# US 12,215,387 B2 · Biomarker predictive of responsiveness to alpha 7 nicotinic acetylcholine receptor activator treatment

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- Number: US 12,215,387 B2
- Document ID: US12215387B2
- Status: Granted
- Kind: B2
- Application number: 17/829,859
- Filed: 2022-06-01
- Published: 2022-10-06
- Granted: 2025-02-04
- Earliest claimed: 2012-12-11
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Dominik Feuerbach; Baltazar Gomez-Mancilla; Yunsheng He; Donald Johns; Cristina Lopez-Lopez; Kevin Hall McAllister; Nicole Pezous; Lisa Sandford; Markus Weiss
- Web page: https://patentgrep.com/patent/US12215387B2

## CPC

- C12Q 1/6883: for diseases caused by alterations of genetic material
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/2086: {Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat (active cores with a complete drug-free outer coat A61K9/28)}
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- C12Q 2600/16: Primer sets for multiplex assays
- C12Q 2600/172: Haplotypes
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention provides methods for predicting therapeutic responsiveness of a subject suffering from cognitive impairments or dysfunctions, psychotic and/or neurodegenerative disorders to an alpha 7 nicotinic acetylcholine receptor activator treatment.

## Claims

### Claim 1

A method for treating an individual suffering from schizophrenia, the method comprising:
administering a therapeutically effective amount of an alpha 7 nicotinic acetylcholine receptor activator to the individual, wherein the individual is selected by:
determining that a genotype of the individual at the genetic locus of the human cytochrome P450, family 1, sub-family A, polypeptide 2 (CYP1A2) gene includes:
(i) a homozygous SNP genotype of rs2069514-A/A; or
(ii) a heterozygous SNP genotype of rs2069514-A/G; or
(iii) a SNP forming a haplotype with said SNP genotypes or a SNP in the same linkage disequilibrium with said SNP genotypes.

### Claim 2 (depends on 1)

The method of claim 1, further comprising detecting the presence of said SNP or SNPs by using at least one probe comprising at least one oligonucleotide that specifically hybridizes with specific regions on the nucleic acid molecule carrying said SNP or SNPs.

### Claim 3 (depends on 1)

The method of claim 1, further comprising detecting the presence of said SNP or SNPs by sequence-specific primer (SSP) typing, sequence-specific oligonucleotide (SSO) typing, sequence based typing (SBT), DNA amplification including polymerase chain reaction (PCR), microarray analysis, northern blot analysis, or reverse transcription PCR.

### Claim 4 (depends on 1)

The method of claim 1, further comprising assessing clinical effectiveness of the treatment of the individual using the alpha 7 nicotinic acetylcholine receptor activator.

### Claim 5 (depends on 1)

The method of claim 1, wherein the alpha 7 nicotinic acetylcholine receptor activator is a compound of formula (I)
wherein
L1 is —CH2—; L2 is —CH2— or —CH2—CH2—; and L3 is —CH2— or —CH(CH3)—; or
L1 is —CH2—CH2—; L2 is —CH2—; and L3 is —CH2—CH2—;
L4 is a group selected from
wherein the bond marked with the asterisk is attached to the aza-bicycloalkyl moiety;
R1 is hydrogen or C1-4alkyl;
X1 is —O— or —NH—;
A2 is selected from
wherein the bond marked with the asterisk is attached to X1;
A1 is a five- to ten-membered monocyclic or fused polycyclic aromatic ring system which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen, and sulfur, wherein the ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein the ring system may be substituted once or more than once by R2, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen;
each R2 independently is C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy, halogen, cyano, or a three- to six-membered monocyclic ring system which may be aromatic, saturated or partially saturated and which may contain from 1 to 4 hetero atoms selected from nitrogen, oxygen, and sulfur, and wherein each ring system may contain not more than 2 oxygen atoms and not more than 2 sulfur atoms, and wherein each ring system may in turn be substituted once or more than once by C1-6alkyl, C1-6halogenalkyl, C1-6alkoxy, C1-6halogenalkoxy, halogen, or cyano, and wherein a substituent on a nitrogen in a heterocyclic ring system may not be halogen; or
two R2 at adjacent ring atoms form a C3-4alkylene group, wherein 1-2 carbon atoms may be replaced by X2, and wherein the C3-4alkylene group may be substituted once or more than once by R3;
each X2 independently is —O— or —N(R4)—;
each R4 independently is hydrogen or C1-6alkyl; and
each R3 independently is halogen or C1-6alkyl;
in free base form or in acid addition salt form.

### Claim 6 (depends on 1)

The method of claim 1, wherein the alpha 7 nicotinic acetylcholine receptor activator is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in free base form or in acid addition salt form.

### Claim 7 (depends on 6)

The method of claim 6, wherein the therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane administered is about 1 mg to about 100 mg per day.

### Claim 8 (depends on 1)

The method of claim 1, wherein the alpha 7 nicotinic acetylcholine receptor activator is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in fumarate salt form.

### Claim 9 (depends on 1)

The method of claim 1, wherein the alpha 7 nicotinic acetylcholine receptor activator is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in mono-fumarate salt form.

### Claim 10 (depends on 1)

The method of claim 1, further comprising administering a second cognition enhancer or a therapeutic compound useful for the treatment of schizophrenia.

### Claim 11

A method for treating an individual suffering from diminished cognitive skills, the method comprising:
administering a therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane to the individual, wherein the individual is selected by: determining that a genotype of the individual at the genetic locus of the human cytochrome P450, family 1, sub-family A, polypeptide 2 (CYP1A2) gene includes:
(i) a homozygous SNP genotype of rs2069514-A/A; or
(ii) a heterozygous SNP genotype of rs2069514-A/G; or
(iii) a SNP forming a haplotype with said SNP genotypes or a SNP in the same linkage disequilibrium with said SNP genotypes.

### Claim 12 (depends on 11)

The method of claim 11, wherein the individual suffers from schizophrenia.

### Claim 13 (depends on 11)

The method of claim 11, wherein (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane is in free base form or in acid addition salt form.

### Claim 14 (depends on 11)

The method of claim 11, wherein (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane is in fumarate salt form.

### Claim 15 (depends on 11)

The method of claim 11, wherein the therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane administered is about 1 mg to about 100 mg per day.

### Claim 16 (depends on 7)

The method of claim 7, wherein the therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane administered is about 10 mg to about 15 mg per day.

### Claim 17 (depends on 7)

The method of claim 7, wherein the therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane administered is about 2 mg per day.

### Claim 18 (depends on 7)

The method of claim 7, wherein the therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane administered is about 100 mg per day.

### Claim 19 (depends on 15)

The method of claim 15, wherein the therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane administered is about 2 mg to about 100 mg per day.

### Claim 20 (depends on 15)

The method of claim 15, wherein the therapeutically effective amount of (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane administered is about 10 mg to about 15 mg per day.