US008598149B2
`
`(12) United States Patent
`Belanoff
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8.598,149 B2
`Dec. 3, 2013
`
`(54) OPTIMIZING MIFEPRISTONE LEVELS IN
`PLASMA SERUM OF PATIENTS SUFFERING
`FROMMENTAL DISORDERS TREATABLE
`WITH GLUCOCORTICOD RECEPTOR
`ANTAGONSTS
`
`(*) Notice:
`
`(75) Inventor: Joseph K. Belanoff, Woodside, CA (US)
`(73) Assignee: Corcept Therapeutics, Inc., Menlo
`Park, CA (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 866 days.
`(21) Appl. No.: 12/199,114
`(22) Filed:
`Aug. 27, 2008
`
`(65)
`
`Prior Publication Data
`US 2009/OO62248A1
`Mar. 5, 2009
`
`Related U.S. Application Data
`(60) Provisional application No. 60/969,027, filed on Aug.
`30, 2007.
`
`(51) Int. Cl.
`A6 IK3I/56
`(52) U.S. Cl.
`USPC ........................................... 514/178; 514/182
`
`(2006.01)
`
`(58) Field of Classification Search
`USPC .................................................. 514/182, 178
`See application file for complete search history.
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`6,964,953 B2 * 1 1/2005 Belanoff ....................... 514,178
`OTHER PUBLICATIONS
`
`Sarkar, European Journal of Obstetrics and Gynecology and Repro
`ductive Biology, 2002: 101: 113-120.*
`Medical Encyclopedia of Medline (http:// http://www.nlm.nih.gov/
`medlineplus/ency/article/003430.htm, Oct. 2005.*
`
`* cited by examiner
`Primary Examiner — San-Ming Hui
`(74) Attorney, Agent, or Firm — Kilpatrick Townsend &
`Stockton LLP.
`ABSTRACT
`(57)
`The present invention provides a method for optimizing lev
`els of mifepristone in a patient Suffering from a mental dis
`order amenable to treatment by mifepristone. The method
`comprises the steps of treating the patient with seven or more
`daily doses of mifepristone over a period of seven or more
`days; testing the serum levels of the patient to determine
`whether the blood levels of mifepristone are greater than 1300
`ng/mL, and adjusting the daily dose of the patient to achieve
`mifepristone blood levels greater than 1300 ng/mL.
`7 Claims, 6 Drawing Sheets
`
`BPRS PSS-Days 7 and 56 Response
`
`40
`
`35 -
`
`359
`%
`
`30 -
`
`% of patients
`who have at 25 -
`east 50%
`reduction
`from baseline 20 -
`in BPRS PSS
`SCOres at
`days 7 and 56
`
`15 -
`
`26%
`
`10 -
`
`5 H
`
`0 -
`
`Corlux
`nE 443
`
`Placebo
`nF 281
`
`Ex. 2003-0001
`
`Corcept Therapeutics, Inc.
`Exhibit 2003
`Neptune Generics, LLC v. Corcept Therapeutics, Inc.
`Case IPR2018-01494
`
`

`

`Figure 1.
`
`BPRS PSS -Days 7 and 56 Response
`
`40
`
`35
`
`35%
`
`30
`
`% of patients
`who have at 25
`least 50%
`reduction
`from baseline 20
`in BPRS PSS
`scores at
`days 7 and 56
`
`15
`
`10
`
`5
`
`0
`
`p < .01
`
`Corlux
`
`n= 443
`
`Placebo
`n= 281
`
`Ex. 2003-0002
`
`

`

`Figure 2.
`
`45
`40
`35
`30
`% of patients
`who have at
`25
`least a 50%
`reduction
`20
`from baseline
`in BPRS PSS
`scores at days 15
`7 and 56
`10
`5
`0
`
`BPRS PSS - Days 7 and 56 Response
`
`40o/o
`
`27%
`
`26%
`
`>1357
`n=269
`p <.001
`
`<1357
`n=146
`
`Placebo
`n=281
`
`~
`00 .
`
`~
`~
`~
`
`~ =
`
`~
`
`c ('D
`
`~
`"'~
`N
`0
`
`....
`
`~
`
`rJJ
`
`('D
`('D
`
`=-
`.....
`N
`....
`0
`
`O'I
`
`d
`r.,;_
`00 u.
`
`\C
`"'00
`"""'
`~
`
`\C = N
`
`Ex. 2003-0003
`
`

`

`Figure 3.
`
`% of patients
`who have at
`least a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`7 and 56
`
`50
`45
`40
`35
`30
`25
`20
`15
`10
`5
`0
`
`BPRS PSS - Days 7 and 56 Response
`
`44°/o
`
`>1661
`n=166
`
`p <.00001
`
`<1661
`n=249
`
`Placebo
`n=281
`
`Ex. 2003-0004
`
`

`

`Figure 4.
`
`% of patients
`who have at
`least a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`7 and 56
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`BPRS PSS - Responses at Days 7 and 56
`
`47°/o
`
`34°/o
`
`Corlux
`n=76
`
`p=.10
`
`Placebo
`n=76
`
`Ex. 2003-0005
`
`

`

`Figure 5.
`
`% of patients
`who have at
`least a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`7 and 56
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`BPRS PSS - Days 7 and 56 Response
`
`54°/o
`
`c ('D
`
`~
`~~
`N
`
`0 ....
`
`~
`
`>1357
`n=56
`p=.026
`
`<1357
`n=13
`
`Placebo
`n=76
`
`Ex. 2003-0006
`
`

`

`Figure 6.
`
`% of patients
`who have at
`least a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`7 and 56
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`BPRS PSS -Days 7 and 56 Response
`
`58o/o
`
`>1661
`n=38
`
`p=.016
`
`<1661
`n=31
`
`Placebo
`n=76
`
`Ex. 2003-0007
`
`

`

`US 8,598,149 B2
`
`1
`OPTIMIZING MIFEPRISTONE LEVELS IN
`PLASMA SERUM OF PATIENTS SUFFERING
`FROM MENTAL DISORDERS TREATABLE
`WITH GLUCOCORTICOID RECEPTOR
`ANTAGONISTS
`
`2
`In a second embodiment, the present invention provides a
`kit for treating a mental disorder amenable to treatment by
`mifepristone, the kit comprising: seven daily doses of mife(cid:173)
`pristone; and a plasma sampling collection device suitable for
`5 detecting mifepristone serum levels.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`CROSS-REFERENCES TO RELATED
`APPLICATIONS
`
`This application claims priority to U.S. Provisional Appli- 10
`cation No. 60/969,027, filed Aug. 30, 2007, the disclosure of
`which is incorporated herein in its entirety.
`
`STATEMENT AS TO RIGHTS TO INVENTIONS
`MADE UNDER FEDERALLY SPONSORED
`RESEARCH AND DEVELOPMENT
`
`NOT APPLICABLE
`
`REFERENCE TO A "SEQUENCE LISTING," A
`TABLE, ORA COMPUTER PROGRAM LISTING
`APPENDIX SUBMITTED ON A COMPACT DISK
`
`NOT APPLICABLE
`
`BACKGROUND OF THE INVENTION
`
`It has been surprisingly discovered that administration of
`the same dose of mifepristone can produce widely varying
`blood serum levels in different patients. The varied blood
`serum levels can result in some patients not receiving an
`efficacious dose of mifepristone. For the same dose of mife(cid:173)
`pristone, the blood serum levels can differ by as much as
`800% from one patient to another. Thus, a method for ensur(cid:173)
`ing that the blood serum levels of mifepristone remain in an
`efficacious and safe range is needed.
`
`BRIEF SUMMARY OF THE INVENTION
`
`In one embodiment, the present invention provides a
`method for optimizing levels of mifepristone in a patient
`suffering from a mental disorder amenable to treatment by
`mifepristone, the method comprising: treating the patient
`with seven or more daily doses of mifepristone over a period
`of seven or more days; testing the serum levels of the patient
`to determine whether the blood levels of mifepristone are
`greater than 1300 ng/mL; and adjusting the daily dose of the
`patient to achieve mifepristone blood levels greater than 1300
`ng/mL.
`In some embodiments, the mental disorder is a member 50
`selected from the group consisting of a stress disorder,
`delirium, mild cognitive impairment (MCI), dementia, psy(cid:173)
`chosis and psychotic major depression. In other embodi(cid:173)
`ments, the stress disorder is a member selected from the group
`consisting of Acute Stress Disorder, Post-Traumatic Stress 55
`Disorder and Brief Psychotic Disorder with Marked Stressor
`(s).
`In another embodiment, each of the seven or more daily
`doses of mifepristone are administered orally. In other
`embodiments, the patient is treated with 28 or more daily 60
`doses over a period of 28 or more days.
`In a further embodiment, the testing is performed by a
`plasma sampling collection device suitable for detecting
`mifepristone serum levels.
`In other embodiments, the adjusting step comprises 65
`increasing the daily dose of the patient to achieve mifepris(cid:173)
`tone blood levels greater than 1300 ng/mL.
`
`FIG.1 shows a comparison of patients receiving Corlux vs.
`placebo on primary endpoint (OC) for all studies. Of the
`patients receiving Corlux, 35% of the patients showed at least
`a 50% reduction from baseline in BPRS PSS scores at days 7
`and 56, versus 26% of patients receiving the placebo.
`FIG. 2 shows a comparison of patients with plasma lev-
`15 els> 1357 ng/mL vs.<1357 ng/mL vs. placebo (OC) for all
`studies. Of the patients having plasma levels of greater than
`1357 ng/mL, 40% of the patients showed at least a 50%
`reduction from baseline in BPRS PSS scores at days 7 and 56,
`versus 27% of patients having plasma levels ofless than 1357
`20 ng/mL and 26% of patients receiving the placebo.
`FIG. 3 shows a comparison of patients with plasma lev(cid:173)
`els> 1661 ng/ml vs. placebo (OC) for all studies. Of the
`patients having plasma levels of greater than 1661 ng/mL,
`44% of the patients showed at least a 50% reduction from
`25 baseline in BPRS PSS scores at days 7 and 56, versus 29% of
`patients having plasma levels of less than 1661 ng/mL and
`26% of patients receiving the placebo.
`FIG. 4 shows a comparison of patients receiving Corlux vs.
`placebo on primary endpoint (OC) for the 1200 mg group. Of
`30 the patients receiving the 1200 mg dose ofCorlux, 47% of the
`patients showed at least a 50% reduction from baseline in
`BPRS PSS scores at days 7 and 56, versus 34% of patients
`receiving the placebo.
`FIG. 5 shows a comparison of patients with plasma lev-
`35 els> 1357 ng/ml vs. placebo (OC) for the 1200 mg group. Of
`the patients in the 1200 mg group having plasma levels of
`greater than 1357 ng/mL, 54% of the patients showed at least
`a 50% reduction from baseline in BPRS PSS scores at days 7
`and 56, versus 31 % of patients having plasma levels of less
`40 than 1357 ng/mL and 34% of patients receiving the placebo.
`FIG. 6 shows a comparison of patients with plasma lev(cid:173)
`els> 1661 ng/ml vs. placebo (OC) for the 1200 mg group. Of
`the patients in the 1200 mg group having plasma levels of
`greater than 1661 ng/mL, 58% of the patients showed at least
`45 a 50% reduction from baseline in BPRS PSS scores at days 7
`and 56, versus 39% of patients having plasma levels of less
`than 1661 ng/mL and 34% of patients receiving the placebo.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`I. Introduction
`
`Administration of the same dose of mifepristone can pro(cid:173)
`duce widely varying mifepristone blood serum levels in dif(cid:173)
`ferent patients. For the same dose, the blood serum levels can
`differ by as much as 800% from one patient to another. For
`those patients with lower blood serum levels, the effective(cid:173)
`ness of mifepristone treatment can suffer significantly. The
`present invention provides a method for optimizing the blood
`serum levels of mifepristone so that the blood serum levels
`remain in an efficacious range and the patient receives the
`necessary treatment.
`The method of the present invention optimizes blood
`serum levels of mifepristone in a patient suffering from a
`mental disorder amenable to treatment by mifepristone by
`first treating the patient with mifepristone. The treatment can
`be for any appropriate period of time, such as seven or more
`
`Ex. 2003-0008
`
`

`

`US 8,598,149 B2
`
`3
`daily doses over a period of seven or more days. Following
`treatment for an appropriate period of time, the serum levels
`of the patient are tested to determine whether the blood levels
`of mifepristone are greater than 1300 ng/mL. The daily dose
`of the patient is then adjusted in order to achieve mifepristone
`blood levels of greater than 1300 ng/mL.
`
`II. Definitions
`
`The term "amenable to treatment by mifepristone" refers to
`a condition that is known to be treated by glucocorticoid
`antagonists such as mifepristone. Conditions such as mental
`disorders (discussed below) are amenable to treatment by
`mifepristone.
`The term "mental disorder" refers to disorders of the mind
`that can be treated with a glucocorticoid antagonist such as
`mifepristone. Mental disorders amenable to treatment by the
`methods of the present invention include, but are not limited
`to, a stress disorder, delirium, mild cognitive impairment
`(MCI), dementia, psychosis and psychotic major depression. 20
`The term "stress disorder" refers to a psychiatric condition
`precipitated by exposure to a traumatic or stressful event.
`Stress disorders include Acute Stress Disorder, Post-Trau(cid:173)
`matic Stress Disorder, and Brief Psychotic Disorder with
`Marked Stressor(s).
`The term "Acute Stress Disorder" refers to a psychiatric
`condition in its broadest sense, as defined in American Psy(cid:173)
`chiatric Association: Diagnostic and Statistical Manual of
`Mental Disorders, Fourth Edition, Text Revision, Washing(cid:173)
`ton, D.C., 2000 ("DSM-IV-TR"). The DSM-IV-TR defines 30
`"Acute Stress Disorder" as characterized by anxiety, disso(cid:173)
`ciative, and other symptoms occurring within 1 month after
`exposure to an extreme traumatic stressor. The DSM-IV-TR
`sets forth a generally accepted standard for diagnosing and
`categorizing Acute Stress Disorder.
`The term "Brief Psychotic Disorder with Marked Stressor
`( s )" refers to a psychiatric condition in its broadest sense, as
`defined in DSM-IV-TR. The DSM-IV-TR defines "Brief Psy(cid:173)
`chotic Disorder with Marked Stressor(s)" as a sudden but
`brief onset of psychotic symptoms developing shortly after 40
`and apparently in response to one or more stressful events.
`The DSM-IV-TR sets forth a generally accepted standard for
`diagnosing and categorizing Brief Psychotic Disorder with
`Marked Stressor(s).
`The term "delirium" refers to a psychiatric condition in its 45
`broadest sense, as defined in American Psychiatric Associa(cid:173)
`tion: Diagnostic and Statistical Manual of Mental Disorders,
`Fourth Edition, Text Revision, Washington, D.C., 2000
`("DSM-IV-TR"). The DSM-IV-TR defines "delirium" as a
`disturbance of consciousness, developing over a short period 50
`of time, accompanied by a change in cognition that cannot be
`better accounted for by a preexisting or evolving dementia.
`The DSM-IV-TR sets forth a generally accepted standard for
`diagnosing and categorizing delirium.
`The term "dementia" refers to a psychiatric condition in its 55
`broadest sense, as defined in American Psychiatric Associa(cid:173)
`tion: Diagnostic and Statistical Manual of Mental Disorders,
`Fourth Edition, Washington, D.C., 1994 ("DSM-IV"). The
`DSM-IV defines "dementia" as characterized by multiple
`cognitive deficits that include impairments in memory and 60
`lists various dementias according to presumed etiology. The
`DSM-IV sets forth a generally accepted standard for such
`diagnosing, categorizing and treating of dementia and asso(cid:173)
`ciated psychiatric disorders.
`The term "mild cognitive impairment (MCI)" refers to a 65
`category of memory and cognitive impairment that is typi(cid:173)
`cally characterized by a clinical dementia rating (CDR) of0.5
`
`4
`(see, e.g., Hughes et al., Brit. J. Psychiat. 140:566-572, 1982)
`and further characterized by memory impairment, but not
`impaired function in other cognitive domains. Memory
`impairment is preferably measured using tests such as a
`"paragraph test". A patient diagnosed with MCI often exhib(cid:173)
`its impaired delayed recall performance. MCI is typically
`associated with aging and generally occurs in patients who
`are 45 years of age or older.
`The term "mifepristone" refers to a family of compositions
`10 also referred to as RU486, or RU38.486, or 17-beta-hydroxy-
`11-beta-( 4-dimethyl-aminophenyl)-17-alpha-(1-propynyl)(cid:173)
`estra-4,9-dien-3-one ), or 11-beta-( 4-dimethylaminophenyl)-
`17-beta-hydroxy-l 7-alpha-(1-propynyl)-estra-4,9-dien-3-
`one), or analogs thereof, which bind to the glucocorticoid
`15 receptor (GR), typically with high affinity, and inhibit the
`biological effects initiated/mediated by the binding of any
`cortisol or cortisol analogue to a GR receptor (as discussed
`within). Salts, hydrates and prodrugs of mifepristone are all
`within the scope of the present invention.
`The term "Post-Traumatic Stress Disorder" refers to a psy-
`chiatric condition in its broadest sense, as defined in DSM(cid:173)
`IV-TR. The DSM-IV-TR defines "Post-Traumatic Stress Dis(cid:173)
`order" as characterized by persistent re-experiencing of an
`extreme traumatic event. The DSM-IV-TR sets forth a gen-
`25 erally accepted standard for diagnosing and categorizing
`Post-Traumatic Stress Disorder.
`The term "psychotic" as used herein refers to a psychiatric
`condition in its broadest sense, as defined in the DSM-IV
`(Kaplan, ed. (1995) supra) and described below. The term
`"psychotic" has historically received a number of different
`definitions, ranging from narrow to broadly described. A
`psychotic condition can include delusions or prominent hal(cid:173)
`lucinations, including prominent hallucinations that the indi(cid:173)
`vidual realizes are hallucinatory experiences, and those with
`35 hallucinations occurring in the absence of insight into their
`pathological nature. Finally, the term includes a psychotic
`condition characterized by a loss of ego boundaries or a gross
`impairment in reality testing. Unlike this definition, which is
`broad and based primarily on symptoms, characterization of
`psychosis in earlier classifications (e.g., DSM-II and ICD-9)
`were more inclusive and focused on the severity of functional
`impairment (so that a mental disorder was termed "psy(cid:173)
`chotic" if it resulted in "impairment" that grossly interferes
`with the capacity to meet ordinary demands oflife). Different
`disorders which have a psychotic component comprise dif(cid:173)
`ferent aspects of this definition of"psychotic." For example,
`in schizophreniform disorder, schizoaffective disorder and
`brief psychotic disorder, the term "psychotic" refers to delu(cid:173)
`sions, any prominent hallucinations, disorganized speech, or
`disorganized or catatonic behavior. In psychotic disorder due
`to a general medical condition and in substance-induced psy-
`chotic disorder, "psychotic" refers to delusions or only those
`hallucinations that are not accompanied by insight. Finally, in
`delusional disorder and shared psychotic disorder, "psy(cid:173)
`chotic" is equivalent to "delusional" (see DSM-IV, supra,
`page 273).
`Objective tests can be also be used to determine whether an
`individual is psychotic and to measure and assess the success
`of a particular treatment schedule or regimen. For example,
`measuring changes in cognitive ability aids in the diagnosis
`and treatment assessment of the psychotic patient. Any test
`known in the art can be used, such as the so-called "Wallach
`Test," which assesses recognition memory (see below,
`Wallach (1980) J. Gerontol. 35:371-375). Another example
`of an objective text which can be used to determine whether
`an individual is psychotic and to measure efficacy of an anti-
`psychotic treatment is the Stroop Colar and Word Test
`
`Ex. 2003-0009
`
`

`

`US 8,598,149 B2
`
`5
`("Stroop Test") (see Golden, C. J., Cat. No. 30150M, In A
`Manual for Clinical and Experimental Uses, Stoelting, Wood
`Dale, Ill.) The Stroop Test is an objective neuropsychiatric
`test that can differentiate between individuals with psychosis
`and those without, and is described in detail below.
`The term "psychosis" refers to a psychiatric symptom,
`condition or syndrome in its broadest sense, as defined in the
`DSM-IV (Kaplan, ed. (1995) supra), comprising a "psy(cid:173)
`chotic" component, as broadly defined above. The term psy(cid:173)
`chosis can refer to a symptom associated with a general 10
`medical condition, a disease state or other condition, such as
`a side effect of drug abuse (a substance-induced disorder) or
`as a side effect of a medication. Alternatively, the term psy(cid:173)
`chosis can refer to a condition or syndrome not associated
`with any disease state, medical condition, drug intake or the 15
`like.
`Psychosis is typically defined as a mental disorder or con(cid:173)
`dition causing gross distortion or disorganization of a per(cid:173)
`son's mental capacity, affective response, and capacity to
`recognize reality, communicate, and relate to others to the 20
`degree of interfering with his capacity to cope with the ordi(cid:173)
`nary demands of everyday life.
`The term "psychotic major depression," also referred to as
`"psychotic depression" (Schatzberg (1992)Am. J. Psychiatry
`149:733-745), "psychotic (delusional) depression" (Ibid.), 25
`"delusional depression" (Glassman (1981) supra) and,
`"major depression with psychotic features" (see the DSM(cid:173)
`III-R), refers to a distinct psychiatric disorder which includes
`both depressive and psychotic features. Individuals manifest(cid:173)
`ing both depression and psychosis, i.e. psychotic depression, 30
`are herein referred to as "psychotic depressives." It has been
`long-recognized in the art as a distinct syndrome, as
`described, for example, by Schatzberg (1992) supra. Illustra(cid:173)
`tive of this distinctness are studies which have found signifi(cid:173)
`cant differences between patients with psychotic andnonpsy- 35
`chotic depression in glucocorticoid activity, dopamine-beta(cid:173)
`hydroxylase activity, levels of dopamine and serotonin
`metabolites, sleep measures and ventricle to brain ratios.
`Psychotic depressives respond very differently to treatment
`compared to individuals with other forms of depression, such 40
`as "non-psychotic major depression." Psychotic depressives
`have a low placebo response rate and respond poorly to anti(cid:173)
`depressant therapy alone (without concurrent anti-psychotic
`treatment). Psychotic depressives are markedly unresponsive
`to tricyclic (anti-depressive) drug therapy (Glassman, et al. 45
`(1975) supra). While psychotic depressives can respond to
`electroconvulsive therapy (ECT), their response time is rela(cid:173)
`tively slow and the ECT has a high level of related morbidity.
`Clinical manifestations and diagnostic parameters of "psy(cid:173)
`chotic major depression" is described in detail in the DSM-IV 50
`(Kaplan, ed. (1995) supra). Thus, due to its unique patho(cid:173)
`physiology, high rate of morbidity and response to treatment,
`there is great practical need to differentially diagnose and
`specifically treat psychotic major depression as compared to
`non-psychotic depression.
`The term "optimizing" refers to the process of testing mife(cid:173)
`pristone blood levels and adjusting the dosage of mifepristone
`administered to the patient in need in order to achieve mife(cid:173)
`pristone blood levels above 1300 ng/mL.
`The terms "treat", "treating" and "treatment" collectively 60
`refer to any indicia of success in the treatment or amelioration
`of an injury, pathology or condition, including any objective
`or subjective parameter such as abatement; remission; dimin(cid:173)
`ishing of symptoms or making the injury, pathology or con(cid:173)
`dition more tolerable to the patient; slowing in the rate of 65
`degeneration or decline; making the final point of degenera(cid:173)
`tion less debilitating; improving a patient's physical or men-
`
`6
`ta! well-being; or, in some situations, preventing the onset of
`dementia. The treatment or amelioration of symptoms can be
`based on objective or subjective parameters; including the
`results of a physical examination, neuropsychiatric exams,
`and/or a psychiatric evaluation.
`The term "testing" refers to determining the mifepristone
`blood levels in a patient. The testing can be performed by any
`suitable instrument, such as a plasma sampling collection
`device capable of detecting mifepristone serum levels.
`
`III. Method for Optimizing Mifepristone Levels
`
`Administration of the same dose ofmifepristone to differ(cid:173)
`ent patients can produce widely varying blood serum levels,
`varying by up to 800% from one patient to another, resulting
`in decreased efficacy. The present invention provides a
`method for optimizing the blood serum levels of mifepristone
`so that the blood serum levels remain in an efficacious range
`and the patient receives the necessary treatment.
`A. Patients in Need
`Patients amenable to treatment with mifepristone accord(cid:173)
`ing to the method of the present invention suffer from any
`mental disorder. Exemplary mental disorders include, but are
`not limited to, a stress disorder, delirium, mild cognitive
`impairment (MCI), dementia, psychosis and psychotic major
`depression.
`Stress disorders treatable by the methods of the present
`invention include, but are not limited to, Acute Stress Disor(cid:173)
`der (ASD), Post-Traumatic Stress Disorder and Brief Psy(cid:173)
`chotic Disorder with Marked Stressor(s ).
`Acute Stress Disorder (ASD) is characterized by a constel(cid:173)
`lation of symptoms, lasting at least two days, that appear and
`resolve within one month of exposure to an extreme traumatic
`stressor. If symptoms appear or persist beyond one month
`after exposure to the traumatic stressor, the patient may be
`considered to suffer from Post-Traumatic Stress Disorder
`rather than ASD. ASD is a common precursor to Post-Trau(cid:173)
`matic Stress Disorder, and up to 80% of trauma survivors
`initially suffering from ASD will meet the diagnostic criteria
`for Post-Traumatic Stress Disorder six months later (see
`Brewin et al., Am J Psychiatry 156:360-6, 1999).
`Patients develop ASD following exposure to an extreme
`traumatic stressor (DSM-IV-TR Criterion A). A person must
`respond to the stressor with intense fear, helplessness, or
`horror to be diagnosed with ASD. ASD may develop from
`direct experience of traumatic events, including violent
`crimes, physical trauma, combat, diagnosis with a life-threat(cid:173)
`ening illness, and natural or manmade disasters. Patients may
`also develop ASD from witnessing or learning about trau(cid:173)
`matic events that happen to others, especially family mem(cid:173)
`bers or close friends. Unexpected exposure to death, dead
`bodies, or body parts may also induce ASD.
`A diagnosis of ASD requires that the person meet several
`other symptomatic criteria. The person must experience three
`55 or more dissociative symptoms in connection with the trau(cid:173)
`matic stressor (Criterion B).Dissociative symptoms include a
`subjective sense of numbing or detachment, a reduction in
`awareness of surroundings, derealization, depersonalization,
`and dissociative amnesia. Furthermore, ASD requires that the
`victim persistently re-experience the traumatic event, though
`recurrent images, thoughts, dreams, illusions, flashbacks,
`sense of reliving the event, or distress upon exposure to
`reminders of the event (Criterion C).The person must display
`marked avoidance of stimuli that arouse recollection of the
`trauma (Criterion D) and marked symptoms of anxiety or
`increased arousal (Criterion E).Finally, in addition to the time
`requirements described above, a diagnosis of ASD requires
`
`Ex. 2003-0010
`
`

`

`US 8,598,149 B2
`
`7
`that the disturbance cause significant distress; or life impair(cid:173)
`ment, and not be due to another psychiatric or physiological
`condition (Criteria F-H).
`Like Acute Stress Disorder, Post-Traumatic Stress Disor(cid:173)
`der (PTSD) emerges following exposure to an extreme trau(cid:173)
`matic stressor, and is characterized by persistent reexperienc(cid:173)
`ing of the traumatic event, avoidance of stimuli associated
`with the trauma, and anxiety or increased arousal. The types
`of traumatic stressors giving rise to PTSD, and the manifes(cid:173)
`tations of PTSD symptoms, are identical to those described 10
`above for ASD, but for three differences. First, the dissocia(cid:173)
`tive symptoms required for a diagnosis of ASD are not
`required for a diagnosis of PTSD, although dissociative
`symptoms may commonly be seen in PTSD patients. Sec(cid:173)
`ondly, PTSD need not arise within one month of exposure to 15
`the traumatic stressor, and may emerge months or years after
`the traumatic event. Thirdly, in contrast to the one month
`maximum duration of symptoms required for a diagnosis of
`ASD, symptoms must persist for at least one month in order
`for a diagnosis of PTSD to be made.
`A Brief Psychotic Disorder is a short-term (between one
`day and one month) disturbance involving the sudden onset of
`at least one psychotic symptom, such as delusions, halluci(cid:173)
`nations, disorganized speech, or grossly disorganized or cata(cid:173)
`tonic behavior. Brief Psychotic Disorders exclude those 25
`induced by a general medical condition. If psychotic symp(cid:173)
`toms develop shortly after, and apparently in response to, one
`or more severely stressful events, the disturbance is diag(cid:173)
`nosed as Brief Psychotic Disorder with Marked Stressor(s)
`(formerly labeled "briefreactive psychosis" in DSM-III-R). 30
`Brief Psychotic Disorder with Marked Stressor( s) is treatable
`by the glucocorticoid receptor antagonists of the present
`invention.
`Delirium is characterized by disturbances of consciousness
`and changes in cognition that develop over a relatively short 35
`period of time. The disturbance in consciousness is often
`manifested by a reduced clarity of awareness of the environ(cid:173)
`ment. The patient displays reduced ability to focus, sustain or
`shift attention (DSM-IV-TR diagnostic Criterion A). Accom(cid:173)
`panying the disturbance in consciousness, delirium patients 40
`display a disturbance in cognition ( e.g., memory impairment,
`disorientation, language difficulties) or perceptual distur(cid:173)
`bances ( e.g., misinterpretations, illusions, or hallucinations)
`(Criterion B). To be considered delirium, these disturbances
`in consciousness, cognition, or perception should develop 45
`over a short period of time and tend to fluctuate during the
`course of the day (Criterion C).
`Delirium may arise from a number of general medical
`conditions, including central nervous system disorders ( e.g.,
`trauma, stroke, encephalopathies), metabolic disorders (e.g., 50
`renal or hepatic insufficiency, fluid or electrolyte imbal(cid:173)
`ances), cardiopulmonary disorders (e.g., congestive heart
`failure, myocardial infarction, shock), and systemic illnesses
`or effects (e.g., infections, sensory deprivation, and postop(cid:173)
`erative states). Glucocorticoid receptor antagonists are also 55
`effective to treat Substance-Induced Delirium ( e.g., delirium
`induced by substance intoxication or withdrawal, medication
`side effects, and toxin exposure). Delirium may arise from
`multiple simultaneous etiologies (e.g., a combination of a
`general medical condition and substance intoxication) and 60
`such delirium, as well as delirium of unknown or unclassified
`origin, may be treated with the glucocorticoid receptor
`antagonists of the present invention.
`Mild cognitive impairment (MCI) is characterized as a
`mild impairment of cognition categorized as a CDR of 0.5 65
`that is associated with deficits in a memory task test, such as
`a paragraph test. An MCI patient is fully oriented, but dem-
`
`8
`onstrates mild consistent forgetfulness. Impairment in cogni(cid:173)
`tive domains other than memory, such as problem solving and
`judgment is doubtful, if present at all, and, further, the MCI
`patient does not demonstrate impairment in functioning in the
`community or at home. A patient with MCI scores normally
`on standard tests of dementia.
`There are various means to diagnose the onset of MCI and
`to assess the efficacy of treatment using the methods of the
`invention. These include the administration of psychiatric
`tests to determine the CDR, the administration of memory
`tests, and the administration of psychiatric tests for dementia,
`which are used to exclude a diagnosis of dementia. The results
`of these test may be considered in conjunction with other
`objective physical tests as described below. These means are
`also useful for assessing the efficacy of the methods of the
`invention in improving memory or decreasing or diminishing
`further impairment in memory or cognitive decline in a
`patient with MCI. Subjective and objective criteria can be
`used to measure and assess the success of a particular GR
`20 antagonist, pharmaceutical formulation, dosage, treatment
`schedule or regimen. The features (symptoms) of and criteria
`for diagnosing MCI are described, e.g., in Petersen et al.,
`Arch. Neural. 56:303-308, 1999.
`The dementia treated in the methods of the invention
`encompasses a broad range of mental conditions and symp(cid:173)
`toms, as broadly described in the DSM-IV. While the practi(cid:173)
`tioner can use any set of prescribed or empirical criteria to
`diagnose the presence of dementia as an indication to practice
`the methods of the invention, some illustrative diagnostic
`guidelines and examples of relevant symptoms and condi(cid:173)
`tions are described below.
`The DSM-IV states that dementias typically associated
`withAlzheimer' s disease ( dementia of theAlzheimer' s type),
`"vascular dementia" (also known as multi-infarct dementia),
`or "dementia due to general medical conditions," e.g., human
`immunodeficiency virus (HIV-1) disease, head trauma, Par-
`kinson' s disease, or Huntington's disease (further discussed,
`below). Dementias can also be "substance-induced pers