111111111111111111111111111111111111111111111111111111111111111111111111111
`US00913 8432B2
`
`c12) United States Patent
`Wolfgang et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,138,432 B2
`Sep.22,2015
`
`(54) METHODS FOR THE ADMINISTRATION OF
`ILOPERIDONE
`
`(71) Applicant: Vanda Pharmaceuticals, Inc.,
`Washington, DC (US)
`
`2004/0091909 A1
`2004/0096874 A1
`2004/0133352 A1
`2005/0032070 A1
`2008/0166357 A1
`2009/0298880 A1
`
`5/2004 Huang
`5/2004 Neville et al.
`7/2004 Bevilacqua eta!.
`2/2005 Raimundo eta!.
`7/2008 Golz eta!.
`12/2009 Wolfgang eta!.
`
`(72)
`
`Inventors: Curt Wolfgang, Germantown, MD (US);
`Mihael Polymeropoulos, Potomac, MD
`(US)
`
`(73) Assignee: Vanda Pharmaceuticals, Inc.,
`Washington, DC (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 14/150,575
`
`(22) Filed:
`
`Jan.8,2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0128433 Al
`
`May 8, 2014
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 14/060,978, filed on
`Oct. 23, 2013, which is a continuation of application
`No.
`11/576,178,
`filed
`as
`application No.
`PCT/US2005/035526 on Sep. 30, 2005, now Pat. No.
`8,586,610.
`
`(60) Provisional application No. 60/614,798, filed on Sep.
`30,2004.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311454
`A61K 311519
`C12Q 1168
`(52) U.S. Cl.
`CPC ............. A61K 311454 (2013.01); A61K 311519
`(2013.01); C12Q 116883 (2013.01); C12Q
`2600/106 (2013.01); C12Q 2600/156 (2013.01);
`C12Q 2600/172 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`FOREIGN PATENT DOCUMENTS
`
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`wo
`
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`4,965,188 A
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`
`Primary Examiner- Diana B Johannsen
`(74) Attorney, Agent, or Firm- Hoffman Warnick LLC
`
`(57)
`
`ABSTRACT
`
`The present invention relates to methods for treating a patient
`with iloperidone or a metabolite thereof, which patient is also
`being treated with fluoxetine, and lowering risk for QT pro(cid:173)
`longation.
`
`1 Claim, No Drawings
`
`Roxane Labs., Inc.
`Exhibit 1001
`Page 001
`
`

`
`US 9,138,432 B2
`Page 2
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`(56)
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`
`Roxane Labs., Inc.
`Exhibit 1001
`Page 002
`
`

`
`US 9,138,432 B2
`Page 3
`
`(56)
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`* cited by examiner
`
`Roxane Labs., Inc.
`Exhibit 1001
`Page 003
`
`

`
`US 9,138,432 B2
`
`1
`METHODS FOR THE ADMINISTRATION OF
`ILOPERIDONE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of U.S. patent applica(cid:173)
`tion Ser. No. 14/060,978, filed Oct. 23, 2013, now abandoned,
`which is a continuation of U.S. patent application Ser. No.
`11/576,178, filed Mar. 28, 2007 (now U.S. Pat. No. 8,586,
`610, issued Nov. 19, 2013), which is a 35 U.S.C. §371
`national stage entry of International Patent Application No.
`PCTIUS2005/035526, filed Sep. 30, 2005, which claims the
`benefit of U.S. Provisional Patent Application No. 60/614,
`798, filed Sep. 30, 2004. Each of the foregoing patent appli(cid:173)
`cations is incorporated herein.
`
`2
`A number of references are directed toward the identifica(cid:173)
`tion of CYP2D6 mutations and their corresponding pheno(cid:173)
`types. For example, United States Patent Application Publi(cid:173)
`cation No. 2003/0083485 to Milos et a!. describes a novel
`5 CYP2D6 variant associated with the PM phenotype and
`methods for assessing whether an individual possesses the
`variant prior to the administration of a drug. United States
`Patent Application Publication No. 2004/0072235 to Dawson
`describes a primer set useful in identifying variants of the
`10 CYP2D6 gene. Similarly, United States Patent Application
`Publication No. 2004/0091909 to Huang describes methods
`for screening an individual for variants in the CYP2D6 gene
`and other cytochrome P450 genes and tailoring the individu(cid:173)
`al's drug therapy according to his or her phenotypic profile.
`15 Finally, United States Patent Application Publication No.
`2004/0096874 to Neville eta!. describes methods for identi(cid:173)
`fYing cytochrome P450 variants.
`
`SEQUENCE LISTING
`
`SUMMARY OF THE INVENTION
`
`The sequence listing contained in the electronic file titled
`"VAND-0002-US-CON2SeqiD _2014-08-29 ," created Aug.
`29, 2014, comprising 14 KB, is hereby incorporated herein by
`reference.
`
`BACKGROUND OF THE INVENTION
`
`Several genes associated with drug metabolism have been
`found to be polymorphic. As a result, the abilities of indi(cid:173)
`vidual patients to metabolize a particular drug may vary
`greatly. This can prove problematic or dangerous where an
`increased concentration of a non-metabolized drug or its
`metabolites is capable of producing unwanted physiological
`effects.
`The cytochrome P450 2D6 gene (CYP2D6), located on 35
`chromosome 22, encodes the Phase I drug metabolizing
`enzyme debrisoquine hydroxylase. A large number of drugs
`are known to be metabolized by debrisoquine hydroxylase,
`including many common central nervous system and cardio(cid:173)
`vascular drugs. One such drug is iloperidone (1-[4-[3-[4-(6- 40
`fluoro-1 ,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy ]-3-
`methoxyphenyl]ethanone). Iloperidone and methods for its
`production and use as an antipsychotic and analgesic are
`described in U.S. Pat. No. 5,364,866 to Strupczewski et a!.
`The diseases and disorders that can be treated by administra- 45
`tion of iloperidone include all forms of schizophrenia (i.e.,
`paranoid, catatonic, disorganized, undifferentiated, and
`residual), schizoaffective disorders, bipolar mania/depres(cid:173)
`sion, cardiac arrhythmias, Tourette's Syndrome, brief psy(cid:173)
`chotic disorder, delusional disorder, psychotic disorder NOS 50
`(not otherwise specified), psychotic disorder due to a general
`medical condition, schizophreniform disorder, and sub(cid:173)
`stance-induced psychotic disorder. P88 is an active metabo(cid:173)
`lite of iloperidone. See, e.g., PCT W02003020707, which is
`incorporated herein by reference.
`Among the unwanted physiological effects associated with
`an increased concentration of iloperidone or its metabolites is
`prolongation of the electrocardiographic QT interval. Muta(cid:173)
`tions in the CYP2D6 gene have been associated with anum(cid:173)
`ber of drug metabolism-related phenotypes. These include 60
`the ultra rapid metabolizer (UM), extensive metabolizer
`(EM), intermediate metabolizer (IM), and poor metabolizer
`(PM) phenotypes. Where a particular drug is capable of pro(cid:173)
`ducing unwanted physiological effects in its metabolized or
`non-metabolized forms, it is desirable to determine whether a 65
`patient is a poor metabolizer of the drug prior to its adminis-
`tration.
`
`20
`
`The present invention comprises the discovery that treat(cid:173)
`ment of a patient, who has lower CYP2D6 activity than a
`normal person, with a drug that is pre-disposed to cause QT
`prolongation and is metabolized by the CYP2D6 enzyme, can
`25 be accomplishing more safely by administering a lower dose
`of the drug than would be administered to a person who has
`normal CYP2D6 enzyme activity. Such drugs include, for
`example, dolasetron, paroxetine, venlafaxin, andiloperidone.
`Patients who have lower than normal CYP2D6 activity are
`30 herein referred to as CYP2D6 Poor Metabolizers.
`This invention also relates to methods for the identification
`of genetic polymorphisms that may be associated with a risk
`for QT prolongation after treatment with compounds metabo(cid:173)
`lized by the CYP2D6 enzyme, particularly iloperidone or an
`active metabolite thereof or a pharmaceutically acceptable
`salt of either (including, e.g., solvates, polymorphs, hydrates,
`and stereoisomers thereof), and related methods of adminis(cid:173)
`tering these compounds to individuals with such polymor(cid:173)
`phisms.
`The present invention describes an association between
`genetic polymorphisms in the CYP2D6 locus, corresponding
`increases in the concentrations of iloperidone or its metabo(cid:173)
`lites, and the effect of such increases in concentrations on
`corrected QT ( QTc) duration relative to baseline. Any number
`offormulas may be employed to calculate the QTc, including,
`for example, the Fridericia formula (QTcF) and the Bazett
`formula (QTcB), among others. The present invention
`includes any such formula or method for calculating a QTc.
`A first aspect of the invention provides a method for treat(cid:173)
`ing a patient with iloperidone or an active metabolite thereof
`or a pharmaceutically acceptable salt of either, comprising
`the steps of determining the patient's CYP2D6 genotype and
`administering to the patient an effective amount of iloperi(cid:173)
`done or an active metabolite thereof or a pharmaceutically
`55 acceptable salt of either based on the patient's CYP2D6 geno(cid:173)
`type, such that patients who are CYP2D6 poor metabolizers
`receive a lower dose than patients who are CYP2D6 normal
`metabolizers.
`Another aspect of the invention provides a method for
`treating a patient who is a CYP2D6 poor metabolizer with
`iloperidone or an active metabolite thereof or a pharmaceu(cid:173)
`tically acceptable salt of either, wherein the patient is admin(cid:173)
`istered a lower dosage than would be given to an individual
`who is not a CYP2D6 poor metabolizer.
`Another aspect of the invention provides a method of treat(cid:173)
`ing a patient with iloperidone or an active metabolite thereof
`or a pharmaceutically acceptable salt of either comprising the
`
`Roxane Labs., Inc.
`Exhibit 1001
`Page 004
`
`

`
`US 9,138,432 B2
`
`3
`steps of determining whether the patient is being adminis(cid:173)
`tered a CYP2D6 inhibitor and reducing the dosage of drug if
`the patient is being administered a CYP2D6 inhibitor.
`Another aspect of the invention provides a method for
`determining a patient's CYP2D6 phenotype comprising the
`steps of administering to the patient a quantity of iloperidone
`or an active metabolite thereof or a pharmaceutically accept(cid:173)
`able salt of either, determining a first concentration of at least
`one of iloperidone and an iloperidone metabolite in the
`patient's blood, administering to the patient at least one 10
`CYP2D6 inhibitor, determining a second concentration of at
`least one of iloperidone and an iloperidone metabolite in the
`patient's blood, and comparing the first and second concen(cid:173)
`trations.
`Another aspect of the invention provides a method for 15
`determining whether a patient is at risk for prolongation of his
`or her QTc interval due to iloperidone administration com(cid:173)
`prising the step of: determining a patient's CYP2D6 metabo(cid:173)
`lizer status by either determining the patient's CYP2D6 geno(cid:173)
`type or CYP2D6 phenotype. In the case that a patient is 20
`determined to be at risk for prolongation of his or her QTc
`interval, the dose of iloperidone administered to the patient
`may be reduced.
`Another aspect of the invention provides a method of
`administering iloperidone or an active metabolite thereof, or 25
`a pharmaceutically acceptable salt of either, for the treatment
`of a disease or disorder in a human patient comprising the
`steps of determining the activity of the patient's CYP2D6
`enzyme on at least one of iloperidone and its metabolites
`relative to the activity of a wild type CYP2D6 enzyme and 30
`reducing the dose of at least one of iloperidone and its phar(cid:173)
`maceutically acceptable salts if the patient's CYP2D6
`enzyme activity is less than that of the wild type CYP2D6.
`Another aspect of the invention relates to modifying the
`dose and/or frequency of dosing with iloperidone or a phar- 35
`maceutically acceptable salt thereof based on the P88:P95
`ratio and/or the (P88+iloperidone):P95 ratio in a blood
`sample of a patient being treated with iloperidone or P88,
`especially patients susceptible to QT prolongation or to harm(cid:173)
`ful effects associated with QT prolongation.
`Another aspect of the invention provides a kit for use in
`determining a CYP2D6 genotype of an individual, compris(cid:173)
`ing a detection device, a sampling device, and instructions for
`use of the kit.
`Another aspect of the invention provides a kit for use in
`determining a CYP2D6 phenotype of an individual, compris(cid:173)
`ing a detection device, a collection device, and instructions
`for use of the kit.
`Another aspect of the invention provides a kit for use in
`determining at least one of a P88 to P95 ratio and a P88 and
`iloperidone to P95 ratio in an individual, comprising a detec(cid:173)
`tion device, a collection device, and instructions for use of the
`kit.
`Yet another aspect of the invention provides a method for
`commercializing a pharmaceutical composition comprising
`at least one of iloperidone, a pharmaceutically acceptable salt
`of iloperidone, an active metabolite of iloperidone, and a
`pharmaceutically acceptable salt of an active metabolite of
`iloperidone, said method comprising: obtaining regulatory
`approval of the composition by providing data to a regulatory
`agency demonstrating that the composition is effective in
`treating humans when administered in accordance with
`instructions to determine whether or not a patient is a
`CYP2D6 poor metabolizer prior to determining what dose to
`administer to the patient; and disseminating information con(cid:173)
`cerning the use of such composition in such marmer to pre(cid:173)
`scribers or patients or both.
`
`4
`The foregoing and other features of the invention will be
`apparent from the following more particular description of
`embodiments of the invention.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Iloperidone is a benzisoxazole-piperidinyl derivative, cur(cid:173)
`rently in development for the treatment of CNS disorders.
`Data from placebo-controlled Phase III studies of iloperidone
`showed a Fridericia correction of QT duration (QTcF)
`increase of 0.1 to 8.5 msec at doses of 4-24 mg, when com(cid:173)
`paring a single ECG at baseline to a single ECG at endpoint.
`At lower doses ofiloperidone (4 mg-16 mg) QTcF prolonga(cid:173)
`tion was minimal (0.1-5 msec). In the most recent study, a
`greater prolongation was observed when higher doses of ilo(cid:173)
`peridone (20-24 mg/day) were studied. The mean change in
`the QTcF at doses 20-24 mg/day was 8.5 msec, and 4.6 msec
`in the 12-16 mg/day dose range in this study. These data
`suggest that treatment with iloperidone can be associated
`with prolongation of the QT interval similar to other drugs in
`this class, and that the effect may be dose sensitive in the
`clinical dose range.
`The research leading to the present invention was designed
`to examine the effect of different doses of iloperidone relative
`to the effect of ziprasidone and quetiapine on QTc duration
`under carefully controlled conditions. To further evaluate the
`possible relationship between exposure to iloperidone and the
`comparators to QTc duration, reassessment after pharmaco(cid:173)
`logical inhibition of the principle metabolic pathways for
`each drug, under steady-state conditions, was also planned.
`Blood samples for pharmacogenetic analysis were col(cid:173)
`lected at screening. Two polymorphisms previously associ(cid:173)
`ated with poor metabolizing status were genotyped in the
`CYP2D6locus and 251 genotypes were collected. The indi(cid:173)
`vidual genotypes were studied for detection of association
`between genotype class and concentrations of iloperidone
`and its metabolites P88 and P95. The functional effect of the
`polymorphisms was also evaluated by analyzing the effect of
`40 the addition of the CYP2D6 inhibitor paroxetine on the con(cid:173)
`centrations of the parent drug and its metabolites.
`The research leading to the present invention identified a
`significant association between CYP2D6 genotype and con(cid:173)
`centrations ofP88 before the addition of inhibitors as well as
`45 the effect of this association on QTc prolongation.
`Iloperidone is a substrate for two P450 enzymes; CYP2D6
`and CYP3A4. Most metabolic clearance of iloperidone
`depends on these two enzymes. CYP2D6 catalyzes hydroxy(cid:173)
`lation of the pendant acetyl group to form metabolite P94,
`50 which is converted to P95 after some additional reactions.
`Addition of the CYP2D6 inhibitor fluoxetine, along with
`iloperidone resulted in increases of the area under the curve
`(AU C) for iloperidone and P88 of 131% and 119% respec(cid:173)
`tively. Addition of the CYP3A4 inhibitor ketoconazole in
`55 interaction studies resulted in a 38-58% increase in the con(cid:173)
`centrations of iloperidone and its main metabolites P88 and
`P95. P88 has a pharmacological profile including affinity for
`the HERG charmel similar to that of iloperidone. P95 is less
`lipophilic and is dissimilar in its binding profile compared to
`60 iloperidone, including having very low affinity for the HERG
`channel. For these reasons P95 is regarded as being pharma(cid:173)
`cologically inactive.
`The addition of metabolic inhibitors in this study therefore
`allowed for an evaluation of the effect of increasing blood-
`65 concentration of iloperidone and/or its metabolites on QT
`duration. More specifically, this study allowed for an evalu(cid:173)
`ation of the effect ofiloperidone on QTc before and after the
`
`Roxane Labs., Inc.
`Exhibit 1001
`Page 005
`
`

`
`US 9,138,432 B2
`
`10
`
`20
`
`25
`
`6
`denaturation (30 sat 95° C.), annealing (30 sat 66° C.), and
`extension, (60s at no C.) followed by 22 cycles: 30 sat 95°
`C., 30 s at 66° C., 60 s+5 s/cycle at no C. A final extension
`followed (7 min at no C.).
`Third Wave Technologies, Inc (Madison, Wis.) developed
`the probe sets for genotyping. Genotyping was performed on
`PCR products using the Invader® assay (Lyamichev 1999)
`(Third Wave Technologies, Inc) according to the manufactur(cid:173)
`er's recommendations.
`The genotypes of individuals distributed among the three
`iloperidone groups were not significantly different (Table 1A
`and 1B).
`
`TABLE 1A
`
`Genotype freguencies by iloperidone dose class for CYP2D6C100T
`
`Iloperidone
`
`dose group
`
`Ilo 8 mg bid
`Ilo 12 mg bid
`Ilo 24mg qd
`
`Total
`
`anumber of individuals
`
`Genotvpe
`
`CT
`
`TT
`
`Total
`
`22
`30
`22
`
`74
`
`14
`
`cc
`
`19a
`23
`15
`
`57
`
`TABLE 1B
`
`Genotype frequencies by iloperidone
`dose class for CYP2D6G 1846A
`
`Iloperidone
`
`Genotvne
`
`dose group
`
`AA
`
`AG
`
`GG
`
`Total
`
`Ilo 8 mg bid
`Ilo 12 mg bid
`Ilo 24mg qd
`
`Total
`
`17
`23
`15
`
`55
`
`20
`30
`21
`
`71
`
`14
`
`5
`addition of the CYP2D6 inhibitor, paroxetine, as well as
`before and after the addition of the CYP3A4 inhibitor, keto(cid:173)
`conazole.
`The CYP2D6 gene is highly polymorphic, with more than
`70 allelic variants described so far. Most embodiments of the 5
`present invention concern the two most common polymor(cid:173)
`phisms within the CYP2D6 gene in Caucasian populations,
`CYP2D6G1846A and CYP2D6P34S (also referred to as
`CYP2D6C100T). These polymorphisms correspond to
`nucleotides 3465 and 1719, respectively, in GenBank
`sequence M33388.1
`(GI:181303). The CYP2D6P34S/
`CYP2D6C100T polymorphism also corresponds to nucle(cid:173)
`otide 100 in GenBank mRNA sequence M20403.1 (GI:
`181349).
`The CYP2D6G1846A polymorphism (known as the 15
`CYP2D6*4 alleles, encompassing *4A, *4B, *4C, *4D, *4E,
`*4F, *4G, *4H, *4J, *4K, and *4L) represents a G to A
`transition at the junction between intron 3 and ex on 4, shifting
`the splice junction by one base pair, resulting in frameshift
`and premature termination of the protein (Kagimoto 1990,
`Gough 1990, Hanioka 1990). The CYP2D6P34S/
`CYP2D6C100T polymorphism (known as the CYP2D6*10
`and CYP2D6*14 alleles) represents a C to T change that
`results in the substitution of a Proline at position 34 by Serine
`(Yokota 1993, Johansson 1994). Both of these polymor(cid:173)
`phisms have been associated with reduced enzymatic activity
`for different substrates (Johansson 1994, Dahl1995, Jaanson
`2002, see also review by Bertilsson 2002)
`Methods
`A. Samples
`128 individuals consented to the pharmacogenetic study. 30
`Blood samples were collected according to the pharmacoge(cid:173)
`netics protocol and after the consent of patients. The DNA
`was extracted from whole blood by Co vance using the PURE(cid:173)
`GENE DNA isolation kit (D-50K).
`The 128 individuals that participated were a good repre- 35
`sentation of the total sample of 165 individuals that partici(cid:173)
`pated in the trial. 22 of 29 total were from the iloperidone 8
`mg bid group, 30 of34 were from the iloperidone 12 mg bid
`group, 22 of 31 from the 24 mg qd group, 3 of 5 of the
`risperidone group, 28 of33 of the ziprazidone group, and 23
`of33 of the quetiapine group.
`B. Genotyping
`Genotypes for the CYP2D6G1846A polymorphism were
`ascertained for 123 of the 128 consenting individuals, while
`genotypes for the CYP2D6C1 OOT polymo