8-yl)methanone. Xanamem™ contains UE2343 as an active ingredient.

Example 1:

Clinical Study

A Phase II, Double-Blind, 12-Week, Randomised, Placebo-Controlled Study was conducted to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects with Mild Dementia due to Alzheimer’s Disease (AD).

Study Sites: Multicentre, up to 20 sites in Australia, United Kingdom and United States of America. Study Design: This is a Phase II, randomized, multi-centre, double-blind, placebo- controlled, proof-of-concept study to assess the safety, tolerability and efficacy of oral Xanamem™ QD in adult subjects with mild dementia due to AD.

At the Baseline visit (Week 0), eligible subjects will be randomised on a 1:1 ratio to receive either 10 mg Xanamem™ administered orally, QD (treatment group) or matching placebo (placebo group). Subjects returned to the study site for the Interim visits (Week 4 and Week 8), EOT (Week 12) and Follow-up (4 weeks post last dose of study drug) visits, at which study assessments were performed.

Subjects were tasked with taking the study drug at the same time each morning with meals (i.e. not in fasted condition) due to a higher bioavailability observed when taken in a fed state. Drug intake when fasted had no safety concern.

Further details of the study are provided below:

Objectives Primary Objective:

The primary objective of the study is to evaluate the extent to which Xanamem™ improves performance from Baseline to end of treatment (EOT) compared to placebo, as measured by changes in AD COMposite Scores (ADCOMs, composite data derived from Alzheimer's Disease Assessment Scales - Cognitive subscale version 14 [ADAS-Cog vl4], Clinical Dementia Rating Scale - Sum of Boxes [CDR-SOB], and MiniMental Status Examination [MMSE]) and ADAS-Cog vl4 as primary endpoints in subjects with mild dementia due to probable AD.

Secondary Obiectives:

Secondary objectives of this study are to assess the extent to which Xanamem™ improves performance from Baseline to EOT compared to placebo, as measured by changes to:

• Rey Auditory Verbal Learning Test(RAVLT)

. MMSE

• Neuropsychiatric Inventory (NPI)

• Neuropsychological Test Batteries (NTB) - Executive Domain

Methodology Randomised, double-blind, placebo -controlled Phase II proof-of-concept. Number of Planned that approximately 174 subjects will be enrolled to ensure that Subjects 156 subjects would complete the 12-week double-blind study period (78 subjects in each treatment group). A 10% drop-out rate is expected.

Diagnosis and 1. Males and females aged 50 years or older at time of informed consent. Main Criteria 2. Female subjects: for Inclusion a) Post-menopausal women, defined as no menses for 12 months without an alternative medical cause. Any concern about the menopausal status of a prospective female subject, a follicle- stimulating hormone test (FSH) should be requested to confirm post-menopausal status. Post-menopausal women confirmed by FSH level > 40 mIU/mL by central laboratory. b) Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and Baseline, and be willing to use highly effective methods of contraception from the Screening visit until 3 months after last dose of study drug. The central laboratory will flag positive serum human chorionic gonadotropin as exclusionary at Screening (re-test of Screening if required). In such cases, the site will perform a local urine pregnancy test at Baseline to determine if the subject can continue to randomisation. c) Are permanently sterile or have had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy. d) Women must not bebreastfeeding.

3. Male Subjects: a) Who are sexually active, fertile men must use highly effective methods of contraception from Day 1 until 3 months after last dose of study drug if their partners are WOCBP. b) Who are permanently sterile or have had bilateral orchiectomy.

4. Diagnosis of mild dementia due to probable AD with increased level of certainty (provided by evidence of clinical deterioration within the 6 months preceding Screening, as assessed by the investigator) as determined by the National Institute of Ageing and the Alzheimer’s Association workgroup. Individual criteria will be included in the electronic case report form.

5. Mild dementia due to probable AD with MMSE of 20 to 26 (inclusive).

6. CDR Global Score of 0.5 to 1.0.

7. A brain magnetic resonance imaging or computed tomography scan in the 12 months preceding Screening (a wider window may be accepted but requires written approval by the ICON Medical Monitor) that, in the investigator’s opinion, is consistent with AD as the principal aetiology of the dementia with no other clinically significant abnormality, e.g. another principal underlying aetiology of the subject’s dementia, or a lesion which could affect cognition e.g. a brain tumour or large stroke.

8. On stable dose of acetylcholinesterase inhibitor (AChEI) and/or memantine (at least 3 months prior to Screening) OR treatment-naive. Initiating AChEIs or memantine during study will not be permitted.

9. Apart from a clinical diagnosis of mild dementia due to probable AD, the subject must be in good health as determined by the investigator, based on medical history and screening assessments.

10. Has a consenting study partner who, in the investigator’s judgement, has frequent and sufficient contact with the subject to be able to provide accurate information as to the subject’s cognitive and functional abilities. Study partner is available to provide information to the investigator and study site staff about the subject and attend all study site visits in person for scale completion for duration of study.

11. Must be willing and able to comply with the requirements of the protocol and must be available to complete the study.

12. Must satisfy medical examiner about fitness to participate in study.

13. Must provide written informed consent to participate in study.

Exclusion 1. Clinically significant abnormalities in vital signs (blood pressure, Criteria heart rate, respiration rate and oral temperature).

2. Clinically significant abnormal haematology, biochemistry and urine examination values, as determined by the investigator. Additionally, abnormal liver and renal function and Vitamin B12 levels below lower threshold may impact cognitive function. The following values will alert flag and are specifically excluded: a) Vitamin B12 < 176pg/mL b) Haemoglobin < 11 g/dL for females and < 12 g/dL for males c) Aspartate aminotransferase > 3 x upper limit of normal (ULN) d) Alanine aminotransferase > 3 x ULN e) Serum creatinine > 2 x ULN f) Urine benzodiazepines when positive: One re -test will be allowed in cases where the subject’s intake of benzodiazepines is within the allowed dose. Re-tests must be performed within 7 days of the last benzodiazepine dose prior to the Baseline visit. A positive re-test for urine benzodiazepines is exclusionary.

Re-testing of laboratory parameters requires a confirmatory value within the screening period permitted in an effort to find all possible well-qualified subjects. The most current result prior to randomisation is the value by which study inclusion will be assessed, as it represents the subject’s most current, clinical state. Consultation with the ICON Medical Monitor (MM) is advised, to identify whether repeat testing of any parameter is acceptable and relevant. Has had a significant systemic illness or infection within the past 4 weeks prior to randomisation, as determined by the investigator. Clinically significant neurological disease other than AD, such as (but not limited to) Parkinson’s disease, multi-infarct dementia, Huntington’s disease, normal pressure hydrocephalus, brain tumour, progressive supranuclear palsy, seizure disorder, subdural haematoma, multiple sclerosis or a history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities. Subjects with clinical evidence of peripheral neuropathy or historical evidence of clinically significant nerve conduction abnormalities. Clinical evidence of neuropathy is defined as: a) Inability to sense a stimulus even at the secondary (more proximal) skin area for pinprick, light touch, and vibration or temperature at the foot, in at least one extremity (in case neurography measures are normal, the case will be discussed with the ICON MM to assess subject eligibility) b) Nerve conduction abnormalities beyond local normal values or inability to measure Sensory Nerve Action Potential or Compound Muscle Action Potential in the primary or a secondary (back-up) nerve c) Neuropathy Total Symptom Score (NTSS)-6 score > 6, but note that subjects are eligible even if they show:

• Missing reflexes of the Achilles tendon (ankle), but a positive patellar (knee) tendon reflex

• Missing ability to name toe or thumb position Has had a stroke within the year prior to randomization, as determined by the investigator. Has a lifetime diagnosis of a major psychiatric disorder (other than dementia), based on the Diagnostic and Statistical Manual of Mental Dis^orders, 4th Edition criteria. This includes but is not limited to schizophrenia, schizoaffective disorder, bipolar affective disorder, alcohol dependence syndrome or major depressive disorder.

8. Has a history of disease directly related to the hypothalamus, the pituitary and/or the adrenal glands which affect the hypothalamic- pituitary-adrenal axis function.

9. Has uncontrolled clinical conditions relating to glucose and lipid metabolism.

10. Clinically significant electrocardiogram (ECG) abnormalities, including QTc interval > 450 msec, following ECG tracings at Screening. A single repeat evaluation will be allowed if the investigator or designee has reason to believe the reading is faulty or to help assess the clinical significance of an abnormality. Any other ECG abnormality that is seen as exclusionary will first be discussed with the ICON MM.

11. Use of any prohibited medication.

12. Participation in another clinical study of an investigational drug or device whereby the last drug/device administration is within 60 days of Screening.

13. Inability to communicate well with the investigator (i.e. language problem, non-fluent English [as scales will be provided in English only], poor mental development or impaired cerebral function).

14. Subject will undergo the tests, ADAS-Cog vl4, CDR-SOB, MMSE, NTB (executive domain) and RAVLT at the indicated time -points to avoid uncontrolled learning effects. Subjects who need to perform these tests externally to and in parallel with this study will be excluded.

15. Subject has ingested any food or drink containing grapefruit, Seville oranges, star fruit, or derived products (e.g. fruit juice), for at least 3 days prior to the first administration of study drug. Subjects must be willing to abstain from ingesting these foods and drinks throughout the study, as it may interfere with the activity of Xanamem^M

Test Product, Oral Xanamem™ capsules, 10 mg administered once a day (QD). Dose and Dosing: Mode of Administration At Week 0, eligible subjects will be randomised to 10 mg/matching placebo QD with a 1 : 1 allocation ratio.

Reference Matching placebo which is identical in appearance to the test product

Therapy except that it contains no active ingredient.

Duration of Subjects should participate in the study for 17 to 20 weeks, including a

Treatment treatment period of 12 weeks.

Formulations of Xanamem and Placebo

Xanamem™ is formulated in green and cream-coloured size 3, Coni-Snap shaped gelatin capsules as an excipient blend at a dose of 10 mg (see Table 1). The dose of Xanamen™ will be 10 mg administered orally, QD. Table 1: Ingredients of Xanamem and Placebo Capsules using Dose of 10 mg (% w/w)

Component Function Placebo 10 mg

UE2343 Active pharmaceutical ingredient 5.26

Lactose 89.74

Croscarmellose Sodium Disintegrant 4.0 4.00

Talc Glidant 0.5 0.05

Magnesium stearate Lubricant 0.5 0.05

Note: the formulations shown are based on % w/w with a nominal capsule fill weight of 190 mg.

Blood Sample Collections and Storage

Sparse PK blood samples were taken from all subjects who participate in the main study. The PK samples taken pre-dose and between 3 and 5 hours post-dose, i.e. the time interval during which peak concentrations were observed in the Phase I studies. PK blood samples will be taken at Week 0 (Baseline), Week 4, Week 8 and Week 12 of the study.

PD blood samples collected from a sub-group of approximately 50 subjects (unless a higher number is defined as a result of the DSMB analysis of the PD data). The PD sampling in this study will complement the previously reported Phase I data, in which most of the subjects were male and only a small number of subjects were aged 50 years or older. If, after evaluation of the PD data by the DSMB, it is considered that an insufficient number of subjects are on active drug, further PD data will be collected.

Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) and Global (CDR-Global)

The Washington University CDR is a global assessment instrument that yields global and SOB scores, with the global score regularly used in clinical and research settings to stage dementia severity. The CDR-SOB score has been considered a more detailed quantitative general index than the global score and provides more information than the global CDR score in participants with mild dementia. CDR Global results are relevant for subject eligibility and thus will also be performed at the Screening visit.

The CDR is obtained through semi- structured interviews of patients and informants, and cognitive functioning is rated in six domains of functioning: memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a five-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment. The global CDR score is computed via an algorithm. CDR Global score is calculated using the Washington University online algorithm. The CDR-SOB is based on summing each of the domain box scores, with scores ranging from 0-18.

Mini-Mental Status Examination (MMSE)

The MMSE is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment and is commonly used in medicine and allied health to screen for dementia. It is also used to estimate the severity and progression of cognitive impairment and to follow the course of cognitive changes in an individual over time; thus making it an effective way to document a participant’s response to treatment. For this study, MMSE results are relevant for subject eligibility and performed at Screening visit.

Biomarker Analysis

A Non-interventional Biomarker Analysis Extension Protocol study was conducted for Participants who were previously enrolled in the above described Phase II, Double-Blind, 12- Week, Randomised, Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects with Mild Dementia due to Alzheimer’s Disease (AD). The objectives for study were:

1. To analyze the levels of biomarkers of Alzheimer’s Disease (AD) proteins, neurodegeneration, and neuro-inflammation in stored plasma samples from participants with mild dementia due to AD enrolled in the previous clinical trial (at baseline and Week 12 and their change from baseline for each treatment)

2. To examine the change from baseline in biomarkers by treatment group to Week 12 by baseline pTaul81 quartile categorization/level

3. To explore the efficacy of Xanamem in relationship to quartiles categorization/level of pTaul81 levels at baseline

4. To correlate the changes from baseline in biomarkers by treatment with changes in cognitive endpoints

From above described clinical study, the extant blood samples of 72 patients were subjected to further disease biomarker analysis. A biomarker laboratory (blinded to treatment assignment), analyzed those blood samples to determine the biomarker variable pTaul81.

The population for the Biomarker Extension Study, compared to the overall population of previous clinical study, is presented in Table 2. Table 2 Baseline Characteristics of Patients Studied

Biomarker Study XanADu Phase 2 N=72 N=185

Age (mean, SD) 71 (8) 71 (8) % female 54% 57% ADASCogl4 (mean, SD) 33 (8) 29 (9) ADCOMS (mean, SD) 0.52 (0.19) 0.50 (0.20) MMSE (mean, SD) 22 (3) 23 (3) CDR-SB (mean, SD) 3.9 (1.6) 3.8 (1.7) pTau (mean, SD) 7.7 (6.8) % pTau > 10.2 pg/mL 13% AP42/40 ratio (mean, SD) 21.9 (15.5) GFAP (mean, SD) 118 (73)

Statistical Analysis for the Biomarker Extension Study

An analysis of overall efficacy was undertaken of the population (n = 72). The group treated with Xanamem (n = 37) exhibited an increase in the mean MMSE score of 0.3, compared to a decrease of 0.6 in the group receiving the Placebo (n = 35). The results revealed a clinically significant benefit to treatment with Xanamem over the Placebo (Cohen’s d = 0.35).

For the cognitive efficacy variables (CDR-SB and MMSE), change from baseline to Week 12 was analyzed by ANCOVA with the following models:

• treatment as fixed effect and baseline cognitive efficacy value as covariate;

• treatment, baseline p-T au 181 (low/high) category, and treatment-by-baseline p-Tau 181 (low/high) category as fixed effects, and baseline cognitive efficacy value as covariate;

• treatment, baseline p-Taul81 (<10.2 pg/mL / >10.2 pg/mL) category, and treatment- by-baseline p-Taul81 (<10.2 pg/mL / >10.2 pg/mL) category as fixed effects, and baseline cognitive efficacy value as covariate; and

• treatment, baseline MMSE (less severe (>24) / more severe (<23)) category, and treatment-by-baseline MMSE (less severe (>24) / more severe (<23)) category as fixed effects, and baseline cognitive efficacy value as covariate.

For the biomarker p-Taul81, change from baseline to Week 12 were analyzed by ANCOVA with the following models:

• treatment as fixed effect and baseline biomarker value as covariate; treatment, baseline p-Taul81 (low/high) category, and treatment-by-baseline p-Taul81 (low/high) category as fixed effects, and baseline biomarker value as covariate; • treatment, baseline p-Taul81 (<10.2 pg/mL / >10.2 pg/mL) category, and treatment- by-baseline p-Taul81 (<10.2 pg/mL / >10.2 pg/mL) category as fixed effects, and baseline biomarker value as covariate; and

• treatment, baseline MMSE (less severe (>24) / more severe (<23)) category, and treatment-by-baseline MMSE (less severe (>24) / more severe (<23)) category as fixed effects, and baseline biomarker value as covariate.

The “high” and “low” baseline p-Tau-181 categories were delineated on the basis of the median value of baseline p-Tau-181 of the dataset (6.74 pg/mL).

Table 3 Higher pTau (> 6.74 pg/mL*) subgroup shows clinically significant effect on CDR-SB (n=34)

Assessment Desired Xanamem Placebo Cohen’s d p value change (n=16) (n=18)

CDR-SB units (mean) Down 0.4 1.0 0.41 0.09

CDR-SB units (median) Down 0.0 0.8

Table 4 High - low data for pTau show benefit on CDR-SB in patients more likely to have AD

Group N Desired Xanamem Placebo Cohen’s d p value change (n=16) (n=18) pTau > 6.74 pg/mL (mean) 34 Down 0.4 1.0 0.41 0.09 pTau > 6.74 pg/mL (median) 34 Down 0.0 0.8 pTau units < 6.74 (mean) 34 Down 0.5 -0.1 0.40 0.08 pTau units < 6.74 (median) 34 Down 0.0 0.0 pTau pg/mL > 10.2 (mean) 9 Down 0.1 0.8 0.62 0.33 pTau pg/mL > 10.2 (median) 9 Down -0.3 0.5 pTau < 10.2 pg/mL (mean) 59 Down 0.5 0.4 -0.06 0.78 pTau < 10.2 pg/mL (median) 59 Down 0.0 0.0

Table 5 High - low data for MMSE shows effect measurable in more severe dementia

Group N Desired Xanamem Placebo Cohen’s d p value change (n=16) (n=18) MMSE 20-23 (mean)* 46 Up 1.7 -0.3 0.93 0.02

MMSE 20-23 (median)* 46 Up 2.0 -1.0

MMSE 24-26 (mean) 26 Up -1.5 -1.4 -0.17 0.88

MMSE 24-26 (median) 26 Up -1.0 -1.0

Table 3 demonstrates that the group most likely to have pathological AD (that is, where pTau > 6.74 pg/mL), exhibited an unexpected clinically significant improvement to CDR-SB when treated with Xanamem, compared the Placebo (Cohen’s d = 0.41, p = 0.09). The treatment effect of a CDR-SB mean 0.6 points (median 0.8 points) for Xanamem compares favorably with that for injectable amyloid antibody therapies (0.4-0.45 points) and approved oral anticholinesterases or memantine (Cohen’s d of approximately 0.2-0.3). Table 4 further demonstrates that the patient group with extreme levels of pTau (where pTau > 10.2 pg/mL), exhibited an unexpected clinically significant improvement to CDR-SB when treated with Xanamem, compared the Placebo (Cohen’s d = 0.62, p = 0.33).

Table 5 demonstrates that the group with lower baseline MMSE of 20-23 exhibited an unexpected clinically significant change in MMSE at the 12 week follow up when treated with Xanamem, compared with the Placebo (Cohen’s d 0.93, p = 0.02).

The change in biomarker pTaul 81 from baseline to Week 12 was also analysed, and no treatment trend was observed in a sample size of 28 and 26 respectfully for change for Xanamem treatment group of -2.37 and change for placebo treatment group of -8.59 (Cohen’s d = 0.08, p = 0.40).

Claims

1. A method of determining whether a human subject suffering, or suspected of suffering, from a neurodegenerative disease is likely to respond to treatment with an 11β-HSDl inhibitor, the method comprising:

(b) determining whether the human subject is likely to respond to treatment with an 11β-HSDl inhibitor based on the baseline level of the tau protein, wherein the baseline level of the tau protein, being equal to or greater than a reference level of the tau protein associated with a neurodegenerative disease is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

2. The method of claim 1, wherein the tau protein is a phosphorylated tau protein (pTau).

3. The method of claim lor claim 2, wherein the tau protein is a phosphorylated tau protein (pTau) having any one or more phosphorylated threonines at position 181, 50, 69, 111, 153, 175, 205, 212, 217, and/or 231, and/or one or more phosphorylated serines at position 46, 199, 202, 235, 262, 293, 324, 356, 396, 404, and/or 422 of the tau protein.

4. The method of any one of claims 1 to 3, wherein the phosphorylated tau protein is pTau- 181.

5. The method of any one of claims 1 to 4, wherein the baseline level of the tau protein (in pg/mL) being equal to or greater than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

6. The method of any one of claims 1 to 5, wherein the baseline level of the tau protein, being equal to or greater than 6.74 pg/mL, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

7. The method of any one of claims 1 to 6, wherein the baseline level of the tau protein, being equal to or greater than 10.2 pg/mL, is indicative that the subject is likely to respond to treatment with the 11β-HSDl inhibitor.

8. The method of any one of claims 1 to 7, wherein the baseline level of the tau protein in the human subject is a baseline level of the tau protein: (i) in a biological sample obtained from the human subject, or (ii) derived from a measured value obtained from an image obtained from a tau-positron emission tomography (PET) scan of a brain region of the human subject. The method of any one of claims 1 to 8, wherein the baseline level of the tau protein in the human subject is a baseline level of the tau protein in a biological sample obtained from the human subject. The method of claim 9, further comprising determining the baseline level of the tau protein in the biological sample obtained from the human subject. The method of claim 9 or claim 10, further comprising performing one or more assays on the biological sample obtained from the human subject to determine the baseline level of the tau protein therein. The method of any one of claims 9 to 11 , wherein the biological sample is whole blood, blood serum, blood plasma, or cerebrospinal fluid. The method of any one of claims 1 to 8, wherein the baseline level of the tau protein in the human subject is a baseline level of the tau protein derived from a measured value obtained from an image obtained from a tau-positron emission tomography (PET) scan of a brain region of the human subject. The method of claim 13, further comprising determining the baseline level of the tau protein from the image obtained from a tau-positron emission tomography (PET) scan of a brain region of the human subject. The method of claim 13 or claim 14, further comprising performing a tau-positron emission tomography (PET) scan of the human subject to obtain an image of the human subject or brain region thereof. The method of any one of claims 1 to 15, wherein the human subject is suffering, or suspected of suffering from a neurodegenerative disease, wherein the neurodegenerative disease is selected from the group consisting of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, multiple system atrophy, Frontal lobe dementia, vascular dementia, and prion diseases. The method of claim 16, wherein the neurodegenerative disease is Alzheimer’s disease. The method of any one of claims 1 to 17, wherein the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disorder is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of cognitive functioning in the treated subject relative to a non-treated subject, an improvement of cognitive impairment in the treated subject relative to a non-treated subject, and/or prevent cognitive decline in a subject predisposed to a disorder or disease associated with cognitive decline. The method of any one of claims 1 to 18, wherein the baseline level of the tan protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide a delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability and/or function, of the treated subject relative to a non-treated subject assessed according to one or more testing criteria methods selected from Cogstate Neuropyschological Testing criteria, Hopkins Verbal Learning Test, Controlled Word Association Test, and Trail Making A and B Tests, CDR-SB, MMSE, ADAS-Cog, CogState Cognition Test Battery, CANTAB test battery, and Amsterdam instrumental activities of daily living. The method of claim 19, wherein the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide a delay in progression of impairment, halt in progression of impairment, and/or improvement in cognitive ability and/or function, of the treated subject relative to a non-treated subject assessed according to CDR-SB, wherein the CDR-SB test score improvement relative to a non-treated subject is at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0, or in a range between about 0.1 and 2.0, 0.1 and 1.0, 0.2 and 1.0, 0.3 and 1.0, 0.4 and 1.0, 0.5 and 1.0, 0.5 and 0.9, and 0.6 and 0.9. The method of any one of claims 1 to 20, wherein the baseline level of the tau protein, being equal to or greater than the reference level of the tau protein associated with a neurodegenerative disease, is indicative that treatment with the 11β-HSDl inhibitor is likely to provide an improvement of a change in baseline in Executive Function and/or Episodic Memory. The method of any one of claims 1 to 21, wherein the human subject has a Mini-Mental State Exam (MMSE) score of less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10. The method of any one of claims 1 to 22, further comprising treating the human subject with an 11β-HSDl inhibitor if it is determined that the human subject is likely to respond to treatment thereto, or if it is determined that there is an increased probability of responsiveness to treatment. The method of any one of claims 1 to 23, wherein the 11β-HSDl inhibitor is selected from the group consisting of ABT384, AZD4017, ABT305, INCB- 13739, BVT.3498, BVT 116429, bezafibrate; CRx-401, diflunisal; BMS-823778; UE2343; and carbenoxolone. The method of any one of claims 1 to 24, wherein the 11β-HSDl inhibitor is selected from a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

Formula I; wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6 ialoalkyl, -O-C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -CN, -CF₃, -OR³, -SR³, -NR³R⁴, -COR³, -CO2R³, -CONR³R⁴, -NR³COR⁴, -SO2R³, - SO2NR³R⁴, and -NR³SO2R⁴; wherein R³ and R⁴ are each independently selected from the group consisting of hydrogen, C1-6alkyl, 3-7-membered carbocyclyl and 3-7- membered heterocyclyl; wherein each 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 3-7-membered carbocyclyl, and 3-7-membered heterocyclyl, is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-Ci- 6haloalkyl, C₂-6alkenyl, C₂-6alkynyl, -CN, -CF₃, -OR⁵, -SR⁵, -NR⁵R⁶, -COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, -SO₂NR⁵R⁶, and -NR⁵SO₂R⁶; and wherein each R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C1-6alkyl. The method of claim 25, wherein the compound of Formula I is a compound of Formula la, or a pharmaceutically acceptable salt, solvate or prodrug thereof:

Formula la; wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6 haloalkyl, -O-C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, -CN, -CF₃, -OR³, -SR³, -NR³R⁴, -COR³, -CO2R³, -CONR³R⁴, -NR³COR⁴, -SO2R³, - SO₂NR³R⁴, and -NR³SO₂R⁴; wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C1-6alkyl, 3-7-membered carbocyclyl and 3-7-membered heterocyclyl; wherein each 3-10-membered carbocyclyl, 3-10-membered heterocyclyl, 3-7- membered carbocyclyl, and 3-7-membered heterocyclyl, is unsubstituted or substituted with one or more substituents selected from the group consisting of hydrogen, halogen, C1-6alkyl, -O-C1-6alkyl, C1-6haloalkyl, -O-C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -CN, -CF3, -OR⁵, -SR⁵, -NR⁵R⁶, -COR⁵, -CO2R⁵, -CONR⁵R⁶, -NR⁵COR⁶, -SO2R⁵, - SO2NR⁵R⁶, and -NR⁵SO2R⁶; and wherein each R⁵ and R⁶ are independently selected from the group consisting of hydrogen and C1-6alkyl. The method of claim 25 or claim 26, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, 3-10-membered carbocyclyl, 3-10- membered heterocyclyl, -OH, -CN, and -NH2; and wherein if present, each 3-10- membered carbocyclyl and 3-10-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl. The method of any one of claims 25 to 27, wherein R¹ and R² are each independently selected from the group consisting of hydrogen, halogen, 6-membered carbocyclyl, 6- membered heterocyclyl, -OH, -CN, and -NH2; and wherein if present, each 6-membered carbocyclyl and 6-membered heterocyclyl may be further substituted with one or more substituents selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF3, -NH2, and C1-6alkyl. The method of any one of claims 25 to 28, wherein R¹ is selected from the group consisting of hydrogen, halogen, -OH, -CN, -CF₃, -NH2, and C1-6alkyl, and R² is independently selected from the group consisting of:

and The method of any one of claims 25 to 29, wherein the compound of Formula I is selected from the group consisting of:

of claims 25 to 30, wherein the compound of Formula I is:

of claims 25 to 31, wherein the compound of Formula I is: