111111111111111111111111111!!),111J1111,1!11111111111111111111111111
`
`(12) United States Patent
`Belanoff
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,921,348 B2
`Dec. 30, 2014
`
`(54) OPTIMIZING MIFEPRISTONE LEVELS IN
`PLASMA SERUM OF PATIENTS SUFFERING
`FROM MENTAL DISORDERS TREATABLE
`WITH GLUCOCORTICOID RECEPTOR
`ANTAGONISTS
`
`(71) Applicant: Corcept Therapeutics, Menlo Park, CA
`(US)
`
`(72) Inventor: Joseph K. Belanoff, Woodside, CA (US)
`
`(73) Assignee: Corcept Therapeutics, Inc., Menlo
`Park, CA (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.: 14/065,792
`
`(22) Filed:
`
`Oct. 29, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2014/0162993 Al
`
`Jun. 12, 2014
`
`Related U.S. Application Data
`
`Continuation of application No. 12/199,114, filed on
`Aug. 27, 2008, now Pat. No. 8,598,149.
`
`Provisional application No. 60/969,027, filed on Aug.
`30, 2007.
`
`Int. Cl.
`A61K 31/56
`GO1N 33/49
`A61K 31/575
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(52) U.S. Cl.
`CPC
`
` GO1N 33/49 (2013.01); A 61K 31/56
`(2013.01); A61K 31/575 (2013.01)
` 514/178
`
`USPC
`(58) Field of Classification Search
` 514/178
`USPC
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6,964,953 B2
`
`11/2005 Belanoff
`
`OTHER PUBLICATIONS
`
`Medical Encyclopedia of Medline (http:// http://www.nlm.nih.gov/
`medlineplus/ency/article/003430.htm), 4 pages, Oct. 2005.
`Sarkar, "Mifepristone: bioavailability, pharmacokinetics and use-
`effectiveness," European Journal of Obstetrics and Gynecology and
`Reproductive Biology, vol. 101, pp. 113-120 (2002).
`
`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
`
`35 -
`
`35'0
`
`30 -
`% of patients
`who have at 25
`least 50%
`reduction
`from baseline
`in BPRS PSS
`scores at
`days 7 and 56
`
`15 H
`
`20 -1
`
`26%
`
`10
`
`Corlux
`n= 443
`
`Placebo
`n= 281
`
`p‹.01
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 1
`
`

`

`lualud 'S11
`
`9 Jo I Oat's
`
`ZH 8ti` I Z6`8 SR
`
`Figure 1.
`
`% of patients
`who have at
`least 50%
`reduction
`from baseline
`in BPRS PSS
`scores at
`days 7 and 56
`
`40
`
`35 -
`
`30 -
`
`25 -
`
`20 -I
`
`15
`
`10 -
`
`5 -?
`
`0
`
`p‹.01
`
`BPRS PSS -Days 7 and 56 Response
`
`35%
`
`26%
`
`Corlux
`
`n=443
`
`Placebo
`n= 281
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 2
`
`

`

`lualud °Sil
`
`9 .19 Z WIN
`
`Zll 817£`1Z6`8 Sf1
`
`Figure 1.
`
`% of patients
`who have at
`least a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`7 and 56
`
`45
`
`40 -
`
`35 -
`
`3O -
`
`25
`
`20
`
`15 -
`
`10-
`
`5
`
`0
`
`BPRS PSS Days 7 and 56 Response
`
`40%
`
`27%
`
`26%
`
`>1357
`n=269
`P <.001
`
`<1357
`n=146
`
`Placebo
`n=281
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 3
`
`

`

`lualud °Sil
`
`9 JO £ PaMS
`
`Zll 817£`1Z6`8 Sf1
`
`Figure 1
`
`% of patients
`who have at
`'east a 50%
`reduction
`from baseline
`Ire BPRS PSS
`scores at days
`7 and 56
`
`
`50
`45 -
`40 -
`
`30
`25
`20
`15 -
`10 -
`-
`0
`
`BPRS PSS - Days 7 and 56 Response
`
`44%
`
`29%
`
`>1661
`n=166
`
`p ‹.00001
`
`<1661
`n=249
`
`Placebo
`n=281
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 4
`
`

`

`lualud °Sil
`
`9 JO 17 JamiS
`
`Zll 817£`1Z6`8 Sf1
`
`Figure 4
`
`% of patients
`who have at
`least a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`I and 56
`
`70
`
`60
`
`50 -
`
`40
`
`30
`
`20
`
`10
`
`0
`
`p= .10
`
`BPRS PSS Responses at Days 7 and 56
`
`47%
`
`34%
`
`Corlux
`n=76
`
`Placebo
`n=76
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 5
`
`

`

`lualud °Sil
`
`rtoz `of *aaa
`
`9 JO S WIN
`
`Zll 817£`1Z6`8 Sf1
`
`Figure 5
`
`% of patients
`who have at
`'east a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`7 and 56
`
`70
`
`60
`
`50
`
`40-
`
`2O
`
`10-
`
`0
`
`BPRS PSS Days 7 and 56 Response
`
`54%
`
`31%
`
`34%
`
`>1357
`n=56
`p= .026
`
`<1357
`n=13
`
`Placebo
`n=76
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 6
`
`

`

`lualud *S'il
`
`9 JO 9 laatiS
`
`Zil 817£`1Z6`8 Sfl
`
`Figure 6.
`
`70
`
`60 -
`
`50 -
`
`40 --
`
`30
`
`20
`
`% of patients
`who have at
`least a 50%
`reduction
`from baseline
`in BPRS PSS
`scores at days
`7 and 56
`
`BPRS PSS -Days 7 and 56 Response
`
`58%
`
`39%
`
`34%
`
`p= .016
`
`Placebo
`n=76
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 7
`
`

`

`US 8,921,348 B2
`
`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-
`pristone; and a plasma sampling collection device suitable for
`5 detecting mifepristone serum levels.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`1
`OPTIMIZING MIFEPRISTONE LEVELS IN
`PLASMA SERUM OF PATIENTS SUFFERING
`FROM MENTAL DISORDERS TREATABLE
`WITH GLUCOCORTICOID RECEPTOR
`ANTAGONISTS
`
`CROSS-REFERENCES TO RELATED
`APPLICATIONS
`
` 10
`This application claims priority to U.S. Provisional Appli-
`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, OR A COMPUTER PROGRAM LISTING
`APPENDIX SUBMITTED ON A COMPACT DISK
`
`Not Applicable
`
`BACKGROUND OF THE INVENTION
`
`15
`
`20
`
`25
`
`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 30
`serum levels can result in some patients not receiving an
`efficacious dose of mifepristone. For the same dose of mife-
`pristone, the blood serum levels can differ by as much as
`800% from one patient to another. Thus, a method for ensur-
`ing that the blood serum levels of mifepristone remain in an 35
`efficacious and safe range is needed.
`
`BRIEF SUMMARY OF THE INVENTION
`
`In one embodiment, the present invention provides a 40
`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 45
`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 so
`selected from the group consisting of a stress disorder,
`delirium, mild cognitive impairment (MCI), dementia, psy-
`chosis and psychotic major depression. In other embodi-
`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-
`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
`levels >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 of less than 1357
`ng/mL and 26% of patients receiving the placebo.
`FIG. 3 shows a comparison of patients with plasma
`levels >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
`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
`the patients receiving the 1200 mg dose of Corlux, 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
`levels >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
`than 1357 ng/mL and 34% of patients receiving the placebo.
`FIG. 6 shows a comparison of patients with plasma
`levels >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
`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-
`duce widely varying mifepristone blood serum levels in dif-
`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-
`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
`daily doses over a period of seven or more days. Following
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 8
`
`

`

`US 8,921,348 B2
`
`4
`3
`impairment is preferably measured using tests such as a
`treatment for an appropriate period of time, the serum levels
`"paragraph test". A patient diagnosed with MCI often exhib-
`of the patient are tested to determine whether the blood levels
`its impaired delayed recall performance. MCI is typically
`of mifepristone are greater than 1300 ng/mL. The daily dose
`associated with aging and generally occurs in patients who
`of the patient is then adjusted in order to achieve mifepristone
`5 are 45 years of age or older.
`blood levels of greater than 1300 ng/mL.
`The term "mifepristone" refers to a family of compositions
`II. Definitions
`also referred to as RU486, or RU38.486, or 17-beta-hydroxy-
`The term "amenable to treatment by mifepristone" refers to
`11 -beta- (4 -dimethyl-aminopheny1)-17 -alpha- (1 -propyny1)-
`a condition that is known to be treated by glucocorticoid
`estra-4,9-dien-3 -one), or 11-beta-(4-dimethylaminophenyl)-
`antagonists such as mifepristone. Conditions such as mental
`disorders (discussed below) are amenable to treatment by 10 17-beta-hydroxy-17 -alpha-(1 -propyny1)-estra-4,9-dien-3 -
`mifepristone.
`one), or analogs thereof, which bind to the glucocorticoid
`The term "mental disorder" refers to disorders of the mind
`receptor (GR), typically with high affinity, and inhibit the
`that can be treated with a glucocorticoid antagonist such as
`biological effects initiated/mediated by the binding of any
`mifepristone. Mental disorders amenable to treatment by the
`cortisol or cortisol analogue to a GR receptor (as discussed
`methods of the present invention include, but are not limited 15 within). Salts, hydrates and prodrugs of mifepristone are all
`to, a stress disorder, delirium, mild cognitive impairment
`within the scope of the present invention.
`(MCI), dementia, psychosis and psychotic major depression.
`The term "Post-Traumatic Stress Disorder" refers to a psy-
`The term "stress disorder" refers to a psychiatric condition
`chiatric condition in its broadest sense, as defined in DSM-
`precipitated by exposure to a traumatic or stressful event.
`IV-TR. The DSM-IV-TR defines "Post-Traumatic Stress Dis-
`Stress disorders include Acute Stress Disorder, Post-Trau- 20 order" as characterized by persistent re-experiencing of an
`matic Stress Disorder, and Brief Psychotic Disorder with
`extreme traumatic event. The DSM-IV-TR sets forth a gen-
`Marked Stressor(s).
`erally accepted standard for diagnosing and categorizing
`The term "Acute Stress Disorder" refers to a psychiatric
`Post-Traumatic Stress Disorder.
`condition in its broadest sense, as defined in American Psy-
`The term "psychotic" as used herein refers to a psychiatric
`chiatric Association: Diagnostic and Statistical Manual of 25 condition in its broadest sense, as defined in the DSM-IV
`Mental Disorders, Fourth Edition, Text Revision, Washing-
`(Kaplan, ed. (1995) supra) and described below. The term
`ton, D.C., 2000 ("DSM-IV-TR"). The DSM-IV-TR defines
`"psychotic" has historically received a number of different
`"Acute Stress Disorder" as characterized by anxiety, disso-
`definitions, ranging from narrow to broadly described. A
`ciative, and other symptoms occurring within 1 month after
`psychotic condition can include delusions or prominent hal-
`exposure to an extreme traumatic stressor. The DSM-IV-TR 30 lucinations, including prominent hallucinations that the indi-
`sets forth a generally accepted standard for diagnosing and
`vidual realizes are hallucinatory experiences, and those with
`categorizing Acute Stress Disorder.
`hallucinations occurring in the absence of insight into their
`The term "Brief Psychotic Disorder with Marked
`pathological nature. Finally, the term includes a psychotic
`Stressor(s)" refers to a psychiatric condition in its broadest
`condition characterized by a loss of ego boundaries or a gross
`sense, as defined in DSM-IV-TR. The DSM-IV-TR defines 35 impairment in reality testing. Unlike this definition, which is
`"Brief Psychotic Disorder with Marked Stressor(s)" as a sud-
`broad and based primarily on symptoms, characterization of
`den but brief onset of psychotic symptoms developing shortly
`psychosis in earlier classifications (e.g., DSM-II and ICD-9)
`after and apparently in response to one or more stressful
`were more inclusive and focused on the severity of functional
`events. The DSM-IV-TR sets forth a generally accepted stan-
`impairment (so that a mental disorder was termed "psy-
`dard for diagnosing and categorizing Brief Psychotic Disor- 40 chotic" if it resulted in "impairment" that grossly interferes
`der with Marked Stressor(s).
`with the capacity to meet ordinary demands of life). Different
`The term "delirium" refers to a psychiatric condition in its
`disorders which have a psychotic component comprise dif-
`broadest sense, as defined in American Psychiatric Associa-
`ferent aspects of this definition of "psychotic." For example,
`tion: Diagnostic and Statistical Manual of Mental Disorders,
`in schizophreniform disorder, schizoaffective disorder and
`Fourth Edition, Text Revision, Washington, D.C., 2000 45 brief psychotic disorder, the term "psychotic" refers to delu-
`("DSM-IV-TR"). The DSM-IV-TR defines "delirium" as a
`sions, any prominent hallucinations, disorganized speech, or
`disturbance of consciousness, developing over a short period
`disorganized or catatonic behavior. In psychotic disorder due
`of time, accompanied by a change in cognition that cannot be
`to a general medical condition and in substance-induced psy-
`better accounted for by a preexisting or evolving dementia.
`chotic disorder, "psychotic" refers to delusions or only those
`The DSM-IV-TR sets forth a generally accepted standard for so hallucinations that are not accompanied by insight. Finally, in
`diagnosing and categorizing delirium.
`delusional disorder and shared psychotic disorder, "psy-
`The term "dementia" refers to a psychiatric condition in its
`chotic" is equivalent to "delusional" (see DSM-IV, supra,
`broadest sense, as defined in American Psychiatric Associa-
`page 273).
`tion: Diagnostic and Statistical Manual of Mental Disorders,
`Objective tests can be also be used to determine whether an
`Fourth Edition, Washington, D.C., 1994 ("DSM-IV"). The 55 individual is psychotic and to measure and assess the success
`DSM-IV defines "dementia" as characterized by multiple
`of a particular treatment schedule or regimen. For example,
`cognitive deficits that include impairments in memory and
`measuring changes in cognitive ability aids in the diagnosis
`lists various dementias according to presumed etiology. The
`and treatment assessment of the psychotic patient. Any test
`DSM-IV sets forth a generally accepted standard for such
`known in the art can be used, such as the so-called "Wallach
`diagnosing, categorizing and treating of dementia and asso- 60 Test," which assesses recognition memory (see below,
`ciated psychiatric disorders.
`Wallach (1980) J. Gerontol. 35:371-375). Another example
`The term "mild cognitive impairment (MCI)" refers to a
`of an objective text which can be used to determine whether
`category of memory and cognitive impairment that is typi-
`an individual is psychotic and to measure efficacy of an anti-
`cally characterized by a clinical dementia rating (CDR) of 0.5
`psychotic treatment is the Stroop Color and Word Test
`(see, e.g., Hughes et al., Brit. I. Psychiat. 140:566-572, 1982) 65 ("Stroop Test") (see Golden, C. J., Cat. No. 30150M, In A
`and further characterized by memory impairment, but not
`Manual for Clinical and Experimental Uses, Stoelting, Wood
`impaired function in other cognitive domains. Memory
`Dale, Ill.) The Stroop Test is an objective neuropsychiatric
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 9
`
`

`

`US 8,921,348 B2
`
`6
`5
`results of a physical examination, neuropsychiatric exams,
`test that can differentiate between individuals with psychosis
`and/or a psychiatric evaluation.
`and those without, and is described in detail below.
`The term "testing" refers to determining the mifepristone
`The term "psychosis" refers to a psychiatric symptom,
`blood levels in a patient. The testing can be performed by any
`condition or syndrome in its broadest sense, as defined in the
`DSM-IV (Kaplan, ed. (1995) supra), comprising a "psy- 5 suitable instrument, such as a plasma sampling collection
`chotic" component, as broadly defined above. The term psy-
`device capable of detecting mifepristone serum levels.
`chosis can refer to a symptom associated with a general
`III. Method for Optimizing Mifepristone Levels
`medical condition, a disease state or other condition, such as
`Administration of the same dose of mifepristone to differ-
`a side effect of drug abuse (a substance-induced disorder) or
`ent patients can produce widely varying blood serum levels,
`as a side effect of a medication. Alternatively, the term psy- io varying by up to 800% from one patient to another, resulting
`chosis can refer to a condition or syndrome not associated
`in decreased efficacy. The present invention provides a
`with any disease state, medical condition, drug intake or the
`method for optimizing the blood serum levels of mifepristone
`like.
`so that the blood serum levels remain in an efficacious range
`Psychosis is typically defined as a mental disorder or con-
`and the patient receives the necessary treatment.
`dition causing gross distortion or disorganization of a per- 15
`A. Patients in Need
`son's mental capacity, affective response, and capacity to
`Patients amenable to treatment with mifepristone accord-
`recognize reality, communicate, and relate to others to the
`ing to the method of the present invention suffer from any
`degree of interfering with his capacity to cope with the ordi-
`mental disorder. Exemplary mental disorders include, but are
`nary demands of everyday life.
`not limited to, a stress disorder, delirium, mild cognitive
`The term "psychotic major depression," also referred to as 20 impairment (MCI), dementia, psychosis and psychotic major
`"psychotic depression" (Schatzberg (1992) Am. J. Psychiatry
`depression.
`149:733-745), "psychotic (delusional) depression" (Ibid.),
`Stress disorders treatable by the methods of the present
`"delusional depression" (Glassman (1981) supra) and,
`invention include, but are not limited to, Acute Stress Disor-
`"major depression with psychotic features" (see the DSM-
`der (ASD), Post-Traumatic Stress Disorder and Brief Psy-
`III-R), refers to a distinct psychiatric disorder which includes 25 chotic Disorder with Marked Stressor(s).
`both depressive and psychotic features. Individuals manifest-
`Acute Stress Disorder (ASD) is characterized by a constel-
`ing both depression and psychosis, i.e. psychotic depression,
`lation of symptoms, lasting at least two days, that appear and
`are herein referred to as "psychotic depressives." It has been
`resolve within one month of exposure to an extreme traumatic
`long-recognized in the art as a distinct syndrome, as
`stressor. If symptoms appear or persist beyond one month
`described, for example, by Schatzberg (1992) supra. Illustra- 30 after exposure to the traumatic stressor, the patient may be
`tive of this distinctness are studies which have found signifi-
`considered to suffer from Post-Traumatic Stress Disorder
`cant differences between patients with psychotic and nonpsy-
`rather than ASD. ASD is a common precursor to Post-Trau-
`chotic depression in glucocorticoid activity, dopamine-beta-
`matic Stress Disorder, and up to 80% of trauma survivors
`hydroxylase activity, levels of dopamine and serotonin
`initially suffering from ASD will meet the diagnostic criteria
`metabolites, sleep measures and ventricle to brain ratios. 35 for Post-Traumatic Stress Disorder six months later (see
`Psychotic depressives respond very differently to treatment
`Brewin et al., Am J Psychiatry 156:360-6, 1999).
`compared to individuals with other forms of depression, such
`Patients develop ASD following exposure to an extreme
`as "non-psychotic major depression." Psychotic depressives
`traumatic stressor (DSM-IV-TR Criterion A). A person must
`have a low placebo response rate and respond poorly to anti-
`respond to the stressor with intense fear, helplessness, or
`depressant therapy alone (without concurrent anti-psychotic 40 horror to be diagnosed with ASD. ASD may develop from
`treatment). Psychotic depressives are markedly unresponsive
`direct experience of traumatic events, including violent
`to tricyclic (anti-depressive) drug therapy (Glassman, et al.
`crimes, physical trauma, combat, diagnosis with a life-threat-
`(1975) supra). While psychotic depressives can respond to
`ening illness, and natural or manmade disasters. Patients may
`electroconvulsive therapy (ECT), their response time is rela-
`also develop ASD from witnessing or learning about trau-
`tively slow and the ECT has a high level of related morbidity. 45 matic events that happen to others, especially family mem-
`Clinical manifestations and diagnostic parameters of "psy-
`bers or close friends. Unexpected exposure to death, dead
`chotic major depression" is described in detail in the DSM-IV
`bodies, or body parts may also induce ASD.
`(Kaplan, ed. (1995) supra). Thus, due to its unique patho-
`A diagnosis of ASD requires that the person meet several
`physiology, high rate of morbidity and response to treatment,
`other symptomatic criteria. The person must experience three
`there is great practical need to differentially diagnose and 50 or more dissociative symptoms in connection with the trau-
`specifically treat psychotic major depression as compared to
`matic stressor (Criterion B). Dissociative symptoms include a
`non-psychotic depression.
`subjective sense of numbing or detachment, a reduction in
`The term "optimizing" refers to the process of testing mife-
`awareness of surroundings, derealization, depersonalization,
`pri stone blood levels and adjusting the dosage of mifepristone
`and dissociative amnesia. Furthermore, ASD requires that the
`administered to the patient in need in order to achieve mife- 55 victim persistently re-experience the traumatic event, though
`pristone blood levels above 1300 ng/mL.
`recurrent images, thoughts, dreams, illusions, flashbacks,
`The terms "treat", "treating" and "treatment" collectively
`sense of reliving the event, or distress upon exposure to
`refer to any indicia of success in the treatment or amelioration
`reminders of the event (Criterion C). The person must display
`of an injury, pathology or condition, including any objective
`marked avoidance of stimuli that arouse recollection of the
`or subjective parameter such as abatement; remission; dimin- 60 trauma (Criterion D) and marked symptoms of anxiety or
`ishing of symptoms or making the injury, pathology or con-
`increased arousal (Criterion E). Finally, in addition to the time
`dition more tolerable to the patient; slowing in the rate of
`requirements described above, a diagnosis of ASD requires
`degeneration or decline; making the final point of degenera-
`that the disturbance cause significant distress; or life impair-
`tion less debilitating; improving a patient's physical or men-
`ment, and not be due to another psychiatric or physiological
`tal well-being; or, in some situations, preventing the onset of 65 condition (Criteria F-H).
`dementia. The treatment or amelioration of symptoms can be
`Like Acute Stress Disorder, Post-Traumatic Stress Disor-
`based on objective or subjective parameters; including the
`der (PTSD) emerges following exposure to an extreme trau-
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2014, Page 10
`
`

`

`US 8,921,348 B2
`
`7
`matic stressor, and is characterized by persistent reexperienc-
`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-
`tations of PTSD symptoms, are identical to those described
`above for ASD, but for three differences. First, the dissocia-
`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-
`ondly, PTSD need not arise within one month of exposure to
`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-
`nations, disorganized speech, or grossly disorganized or cata-
`tonic behavior. Brief Psychotic Disorders exclude those
`induced by a general medical condition. If psychotic symp-
`toms develop shortly after, and apparently in response to, one
`or more severely stressful events, the disturbance is diag-
`nosed as Brief Psychotic Disorder with Marked Stressor(s)
`(formerly labeled "brief reactive psychosis" in DSM-III-R).
`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
`period of time. The disturbance in consciousness is often
`manifested by a reduced clarity of awareness of the environ-
`ment. The patient displays reduced ability to focus, sustain or
`shift attention (DSM-IV-TR diagnostic Criterion A). Accom-
`panying the disturbance in consciousness, delirium patients
`display a disturbance in cognition (e.g., memory impairment,
`disorientation, language difficulties) or perceptual distur-
`bances (e.g., misinterpretations, illusions, or hallucinations)
`(Criterion B). To be considered delirium, these disturbances
`in consciousness, cognition, or perception should develop
`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.,
`renal or hepatic insufficiency, fluid or electrolyte imbal-
`ances), cardiopulmonary disorders (e.g., congestive heart
`failure, myocardial infarction, shock), and systemic illnesses
`or effects (e.g., infections, sensory deprivation, and postop-
`erative states). Glucocorticoid receptor antagonists are also
`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
`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
`that is associated with deficits in a memory task test, such as
`a paragraph test. An MCI patient is fully oriented, but dem-
`onstrates mild consistent forgetfulness. Impairment in cogni-
`tive domains other than memory, such as problem solving and
`judgment is doubtful, if present at all, and, further, the MCI
`
`5
`
`8
`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
`10 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
`15 patient with MCI. Subjective and objective criteria can be
`used to measure and assess the success of a particular GR
`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.,
`20 Arch. Neurol. 56:303-308, 1999.
`The dementia treated in the methods of the invention
`encompasses a broad range of mental conditions and symp-
`toms, as broadly described in the DSM-IV. While the practi-
`tioner can use any set of prescribed or empirical criteria to
`25 diagnose the presence of dementia as an indication to practice
`the methods of the invention, some illustrative diagnostic
`guidelines and exampl