U8006964953B2
`
`(12) United States Patent
`US 6,964,953 B2
`(10) Patent N0.:
`Belanofl'
`(45) Date of Patent:
`Nov. 15,2005
`
`(54) METHODS FOR TREATING STRESS
`DISORDERS USING GLUCOCORTICOID
`RECEPTOR-SPECIFIC ANTAGONISTS
`
`(75)
`
`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. N0.: 10/102,448
`
`(22) Filed:
`
`Mar. 19, 2002
`
`(65)
`
`Prior Publication Data
`US 2002/0169152 A1
`Nov. 14, 2002
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/278,523, filed on Mar.
`23, 2001.
`
`Int. Cl.7 .............................................. A61K 31/56
`(51)
`(52) U.S. Cl.
`....................................... 514/178; 514/179
`(58) Field of Search ................................. 514/178, 179
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`................. 514/419
`9/1995 Politi et al.
`5,447,951 A ’*
`. 514/179
`11/2000 Schatzberg et al
`6,150,349 A *
`
`.............. 514/381
`8/2002 Aspnes et al.
`6,441,015 B2 *
`FOREIGN PATENT DOCUMENTS
`
`EP
`W0
`W0
`W0
`
`1 157 695 A1
`WO 99/17779 A1
`WO 00/54766 A1
`WO 01/37840
`
`11/2001
`4/1999
`9/2000
`5/2001
`
`OTHER PUBLICATIONS
`
`Behl, C. et a1., (1997), “Protection against oxidative stress-
`induced neuronal cell death-A novel role for RU486,” Euro-
`pean J. of Neurosci, 9:912-920.
`of
`role
`potential
`“The
`Heim, C.
`et
`a1.,
`(1999),
`hypocortisolism in the pathophysiology of stress—related
`bodily disorders,” Psychunearoenducrinolugy, 25 :1-25 .
`
`Sapolsky, R. et a1., (1994), “The physiological relevance of
`glucocorticoid endangement of the hippocampus,” Ann NY
`Acad. Sci. 746:294-304.
`
`Starkman, M. et a1., (1999), “Decrease in cortisol reverses
`human hippocampal
`atrophy following treatment of
`Cushing’s disease,” Biol Psychiatry, 46: 1595-1602.
`Yedua, R, (2000), “Biology of posttraumatic stress disorder,
`” J Clin. Psychiarty, 61 Suppl 7(5):14-21.
`Porter, N. et a1., (1998), “Stress Hormone and Brain Aging:
`Adding Insult to Inj ury?,” Nature Neuroscience, 1:1, pp. 3-4.
`Sapolsky, R., (2000), “Glucocorticoids and Hippocampal
`Atrophy
`in Neuropsychiatric Disorders,” Arch Gen
`Psychiatry, 57:925—935.
`Cherkin et a1., “Interruption by Halothane of Memory
`Consolidation in Chicks”, Fed. Proc., 24: 328 (1995).
`Shors, “Acute Stress Rapidly and Persistently Enhances
`Memory Formation in the Male Rat”, Nearobiol. Learn.
`Mem. 75: 10—29 (2001).
`Saudi et
`a1., “Corticosteroid Receptor Antagonists are
`Amnestic for Passive Avoidance Learning in Day-old
`Chicks”, Earn. J. Neurosci . 6: 1292-1297 (1994).
`Saudi et a1., “Experience—dependent Facilitating Elfect of
`Corticosterone on Spatial Memory Formation in the Water
`Maze”, Euro. J. Neurosci. 9: 637-642 (1997).
`Van Der Lely, A.J., et
`a1., “Rapid Reversal of Acute
`Psychosis in the Cushing Syndrome with the Cortisol-
`Receptor Antagonist Mitepristone (RU 486),” Annals of
`Internel Medicine, Jan. 15, 1991, pp. 143-144, vol. 114, No.
`2, New York, NY.
`
`* cited by examiner
`
`Primary Examiner—Barbara P. Badio
`(74) Attorney, Agent, or Firm—Townsend and Townsend
`and Crew LLP
`
`(57)
`
`ABSTRACT
`
`This invention generally pertains to the field of psychiatry.
`In particular, this invention pertains to the discovery that
`agents which inhibit the binding of cortisol to its receptors
`can be used in methods [or treating stress disorders. Mife-
`pristone, a potent specific glucocorticoid receptor antago-
`nist, can be used in these methods. The invention also
`provides a kit for treating stress disorders in a human
`including a glucocorticoid receptor antagonist and instruc-
`tional material teaching the indications, dosage and schedule
`of administration of the glucocorticoid receptor antagonist.
`
`16 Claims, N0 Drawings
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`US 6,964,953 B2
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`1
`METHODS FOR TREATING STRESS
`DISORDERS USING GLUCOCORTICOID
`RECEPTOR-SPECIFIC ANTAGONISTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims priority to US. patent application
`Ser. No. 60/278,523 filed Mar. 23, 2001, which is explicitly
`incorporated herein by reference in its entirety and for all
`purposes.
`
`FIELD OF THE INVENTION
`
`This invention generally pertains to the field of psychiatry.
`In particular, this invention pertains to the discovery that
`agents which inhibit the binding of cortisol to the glucocor-
`ticoid receptor can be used in methods of treating stress
`related disorders.
`
`15
`
`INTRODUCTION
`
`2
`docrinology 2521725 (2000). Hypocortisolism in stress dis—
`order patients may be reconciled with the elevated cortisol
`levels brought about by acute stress by assuming that
`persistent stress disorders represent a persistent state of
`cortisol hypersensitivity. That is, exposure to acute stressors
`may trigger negative feedback mechanisms that ultimately
`lead to decreased cortisol secretion. Persistently low levels
`of cortisol may leave the hypothalamic-pituitary-adrenal
`axis ‘primed’ to respond to even minor elevations in circu-
`lating
`glucocorticoid
`levels. As
`a
`result, minor
`stressors—resulting in small elevations in glucocorticoid
`levels—can provoke traumatic responses in patients suffer-
`ing from persistent stress disorders. See Yehuda, J Clin
`Psychiatry 61 Suppl 7(5):14—21 (2000).
`There has been no evidence prior to this invention,
`however, that a glucocorticoid receptor antagonist can be an
`effective treatment for stress disorders, especially in patients
`having cortisol levels that fall within a normal range. Many
`of the actions of cortisol are mediated by binding to the type
`I (mineralocorticoid) receptor, which is preferentially occu—
`pied, relative to the type II (glucocorticoid) receptor, at
`physiological cortisol
`levels. As cortisol
`levels increase,
`more glucocorticoid receptors are occupied and activated.
`Because cortisol plays an essential role in metabolism,
`inhibition of all cortisol-mediated activities, however, would
`be fatal. Therefore, antagonists that specifically prevent
`glucocorticoid receptor functions, but do not antagonize
`mineralocorticoid receptor functions are of particular use in
`this invention. Mifepristone and similar antagonists are
`
`examples of this category of receptor antagonists.
`
`
`
`Mifepristone has been noted as being e ‘ective at abro-
`gating some of the age-associated electrophysiological
`changes in the rat hippocampus (Talmi et al., Neurobiol. of
`Aging 1729—14, 1996) and also as providing protection
`against oxidative stress-induced neuronal cell death in the
`mouse hippocampus (Behl et al., European J. of Neuorsci.
`9:912—920, 1997). There have been no studies, however, that
`have shown that mifepristone can forestall or reverse the
`loss of hippocampal atrophy associated with stress disor-
`ders.
`The present inventor has determined that glucocorticoid
`receptor antagonists such as mifepristone are effective
`agents for the specific treatment of stress disorders in
`patients with normal or decreased cortisol
`levels. The
`present invention therefore fulfills the need for an effective
`treatment for stress disorders by providing methods of
`administering glucocorticoid receptor antagonists to treat
`patients diagnosed with stress disorders.
`
`SUMMARY OF THE INVENTION
`
`The invention provides a method of ameliorating the
`symptoms of a stress disorder in a patient who has normal
`or decreased cortisol levels. The method comprises admin-
`istration of a therapeutically effective amount of a gluco—
`corticoid receptor antagonist to the patient, who may be
`diagnosed with Post-Traumatic Stress Disorder, Acute Stress
`Disorder, or Brief Psychotic Disorder with Marked Stressor
`(s).
`the method of
`In one embodiment of the invention,
`treating a stress disorder uses a glucocorticoid receptor
`antagonist comprising a steroidal skeleton with at least one
`phenyl-containing moiety in the 11-beta position of the
`steroidal skeleton. The phenyl-containing moiety in the
`11—beta position of the steroidal skeleton can be a dimethy—
`laminophenyl moiety. In alternative embodiments, the glu-
`cocorticoid receptor antagonist comprises mifepristone, or,
`
`NEPTUNE GENERICS — Ex. 1010
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`30
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`35
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`Stress disorders are environmentally induced psychiatric
`conditions. Exposure to one or more traumatic stressful
`events can lead to acute or extended periods in which the ,
`victim experiences dissociative symptoms and re—experi—
`ences the traumatic event. In some individuals, exposure to
`traumatic stressors can even induce brief episodes of mental
`dysfunction and disorganization so severe as to be classified
`as psychotic. While antidepressant drugs such as selective
`serotonin reuptake inhibitors,
`tricyclics, and monoamine
`oxidase inhibitors have shown promise in trials against
`Post-Traumatic Stress Disorder, there is no currently avail-
`able pharmaeotherapy generally effective against stress dis-
`orders in general or in mixed patient populations. See
`Marshall & Pierce, Harvard Rev Psychiatry 72247—55
`(2000).
`Cortisol, which is secreted in response to ACTH (corti-
`cotropin), shows circadian rhythm variation, and further, is
`an important element in responsiveness to many physical
`and psychological stresses. It has been proposed that, with
`age, the cortisol regulatory system becomes hyperactivated
`in some individuals, resulting in hypercortisolemia. It has
`additionally been postulated that high levels of cortisol are
`neurotoxic, particularly in the hippocampus, a brain struc—
`ture that is thought
`to be central
`to the processing and
`temporary storage of complex information and memory
`(see, e,g., Sapolsky et al.,Ann. NYAcad. Sci. 746:294—304,
`1994; Silva,Annu. Rev. Genet. 3125277546, 1997; de Leon
`et al., J. Clin. Endocrinol & Metab. 8223251, 1997; Maeda
`et al., supra).
`Persistent high levels of circulating cortisol are associated
`with loss of volume in the hippocampus. See Starkman et al.,
`Biol Psychiatry 32:75 6—764, 1992. Moreover, surgical treat-
`ment of the adrenal glands to reduce excessive cortisol
`secretion can reverse the hippocampal atrophy caused by
`high cortisol levels. See Starkman et al., Biol Psychiatry
`46:1595—602, 1999. Hippocampal atrophy is also a charac-
`teristic of Post—Traumatic stress disorder, and there is evi—
`dence to suggest
`that elevated levels of glucocorticoids
`associated with stress disorders contribute to loss of hippoc-
`ampal volume. See Sapolsky, Arch Gen Psychiatry
`57:925—935 (2000).
`
`Despite the association between stress and cortisol secre-
`
`
`
`tion, evidence has accumulated that many patients su ering
`from persistent stress disorders have lowered, rather than
`elevated, cortisol levels. See Heim et al., Psychoneuroen-
`
`6O
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`US 6,964,953 B2
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`the glucocortieoid receptor antagonist is selected from the
`group consisting of RU009 and RU044.
`In other embodiments, the glucocortieoid receptor antago—
`nist is administered in a daily amount of between about 0.5
`to about 20 mg per kilogram of body weight per day;
`between about 1 to about 10 mg per kilogram of body weight
`per day; or between about 1 to about 4 mg per kilogram of
`body weight per day. The administration can be once per
`day. In alternative embodiments, the mode of glucocorticoid
`receptor antagonist administration is oral, or by a transder-
`mal application, by a nebulized suspension, or by an aerosol
`spray.
`The invention also provides a method of preventing,
`delaying, or lessening the emergence of stress disorder
`symptoms in a patient who has been exposed to a traumatic
`stressor, but who has not yet developed the characteristic
`symptoms of a stress disorder. The method comprises
`administering an effective amount of a glucocortieoid recep—
`tor antagonist to the patient within 30 days of exposure to a
`traumatic stressor.
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`The invention also provides a kit for the treatment of a
`stress disorder in a human, the kit comprising a glucocor-
`tieoid receptor antagonist, and, an instructional material
`teaching the indications, dosage and schedule of adminis-
`tration of the glucocortieoid receptor antagonist. In alterna— ’
`tive embodiments, the instructional material indicates that
`the glucocorticoid receptor antagonist can be administered
`in a daily amount of about 0.5 to about 20 mg per kilogram
`of body weight per day, of about I to about 10 mg per
`kilogram of body weight per day, or about 1 to about 4 mg
`per kilogram of body weight per day. The instructional
`material can indicate that cortisol contributes to the stress-
`induced symptoms in patients with stress disorders, and that
`the glucocortieoid receptor antagonist can be used to treat
`stress disorders.
`In one embodiment,
`the glucocorticoid
`receptor antagonist in the kit is niifepristone. The mifepris-
`tone can in tablet form.
`
`30
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`35
`
`A further understanding of the nature and advantages of
`the present invention is realized by reference to the remain-
`ing portions of the specification and claims.
`All publications, patents and patent applications cited
`herein are hereby expressly incorporated by reference for all
`purposes.
`
`4o
`
`DEFINITIONS
`
`The term “treating” refers to any indicia of success in the
`treatment or amelioration of an injury, pathology or condi—
`tion, including any objective or subjective parameter such as
`abatement; remission; diminishing of symptoms or making
`the injury, pathology or condition more tolerable to the
`patient; slowing in the rate of degeneration or decline;
`making the final point of degeneration less debilitating;
`improving a patient’s physical or mental well-being. 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 psy—
`chiatric evaluation. For example, the methods of the inven-
`tion success fully treat a patient’s stress disorders by
`decreasing the incidence of dissociative symptoms, re-ex-
`perience of traumatic events, or psychotic behavior.
`The term “stress disorder” refers to a psychiatric condi-
`tion precipitated by exposure to a traumatic or stressful
`event. Stress disorders include Acute Stress Disorder, Post—
`Traumatic Stress Disorder, and Brief Psychotic Disorder
`with Marked Stressor(s).
`
`60
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`65
`
`4
`The term “Acute Stress Disorder” refers to a psychiatric
`condition in its broadest sense, as defined in American
`Psychiatric Association: Diagnostic and Statistical Manual
`of Mental Disorders, Fourth Edition, Text Revision, Wash-
`ington, DC, 2000 (“DSM-IV—TR”). The DSM-IV—TR
`defines “Acute Stress Disorder” as characterized by anxiety,
`dissociative, 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 diagnos-
`ing and categorizing Acute Stress Disorder.
`The term “Post—Traumatic Stress Disorder” refers to a
`psychiatric condition in its broadest sense, as defined in
`DSM-IV—TR. The DSM-lV—TR defines “Post-Traumatic
`Stress Disorder” as characterized by persistent re-experienc-
`ing of an extreme traumatic event. The DSM—IV—TR sets
`forth a generally accepted standard for diagnosing and
`categorizing Post-Traumatic 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
`Psychotic Disorder with Marked Stressor(s)” as a sudden but
`brief onset of psychotic symptoms developing shortly after
`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 Stress0r(s).
`The term “cortisol” refers to a family of compositions also
`referred to hydrocortisone, and any synthetic or natural
`analogues thereof.
`The term “glucocorticoid receptor” (“GR”) refers to a
`family of intracellular receptors also referred to as the
`cortisol receptor, which specifically bind to cortisol and/or
`cortisol analogs. The term includes isoforms of GR, recom—
`binant GR and mutated GR.
`The term “mifepristone” refers to a family of composi-
`tions also referred to as RU486, or RU38.486, or 17-beta-
`hydroxy-ll-beta-(4-dimethyl-aminophenyl)—l7-alpha-(
`1—propynyl)—estra—4,9—dien—3—one), or
`11—beta—(4dimethy—
`laminophenyl)-l7-beta-hydroxy-l7-alpha-(1-propynyl)-es-
`tra—4,9-dien-3-one), or analogs thereof, which bind to the
`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. Chemical names for
`RU-486 vary, for example, RU486 has also been termed:
`11B-[p-(Dimethylamino)phenyl]
`-17B-hydroxy-17-(1-pro-
`pynyl)-estra-4,9-dien-3-one;
`llB-(4-dimethyl-aminophe-
`nyl)—17B—hydroxy—17A—(prop—1—ynyl)—estra—4,9—dien—3—one;
`l7B-hydroxy-1lB-(4-dimethylaminophenyl-l)—17A—(pro-
`pynyl-11)-estra-4,9-diene-3-one; 17B-hydroxy-11B-(4-dim-
`ethylaminophenyl-l)-l 7A-(propynyl-l)-E;(l113,1 7B)-l l-[
`4—dimethylamino)—phenyl] —l7—hydr0xy—l7—( l—propynyl)es—
`Ira-4,9-dien-3-one; and 11B-[4-(N,N-dimethylamino)phe-
`nyl] -17A—(prop-1-ynyl)-D-4,9-estradiene-17B-ol-3-one.
`The term “specific glucocorticoid receptor antagonist”
`refers to any composition or compound which partially or
`completely inhibits (antagonizes) the binding of a glucocor—
`ticoid receptor (GR) agonist, such as cortisol, or cortisol
`analogs, synthetic or natural, to a GR. A“specific glucocor-
`tieoid receptor antagonist” also refers to any composition or
`compound which inhibits any biological response associated
`with the binding of a GR to an agonist. By “specific”, we
`intend the drug to preferentially bind to the GR rather than
`the mineralocorticoid receptor (MR) at a rate of at least
`lOO-fold, and frequently lOOO-fold.
`A patient “not otherwise in need of treatment with a
`glucocorticoid receptor antagonist” is a patient who is not
`suffering from a condition which is known in the art to be
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`effectively treatable with glucocorticoid receptor antago—
`nists. Conditions known or reported in the art to be effec-
`tively treatable with glucocorticoid receptor antagonists
`include Cushing’s disease,
`schizophrenia
`and mania,
`dementia, delirium, and psychotic major depression.
`DETAILED DESCRIPTION OF TIIE
`INVENTION
`
`This invention pertains to the surprising discovery that
`agents that can inhibit glucocorticoid receptor-mediated
`biological responses are effective for treating stress disor-
`ders. In treating stress disorders, the methods of the inven—
`tion can preferably relieve the symptoms of a stress disorder
`or lead to complete resolution of the underlying disorder
`itself In one embodiment, the methods of the invention use
`agents that act as glucocorticoid receptor (GR) antagonists,
`blocking the interaction of cortisol with GR,
`to treat or
`ameliorate a stress disorder or symptoms associated with a
`stress disorder. The methods of the invention are effective in
`ameliorating the symptoms of a stress disorder patient
`afflicted with either decreased, normal or increased levels of
`cortisol or other glucocorticoids, natural or synthetic.
`Cortisol acts by binding to an intracellular, glucocorticoid
`receptor (GR). In man, glucocorticoid receptors are present
`in two forms: a ligand-binding GR-alpha of 777 amino
`acids; and, a GR—beta isoform that differs in only the last
`fifteen amino acids. The two types of GR have high allinity
`for their specific ligands, and are considered to function
`through the same transduction pathways.
`The biologic effects of cortisol, including pathologies or
`dysfunctions caused by hypercortisolemia, can be modu-
`lated and controlled at the GR level using receptor antago-
`nists. Several different classes of agents are able to act as GR
`antagonists, i.e.,
`to block the physiologic effects of GR-
`agonist binding (the natural agonist
`is cortisol). These
`antagonists include compositions which, by binding to GR,
`block the ability of an agonist to effectively bind to and/or
`activate the GR. One family of known GR antagonists,
`mifepristone and related compounds, are effective and
`potent anti—glucocorticoid agents in humans (Bertagna, J.
`Clin. Endocrinol. Alefflb. 59:25, 1984). Mifepristone binds
`to the GR with high affinity, with a K of dissociation <10"9
`M (Cadepond,AImu. Rev. Med. 482129, 1997). Thus, in one
`embodiment of the invention, mifepristone and related com—
`pounds are used to treat stress disorders.
`Stress disorders typically manifest
`themselves with a
`variety of symptoms, including purely psychological symp-
`toms sueh as re-experiencing traumatic events, physiologi-
`cal reactions such as persistent arousal, and psychiatric
`symptoms such as psychotic delusions. Thus, a variety of
`means of diagnosing stress disorders and assessing the
`success of treatment, i.e., the success and extent the symp-
`toms of stress disorders are lessened by the methods of the
`invention, can be used, and a few exemplary means are set
`forth herein. These means can include classical, subjective
`psychological evaluations and neuropsychiatric examina-
`tions as described below.
`
`As the methods of the invention include use of any means
`to inhibit the biological effects of an agonist—bound GR,
`illustrative compounds and compositions which can be used
`to treat stress disorders are also set forth. Routine procedures
`that can be used to identify further compounds and compo-
`sitions able to block the biological response caused by a
`GR—agonist interaction for use in practicing the methods of
`the invention are also described. As the invention provides
`for administering these compounds and compositions as
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`pharmaceuticals, routine means to determine GR antagonist
`drug regimens and formulations to practice the methods of
`the invention are set forth below.
`
`1. Diagnosis of Acute Stress Disorder
`Acute Stress Disorder (ASD) is characterized by a con-
`stellation of symptoms, las ing 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 su er from Post-Traumatic Stress
`Disorder rather than ASD. ASD is a common precursor to
`Post—Traumatic Stress Disorder, and up to 80% of trauma
`survivors initially suffering from ASD will meet the diag-
`nostic criteria for Post-Traumatic Stress Disorder six months
`
`
`
`later (see Brewin et al., Am J Psychiatry 1562360—6, 1999).
`Patients develop ASD following exposure to an extreme
`traumatic stressor (DSM-IV—TR Criterion A). Aperson 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-
`threatening illness, and natural or manmade disasters.
`Patients may also develop ASD from witnessing or learning
`about traumatic events that happen to others, especially
`family members 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 or more dissociative symptoms in connection with the
`traumatic stressor (Criterion B). Dissociative symptoms
`include a subjective sense of numbing or detachment, a
`reduction in awareness of surroundings, derealization, dep-
`ersonalization, and dissociative amnesia. Furthermore,ASD
`requires that the victim persistently re-experience the trau-
`matic 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 symp-
`toms of anxiety or increased arousal (Criterion E) Finally,
`in addition to the time requirements described above, a
`diagnosis of ASD requires that the disturbance cause sig—
`nificant distress; or life impairment, and not be due to
`another psychiatric or physiological condition (Criteria
`F-II).
`ASD may be diagnosed and evaluated with any one of
`several objective, standardized test instruments known in the
`art, although skilled clinicians may readily diagnose ASD
`through unstructured clinical interactions. Standardized test
`instruments
`are
`constructed by
`experienced clinical
`researchers based on DSM diagnostic criteria, and are typi-
`cally validated through statistical studies and comparisons of
`various patient populations. Generally, standardized instru—
`ments assess both manifest psychological or physiological
`symptoms as well as internal thought processes. Standard-
`ized test instruments may comprise structured clinical inter-
`views that are administered by a health care practitioner, or
`they may comprise self—reporting questionnaires that are
`completed by the putative patient. Either clinician-adminis-
`tered or self-reported test
`instruments may be used to
`identify ASD patients who will benefit from anti-glucoeor-
`ticoid therapy.
`test
`Guidance, procedures and recommendations for
`instruments used to diagnose stress disorders may be found
`in Standards of Traumalolugy Practice, April 2000 revision
`(Academy of Traumatology, Tallahassee, Fla.). Clinician-
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`administered test instruments for suitable for identifying
`patients in need of anti-glucocorticoid therapy for ASD
`include the Acute Stress Disorder Interview (ASDI; Bryant
`et al., PsychologicalAssessment 102215—20 (1998)), Self-
`reported instruments include the modified Stanford Acute
`Stress Reaction Questionnaire (SASRQ; Cardena et al., J
`Traumatic Stress 13:719—734 (2000)) and the Acute Stress
`Disorder Scale (ASDS; Bryant et al., Psychological Assess-
`ment 12:61—68 (2000)). Cutoff scores yielding the most
`statistically valid division of patients into ASD and non—
`ASD populations have been established and reported for
`each test (e.g., a score of 9 or greater for the dissociative
`cluster and 28 or greater on the reexperiencing, avoidance,
`and arousal clusters for the ASDS) and may be used to select
`patients for anti—glucocorticoid therapy.
`
`2. Diagnosis of Post-Traumatic Stress Disorder
`Like Acute Stress Disorder, Post-Traumatic Stress Disor-
`der (PTSD) emerges following exposure to an extreme
`traumatic stressor, and is characterized by persistent reex—
`periencing 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
`manifestations of PTSD symptoms, are identical to those
`described above for ASD, but for three differences. First, the
`dissociative 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.
`Skilled clinicians routinely diagnose patients with PTSD
`based on unstructured clinical
`interactions. Nonetheless,
`several
`self-reported and clinician-administered rating
`scales may be used to diagnose PTSD and are suitable to
`select patients in need of anti-glucocorticoid therapy. Clini-
`cian-administered rating scales include the Structured Inter-
`view for PTSD (SI-PTSD; Davidson et al., J Nervous
`Mental Disease 177:336—41 (1989)), the Clinician Admin-
`istered PTSD Scale (CAPS; Blake et al., Behavior Therapist
`13:187—8 (1990)) and the Short Screening Scale for DSM-
`IV PTSD (Breslau et al., Am J Psychiatry 156:908—11
`(1999)). Suitable self-reported rating scales include the
`complete and short—form Mississippi Scale for Combat—
`Related PTSD (Keane et al., J Consult Clin Psychol
`56:85—90 (1988), Fontana & Rosenbeck,J Traumatic Stress
`7:407—14 (1994)), the Revised Civilian Mississippi Scale for
`PTSD (Norris & Perilla, J Traumatic Stress 92285—98
`(1996)), and the Davidson Trauma Scale (Davidson et al.,
`Psychological Med 27:153—60 (1997)). Similar to the rating
`scales for ASD, cutoff scores for PTSD diagnosis are deter-
`mined by selecting a score that yields optimum sensitivity,
`specificity, positive predictive value and negative predictive
`value (e.g., a score of 4 or greater on the Short Screening
`Scale for DSM-IV PTSD, Breslau et al., supra).
`3. Diagnosis of Brief Psychotic Disorder with Marked
`Stressor(s)
`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,
`hallucinations, disorganized speech, or grossly disorganized
`or catatonic behavior. Brief Psychotic Disorders exclude
`those induced by a general medical condition. If psychotic
`symptoms develop shortly after, and apparently in response
`
`8
`to, one or more severely stressful events, the disturbance is
`diagnosed 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.
`Brief Psychotic Disorder with Marked Stressor(s) is gen—
`erally diagnosed in unstructured clinical
`interactions,
`in
`which skilled clinicians assess whether a patient’s symptoms
`fall within the DSM-IV—TR criteria for the disorder. Brief
`
`Psychotic Disorder with Marked Stressor(s) may also be
`diagnosed with a standardized test instrument in a structured
`clinical interview. Asuitable standardized instrument is First
`et al., Structured Clinical Interview for DSAI—IV Axis I
`Disorders, Research Version, Patient Edition With Psychotic
`Screen (SCID-I/P W/PSY SCREEN), New York: Biometrics
`Research, New York State Psychiatric Institute (1997).
`
`4. General Laboratory Procedures
`When practicing the methods of the invention, a number
`of general
`laboratory tests can be used to assist
`in the
`diagnosis, progress and prognosis of the patient with stress
`disorders, including monitoring of parameters such as blood
`cortisol, drug metabolism, brain structure and function and
`the like. These procedures can be helpful because all patients
`metabolize and react to drugs uniquely. In addition, such
`monitoring may be important because each GR antagonist
`has different pharmacokinetics. Different patients and dis-
`ease conditions may require different dosage regimens and
`formulations. Such procedures and means to determine
`dosage regimens and formulations are well described in the
`scientific and patent literature. A few illustrative examples
`are set forth below.
`
`a. Determining Blood Cortisol Levels
`Varying levels of blood cortisol, especially high levels of
`cortisol, have been associated with stress disorders, although
`the invention may also be practiced upon patients with
`apparently normal levels of blood cortisol. See Mazure et al.,
`Biol Psychiatry 412865—70 (1997). Thus, monitoring blood
`cortisol and determining baseline cortisol levels are useful
`laboratory tests to aid in the diagnosis, treatment and prog—
`nosis of a stress disorder patient. A wide variety of labora-
`tory tests exist that can be used to determine whether an
`individual
`is normal, hypo- or hypercortisolemic. Stress
`disorder patients typically have normal levels of cortisol that
`are often less than 25 pig/d1 in the afternoon, and frequently
`about 15 ,ug/dl or less in the afternoon, although the values
`often fall at the high end of the normal range, which is
`generally considered to be 5—15 ttg/dl in the afternoon.
`lmmunoassays such as
`radioimmunoassays are com-
`monly used because they are accurate, easy to do and
`relatively cheap. Because levels of circulating cortisol is an
`indicator of adrenocortical function, a variety of stimulation
`and suppression tests, such as ACTH Stimulation, ACTH
`Reserve, dexamethasone suppression test (see, e.g., Green-
`wald, Am. J. Psychiatry 143:442—446, 1986), can also
`provide diagnostic, prognostic or other information to be
`used adjunctively in the methods of the invention.
`One such assay available in kit form is the radioimmu—
`noassay available as “Double Antibody Cortisol Kit" (Diag-
`nostic Products Corporation, Los Angeles, Calif), Acta
`Psychiatr Scand. 70:239—247, 1984). This test is a com-
`petitive radioimmunoassay in which 125I-labeled cortisol
`competes with cortisol from an clinical sample for antibody
`s