USOO8450379B2
`
`(12) Ulllted States Patent
`(10) Patent N0.:
`US 8,450,379 B2
`
`Belanoff
`(45) Date of Patent:
`May 28, 2013
`
`(54) NIETHODS FOR TREATING MIGRAINE
`
`,
`~
`.
`,
`;
`Joseph K. Belanoff, Woods1de, CA (US)
`Inventor.
`(75)
`.
`(73) Ass1gnee: Corcept Therapeutics, Inc., Menlo
`Park, CA (US)
`.
`.
`.
`.
`Subject to any dlsclaimer, the term of this
`patent is extended or adjusted under 35
`U-S-C- 154(1)) by 1041 dayS-
`
`.
`( * ) Notice:
`
`(21) Appl. N0.: 10/703,069
`
`(22) Filed:
`
`NOV. 5, 2003
`
`(65)
`
`Prior Publication Data
`
`US 2004/0132703 A1
`
`JUL 8, 2004
`
`(60)
`
`(51)
`
`Related US. Application Data
`.
`.
`,
`.
`.
`Pr0v1s1onal application NO~ 60/424:199> filed on NOV-
`5,2001
`
`Int. Cl.
`A61K 31/045
`A61K 31/05
`
`(2006.01)
`(2006.01)
`
`514/2395
`6,166,013 A * 12/2000 Coghlan et al.
`6,380,223 B1 *
`4/2002 Dow et a1.
`..................... 514/357
`6,579,898 B2
`6/2003 Humphrey
`........... 514/183
`6,589,947 B1 fl
`7/2003 Hamanaka et a1.
`'
`.
`...................
`/
`*
`
`8 2003 Moms et al
`2003/0148987 A1
`514/44
`
`
`FOREIGN PATJNl DOCUMLNTS
`wo 98/03179 A
`1/1998
`
`wo
`
`OTHER PUBLICATIONS
`Hardinan ct al. “The pharmaceutical Basis of Thcrapcutics," 1996,
`pp. 1430—1431:“
`Morgan et al. “Dscovery ofpotent, nonsteroidal, and highly selective
`glucocorticoid receptor anmgonists,” J. Med. Chem. Jun. 2002, vol.
`45, N0. 12, pp. 2417-2424.*
`The Merck Manual, fifteenth edition, 1987, pp. 1355-1356.*
`Kettel, L.M. et al; “Endocrine Responses to Long-Term Administra-
`tion of the Antiprogesterone TU—486 in Patients with Pelvic
`Endometriosis”; Fertility and Sterility, 1991; pp. 402-407; vol. 56,
`No. 3; (Abstract from database BIOSIS 0n ACS; Accession No.
`19915505867).
`Adelman, J., et 211., “Current options for the prevention and treatment
`ofmigraine," Clinical Therapeutics. vol. 23(6): 772-788 (Jun. 2001).
`Agarwal, M.K., “The antiglucocorticoid action of mifepristone,”
`Pharmacology and Therapeutics, vol. 70(3): 183-213 (1996).
`Sicuteri,
`17., et al.., “Naloxone effectiveness on spontaneous and
`induced perspective disorders in migraine,” Headache, vol. 23(4):
`179'183 (19331
`
`(52) U.S. Cl.
`USPC ........... 514/729; 514/724, 514/730, 514/731,
`514/732‘ 514/733
`’
`
`(58) Field of Classification Search
`USPC .................................. 514/179, 7294733, 724
`Scc application filc for complete scarch history.
`
`. d b
`.
`*
`0110
`Y 0mm“
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`E. "
`7 S]
`P
`W
`73;"? W7"? ’ mu?“ :2? mick Townsend &
`étoclétonarne)! ‘ g9" ’ 0’ m"
`P
`‘
`
`(56)
`
`References Cited
`US. PATENT DOCUMENTS
`5,250,529 A *
`10/1993 'l'heoharides ............ 514/254.07
`5,468,741 A
`ll/l995 Yen
`5,521,166 A *
`5/1996 Gnibb
`
`514/170
`
`ABS 1 RAL 1
`(57)
`This invention relates to the discovery that agents capable of
`inhibiting the biological action ofthe glucocorticoid receptor
`can be used in methods for treating migraine in a subject.
`
`8 Claims, No Drawings
`
`NEPTUNE GENERICS — Ex. 1027
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`NEPTUNE GENERICS – Ex. 1027
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`US 8,450,379 B2
`
`1
`METHODS FOR TREATING MIGRAINE
`
`
`
`
`CROSS R A F A RENC A S TO RELATED
`
`APPLICATIONS
`
`This application claims priority to US. 60/424,199, filed
`Nov. 5, 2002, which is incorporated herein by reference in its
`entirety.
`
`FIELD OF THE INVENTION
`
`This invention relates to the discovery that agents capable
`ofinhibiting the biological action ofthe glucocorticoid recep—
`tor can be used in methods for reducing, eliminating, or
`preventing migraine in a subject.
`
`BACKGROUND OF THE INVENTION
`
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`Migraine is a common, underdiagnosed, and undertreated
`neurological disorder. Although migraine is the most com-
`mon cause of severe, recurring headache, headache is only
`one of them any ways the disease manifests itself. Migraine
`may also include visual disturbances, alterations in con-
`sciousness, photophobia, or phonophobia. The condition can ,
`be truly debilitating and the pain can interfere with a person’ s
`ability to live a normal productive life. Indeed, attacks can
`force the sufferer to abandon everyday activities for up to 3
`day. Even in symptom—free period, sufferers may live in fear
`of the next attack.
`More than 23 millionAmericans older than 12 years ofage
`experience migraine, with a 17.6% prevalence in females and
`5.7% in males. Given the high prevalence of sufferers, it is not
`surprising that American businesses lose upwards of 50 bil-
`lion dollars annually because of absenteeism, reduced worker
`productivity, and medical expenses secondary to migraine,
`Thus, the economic and social consequences of migraine are
`enormous.
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`Of the different types ofmigraines, classical migraine (mi-
`graine with aura) and common migraine (migraine Without
`aura) are the two most prevalent. Although mi graineis caused
`by intermittent brain dysfunction, the precise pathophysi—
`ological mechanisms involved are not understood.
`Drugs that have been used in an attempt to treat migraine
`include: ergotamine and ergotamine-like agents; serotonin
`agonists; and caffeine with crgots or other pharmacologic
`agents (see e.g., Silberstein, S. D., Curr. Opinion Neurology
`7:258-263 (1994); Welch, K. M. A., New Engl J. Med. 329:
`1476-1483 (1993); Dumar, K. L., J. Gen. Int. Med. 9:339-348
`(1994); Saadah, I—I., Headache 32:95-97 (1992); and Becker,
`Arzneimittelforshung (42(4):552—555 (1992)). All of these
`drugs are thought to initially relieve migraine-associated pain
`by causing vasoconstriction. Unfortunately,
`this leads to
`numerous side effects such as chestpain or pressure, flushing,
`generalized tingling sensations, nausea, vomiting, pain in the
`legs and arms, asthenia, drowsiness, and dizziness. Acute
`ergotism is a particularly pernicious side effect ofergot drugs
`and is characterized by severe central and peripheral vaso-
`constriction, nausea, vomiting, diarrhea, colic, headache, ver-
`tigo, paresthesia, and possibly convulsive seizures.
`Patients have, on occasion, found total or partial relief for
`some forms of migraine through the use of non-prescription
`analgesics. As outlined by VVelch (New Engl J. Med. 329:
`1476-1483 (1993)), the initial dosages of such analgesics are
`typically: aspirin, 500—650 mg; acetaminophen, 500 mg;
`naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg;
`and, ibuprofen 200 mg. However, the absorption of these and
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`other agents during a migraine attack has been shown to be
`impaired, apparently due to gastric stasis.
`While significant advances have been made in dealing with
`migraine. none has proven to be broadly effective for an
`extended time frame, since the side effects associated with the
`various options limits their value.
`Clearly, there is a need in the art for an effective migraine
`treatment. Ideally a migraine drug formulation should be
`nonaddictive and free of vasoactive agents. This requires the
`exclusion of ergots, serotonin agonists such as stunatriptan,
`and caffeine. The formulation should relieve or eliminate
`migraine symptoms, and should be effective when used for
`acute treatment or when used prophylactically. The invention
`disclosed herein meets these and other needs. The current
`invention is based, at least in part, on the surprising discovery
`that glucocorticoid receptor antagonists are effective agents
`for the treatment of migraine.
`Corticosteroids are steroid hormones released by the adre-
`nal glands. The most significant human adrenal corticoster-
`oids are cortisol, corticosterone and aldosterone. Corticoster-
`oids produce cellular effects following binding to receptors
`located in the cytoplasm of the cell. Two general classes of
`corticosteroid receptors are now recognized, the mineralocor-
`ticoid receptors (also termed type I, or MR) and the gluco-
`corticoid receptors (also termed type II, or GR).
`Mineralocorticoid receptors (MRs) bind cortisol with ten—
`fold higher afIInity than glucocorticoid receptors (GRs) bind
`glucocorticoids. Thus, the activation of the two classes of
`receptors may differ depending on the corticosteroid (corti-
`sol) concentration. Blood levels ofthe glucocorticoid cortisol
`vary over a Wide range during the day. In general, normal
`cortisol concentrations in the blood range from about 0.5 nM
`to about 50 nM; however, in response to stress, cortisol con-
`centration may exceed 100 nM.
`Glucocorticoid blockers are agents that block or reduce the
`effects of glucocorticoids. Such interference with glucocor-
`ticoid action may, for example, be due to interference with
`binding of glucocorticoid agonists to glucocorticoid recep-
`tors (GR), or to interference with the action of agonist—bound
`GR at the cell nucleus, or to interference with expression or
`processing ofgene products induced by the action of agonist-
`bound GR at the nucleus, Glucocorticoid receptor antagonists
`(GR antagonists) are compounds which inhibit the effect of
`the native ligand or of glucocorticoid agonists on GR. One
`mode of action of GR antagonists is to inhibit the binding of
`GR ligands to GR. A discussion of glucocorticoid antagonists
`may be found in Agarwal et al. “Glucocorticoid antagonists”,
`FEBS Lett., 217:221—226 (1987). An example of a GR
`antagonist is mifepristone, (116,176) 11[4 (dimethylamino)
`phenyll-l7 hydroxy-l7 (1 propynyl)estra-4,9 dien-3 one,
`also known as RU-486 or RU-38486. See US, Pat. No. 4,368,
`085. Mifepristonc binds specifically to GR with an affinity
`about 18 times that of the affinity of cortisol for GR. GR
`antagonists may be steroids, such as mifepristone, or non-
`steroids.
`The present inventors have determined for the first time
`that glucocorticoid receptor antagonists are effective agents
`for the treatment of migraine. Thus, the present invention
`fulfills the need for an effective method for the treatment of
`migraine by providing methods of administering glucocorti-
`coid receptor antagonists to a subjec .
`
`BRIEF SUB/[MARY OF III ‘ INV ‘N 1 ION
`
`
`
`The present invention is based at least in part, upon the
`discovery that administration of a glucocorticoid receptor
`antagonist provides an effective and ofimproved treatment of
`
`NEPTUNE GENERICS — Ex. 1027
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`US 8,450,379 B2
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`3
`migraine. Thus, in one aspect, the invention is directed toward
`methods of treating migraine in a subject, provided that the
`subject is not otherwise in need oftreatment with a glucocor—
`ticoid receptor antagonist, and provided that the subject is not
`also being treated with triptans nor any other pharmaceuti-
`cally prescribed entity that is predominantly metabolized by
`a cytochrome P450—3A4 isoenzyine.
`In one aspect of the invention, the glucocorticoid receptor
`antagonist comprises a steroidal skeleton with at least one
`phenyl-containing moiety in the ll-beta position of the ste-
`roidal skeleton. In one aspect, the phenyl-containing moiety
`in the ll—beta position of the steroidal skeleton is a dimethy—
`laininophenyl moiety. In another aspect, the glucocorticoid
`receptor antagonist is mifepristone.
`In one aspect of the present invention, the glucocorticoid
`rcccptor antagonist is sclcctcd from thc group consisting of
`1 1 [3—(4—dimethylaminoethoxyphenyl)— 17(X—propynyl— 17B—
`hydroxy-4,9-estradien—3-one and l7|3-hydroxy-17o.—l 9-(4-
`methylphenyl)androsta-4,9(1l)-dien-3-one.
`In
`another
`aspect,
`the glucocorticoid receptor antagonist is selected
`from the group consisting 4a(S)—Benzyl—2(R)—prop—l—ynyl—
`1,2,3 ,4,40.,9, 1 0, 100t(R)-octahydro-phenanthrene-2,7-diol
`and 4o.(S)-Benzyl-2(R)-chloroethynyl-l,2,3,4,4(x,9,10,100.
`(R)-octahydro-phenanthrene-2,7-diol.
`In anothcr onc aspcct, thc glucocorticoid roccptor antago-
`nist is (116,17B)—11—(1,3—benzodioxol—5—yl)—17—hydroxy—17—
`(l -propynyl)estra-4, 9-dien-3 -one.
`In another aspect of the present invention, the glucocorti-
`coid receptor antagonist is administered in a daily amount of
`between about 0.5 to about 35 mg per kilogram of body
`weight per day. In another aspect, the glucocorticoid receptor
`antagonist is administered in a daily amount ofbetween about
`5 to about 15 mg per kilogram of body weight per day.
`In onc aspect of thc prcscnt invcntion, thc administration is
`once per day. In yet another aspect, the mode of administra—
`tion is by a transdermal application, by a nebulized suspen-
`sion, or by an aerosol spray. In another aspect, the mode of
`administration is oral.
`In another aspect the invention also provides a kit for
`treating migraine in a subject. The kit comprises a specific
`glucocorticoid receptor antagonist and an instructional mate-
`rial teaching the indications, dosage and schedule of admin-
`istration ofthc glucocorticoid roccptor antagonist to a patient
`suffering from migraine.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Definitions
`
`The term “migraine” refers to a symptom complex occur-
`ring periodically that is characterized by one or more of the
`following symptoms: pain in the head that may be exacer-
`bated by movement or physical activity; nausea and/or vom-
`iting, diarrhea, photophobia, visual disturbances including
`scintillating appcaranccs of light; altcrations in conscious-
`ness including seizure, syncope. and confused state; vertigo,
`light headedness, scalp tenderness, or paresthesia. The par-
`ticular combination of symptoms and their frequency and
`severity are used to classify migraine into numerous sub-
`classes (see, e.g. Headache Classification Committee of the
`International Headache Society: The International Classy?-
`caiion ofHeadache Disorders, 2’” edition. Cephalalgia 24,
`supplement 1, 2004; available from Blackwell Publishing,
`9600 Garsington Road, Oxford OX4 2DQ, UK). Not cvcry
`migraine needs to meet all migraine criteria to be classified as
`migraine. For example, a person may have a left-temporal
`throbbing headache ofmoderate intensity worsened by physi-
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`cal activity. These headache features meet migraine criteria.
`However, this headache may not be accompanied by nausea
`or hypersensitivity to light or noise and, therefore, not fulfill
`all the criteria for migraineYet, if some ofthis person’s other
`headaches meet all the migraine criteria, then one can say that
`this headache is also a migraine.
`The term “migraine attack” refers to the experience of
`migraine symptoms. The experience may include the early
`premonitory symptoms, as well as any symptoms that occur
`during a migraine.
`The term “headache” refers to pain in various parts of the
`head, not confined to the area of distribution of any nerve.
`Many types of headaches are known. For example, the clas-
`sification system published by the Headache Classification
`Committee of the International Headache Society (IHS) in
`1988 lists more than 100 types of headache (Headache Clas-
`sification Committee of the International Headache Society:
`The Internatianal Classification q/‘Headache Disorders, 2”“
`edition, supra).
`The term “prophylactic” refers to an agent that acts to
`prevent disease, such as migraine. In one aspect, a glucocor-
`ticoid rcccptor antagonist of thc invcntion is administcrcd
`prophylactically to prevent the onset of migraine.
`The terms “treating", “treatment”, “to treat” refer to means
`for preventing, reducing, or eliminating migraine and or the
`accompanying symptoms in a subject. Treatment refers to any
`indicia of success in prevention, reduction, elimination, or
`amelioration of migraine, including any objective or subj ec—
`tive parameter such as abatement; remission; diminishing of
`symptoms, prevention, or lessening of migraine symptoms or
`making the condition more tolerable to the subject; making
`the migraine less debilitating; or improving a patient’s physi—
`cal or mental well-being. For example, success of treatment
`by methods ofthe invention could be measured by comparing
`the frequency and severity of migraine attacks in the year
`bcforc trcatmcnt with anti-glucocorticoids of the invcntion
`was initiated, with the year following the initiation of treat—
`ment. The prevention, treatment or amelioration ofsymptoms
`can be based on objective or subjective parameters; including
`the results of a physical examination, or personal interview
`regarding symptom severity and quality of life, or any other
`appropriate means known in the art.
`The term “cortisol” refers to a family of compositions also
`referred to as hydrocortisone, and any synthetic or natural
`analogucs thcrcof.
`The term “glucocorticoid receptor” (“GR”) refers to a fam—
`ily 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, recombinant GR
`and mutated GR.
`The term “mifepristone” refers to a family of compositions
`also referred to as RU486, or RU38.486, or l7-[3-hydroxy-
`1 1-[3-(4-dimethyl-aminophenyl)—17-a-(1 -propynyl)-estra -4,
`9-dicn-3-onc), or
`ll-[3-(4dimcthylaminophcnyl)-l7-|3-hy-
`droxy—l7—(x—(1—propynyl)—estra—4,9—dien—3—one), or analogs
`thereof, whichbind to the GR, typically with high affinity, and
`inhibit the biological effects initiated/mediated by the bind-
`ing of any cortisol or cortisol analogue to a GR receptor.
`Chemical names for RU—486 vary; for example, RU486 has
`also been termed: l 1 [3-[p-G)imethylamino)phenyl]-17-[3-hy-
`droxy- 17-(1 -propynyl)-estra-4,9-dien-3-one;
`llB-(4-dim-
`ethyl-aminophenyl)— 17B-hydroxy-1 7:1— (prop- 1 -ynyl) -estra -
`4,9-dicn-3 -onc;
`l7[3-hydroxy-l lB-(4-
`dimethylaminophenyl—1)—170t—(propynyl—1)—estra—4,9—diene—
`3-one;
`l7B-hydroxy-l l[3-(4-dimethylaminophenyl-1)-17(1-
`(propynyl-l )-E;
`(l l[5,l7[3)-l l -[4-dimethylamino)-phenyl]-
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`US 8,450,379 B2
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`17—hydroxy—17—(1—propynyl)estra—4,9—dien—3—one; and 116—
`[4-(N.N-dimethylamino) phenyl]-l7ct-(prop-1-ynyl)-D—4,9-
`estradiene-l 7 [3-01-3 -one.
`The term “specific glucocorticoid receptor antagonis ”
`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-
`ticoid 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) with an affinity at least 100-
`fold, and frequently 1000-fold.
`A subject “not otherwise in need of treatment with a glu—
`cocorticoid receptor antagonist” is an individual or patient
`who is not being treated with antiglucocorticoid compounds
`for any disorder accepted by the medical community to be
`effectively treatable with antiglucocorticoid compounds.
`Conditions known in the art and accepted by the medical
`community to be effectively treatable with glucocorticoid
`receptor antagonists include: Cushing’s disease, drug with-
`drawal, dementia, stress disorders, anxiety disorders (US.
`Pat. No. 5,741,787), depression, psychotic major depression
`(U.S. Pat. No. 6,150,349), schizoaffective disorder, diabetes,
`rheumatoid arthritis, autoimmune disease, HIV infection,
`dermatitis, inflammation, fibromyalgia, central nervous sys-
`tem disease, neurodegeneration, neural injuries, pelvic pain,
`and various cancers.
`A subject “not also being treated with triptans nor any other
`pharmaceutically prescribed entity that
`is predominantly
`metabolized by a cytochrome P450-3A4 isoenzyme” is an
`individual or patient who is not also being treated with triptan
`drugs such as elitriptan or sumatriptan for any disorder
`accepted by the medical community to be effectively treat-
`able with triptan drugs. Triptan drugs are thought to act
`through their affect on the metabolic activity ofthe P450-3A4
`enzyme. Thus, a subject “not also being treated with triptans
`nor any other pharmaceutically prescribed entity that is pre-
`dominantly metabolized by a cytochrome P450-3A4 isoen-
`zyme” is not being treated with any drugs that affect the
`metabolic activity of the P450—3A4 enzyme in a manner
`similar to the mamier in which triptan drugs affect the P450-
`3A4 enzyme.
`I. Introduction
`This invention pertains to the surprising discovery that
`agents that can inhibit glucocorticoid—induced biological
`responses are effective for treating migraine. In treating
`migraine, the methods ofthe invention can ameliorate, elimi-
`nate, reduce or prevent the symptoms of migraine. In one ,
`embodiment, the methods of the invention use agents that act
`as GR antagonists, blocking the interaction of cortisol with
`GR, to treat migraine. The methods ofthe invention are effec-
`tive in treating migraine in an afflicted patient.
`Cortisol acts by binding to an intracellular, glucocorticoid
`receptor (GR).
`In humans, 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
`affinity for their specific ligands, and are considered to func—
`tion through the same signal transduction pathways.
`The biological effects of cortisol, including pathologies or
`dysfunctions caused by hypercortisolemia, can be modulated
`and controlled at the GR level using receptor antagonists.
`Several different classes of agents are able to act as GR
`antagonists, i.e., to block the physiologic effects of GR-ago-
`nist binding (the natural agonist is cortisol). These antago-
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`nists 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—gluco—
`corticoid agents in humans (Bertagna, J. Clin. Endocrinol.
`Metab. 59:25, 1984). Mifepristone binds to the GR with high
`affinity, with a K of dissociation<10‘9 M (Cadepond, Annu.
`Rev. Med 482129, 1997). Thus, in one embodiment of the
`invention, mifepristone and related compounds are used to
`treat migraine in a subject.
`As the methods of the invention include use of any means
`to inhibit the biological effects ofan agonist-bound GR, illus-
`trative compounds and compositions which can be used to
`treat migraine in a subject are also set forth. Routine proce-
`dures that can he used to identify fiarther compounds and
`compositions 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 phar-
`maceuticals, routine means to determine GR antagonist drug
`regimens and fonnulations to practice the methods of the
`invention are set forth below.
`11. Diagnosis of Migraine in a Subject
`Migraine is diagnosed by determining whether some of a
`person’s recurrent headaches meet migraine criteria as dis—
`closed in The International Classification ofHeadache Dis—
`orders, 2’” edition, Headache Classification Committee of
`the International Headache Society: Cephalalgia 24, supple-
`ment 1, 2004; which is incorporated herein by reference. For
`example, the diagnostic criteria set forth by the International
`Headache Society for diagnosis ofmigraine without aura are
`shown in Table l. Migraines without aura are idiopathic syn-
`dromes comprising a recurring headache disorder, manifest-
`ing in attacks lasting 4—72 hours,
`in which headaches are
`typically unilateral, throbbing, of moderate to severe inten-
`sity, aggravated by routine physical activity, and accompa-
`nied by nausea and intolerance to brigttness and noise.
`
`A.
`
`B.
`
`C.
`
`I).
`
`TABLE 1
`
`International Headache Society Diagnostic
`Criteria For Migraine Without Aura
`At least 5 attacks that fulfill criteria in
`B, C, D, and E
`Headache attacks that last 4 to 72 hrs
`(untreated or unsuccessfully treated)
`Headache has at least 2 ofthe following
`characteristics:
`Unilateral site
`Pulsating quality
`Moderate to severe intensity
`Aggravation by walking stairs or similar
`routine physical activity
`During headache, at least 1 ofthe
`followlng symptoms:
`Nausea or vomiting (or hoth)
`Photophohia and phonophohia
`No evidence of related organic disease
`
`Similarly, the Intemational Headache Society provides a
`set of diagnositic criteria for migraine with aura. These diag-
`nostic criteria are shown in Table 2.
`
`TABLE 2
`
`International Headache Society Criteria For Migraine With Aura
`A.
`At least 2 attacks that fulfill criteria in B and C
`B.
`At least 3 of the following 4 characteristics:
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`US 8,450,379 B2
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`7
`TABLE 2-continued
`
`International Headache Society Criteria For Migraine Wifli Aura
`
`One or more completely reversible aura symptoms that
`indicate focal cerebral cortical or brain-stem
`dysfunction (or both)
`At least one aura symptom develops gradually over
`more than 4 min or two or more symptoms occur
`in succession
`No aura symptom lasts more than 60 min
`Headache follows aura in less than 1 hr
`No evidence of related organic disease
`
`C.
`
`5
`
`10
`
`15
`
`Most migraines seen in physicians’ offices are migraine
`without aura (formerly called “common migraine”) and
`migraine with aura (formerly called “classic migraine”).
`Migraine aura without headache is also quite common, and is
`seen often by ophthalmologists. Neurologists and headache
`specialists often treat status inigrainosus, characterized by a
`headache phase of over 72 hours. The other migraine types
`are fully described in The International Classification of
`Headache Disorders, 2'", edition, supra.
`Not every migraine needs to meet all of the migraine cri-
`teria. For example, a person may have a left-temporal throb-
`bing headache of moderate intensity worsened by physical
`activity. These headache features meet migraine criteria.
`However, this headache may not be accompanied by nausea
`or hypersensitivity to light or noise and, therefore, does not
`fulfill all the criteria for migraine. Yet, ifsome ofthis person’ 5
`other headaches meet all the migraine criteria, then one can 30
`say that this headache is also a migraine.
`A meticulous history is helpful in assessing and diagnosing
`any migraine patient. Useful information regarding the his—
`tory of a subject patient‘s headache might include. but would
`not be limited to: age of onset; family history; site or sites of 35
`pain; duration; character;
`intensity; mode of onset;
`time
`between onset to peak pain; temporal profile; aggravating or
`precipitating factors; alleviating factors; associated neuro—
`logic, ophthalmologic and autonomic features; prior and cur-
`rent medication use, caffeine use; history of head trauma; 40
`results of prior neuroimaging studies; a complete review of
`systems; or why the patient is currently seeking medical
`attention.
`Ill. General Laboratory Procedures
`W’hen practicing the methods ofthe invention, a number of 45
`general laboratory tests can be used to assist in the diagnosis,
`progress and prognosis of the patient with migraine, includ—
`ing monitoring of parameters such as blood cortisol, drug
`metabolism, brain structure and function and the like. These
`procedures can be helpfiil because all patients metabolize and 50
`react to drugs uniquely. In addition, such monitoring may be
`important because each GR antagonist has different pharma-
`cokinetics. Different patients and disease conditions may
`require different dosage regimens and formulations. Such
`procedures and means to determine dosage regimens and 55
`formulations are well described in the scientific and patent
`literature. A few illustrative examples are set forth below.
`a. Determining Blood Cortisol Levels
`The invention may be practiced upon patients with appar-
`ently normal levels of blood cortisol. However, since the 60
`treatment for migraine comprises administration of a gluco-
`corticoid receptor antagonist, monitoring blood cortisol and
`determining baseline cortisol levels are useful laboratory tests
`to aid in the diagnosis, treatment and prognosis of a migraine
`patient. A wide variety of laboratory tests exist that can be 65
`used to determine whether an individual is normal, hypo- or
`hypercortisolemic. Migraine patients typically have normal
`
`8
`levels of cortisol that are often less than 25 ug/dl in the
`morning, and frequently about 15 ug/dl or less in the after-
`noon, although the values often fall at the high end of the
`normal range, which is generally considered to be 5-15 rig/d1
`in the afternoon.
`Immunoassays such as radioimmunoassays are commonly
`used because they are accurate, easy to do and relatively
`cheap. Because levels of circulating cortisol are an indicator
`of adrenocortical function, a variety of stimulation and sup-
`pression tests, such as ACTH Stimulation, ACTH Reserve, or
`dexamethasone suppression (see, e. g., Greenwald, Am. J.
`Psychiatry 143:442-446, 1986), can also provide diagnostic,
`prognostic or other information to be used adjtmctively in the
`methods of the invention.
`One such assay available in kit form is the radioimmunoas—
`say available as “Double Antibody Cortisol Kit” (Diagnostic
`Products Corporation, Los Angeles, Calif), (Acta Psychiatr.
`Scand. 70:239-247, 1984). This test is a competitive radioim-
`munoassay in which 125l—labeled cortisol competes with cor—
`tisol from an clinical sample for antibody sites. In this test,
`due to the specificity of the antibody and lack of any signifi-
`cant protein effect, serum and plasma samples require neither
`preextraction nor predilution. This assay is described in fur-
`ther detail in Example 2, below.
`b. Determination of Blood/Urine Mifepristone Levels
`Because a patient’s metabolism, clearance rate, toxicity
`levels, etc. differs with variations in underlying primary or
`secondary disease conditions, drug history, age, general
`medical condition and the like, it may be necessary to mea—
`sure blood and urine levels of GR antagonist. Means for such
`monitoring are well described in the scientific and patent
`literature. As in one embodiment of the invention mifepris-
`tone is administered to treat migraine, an illustrative example
`ofdetermining blood and urine mifepristone levels is set forth
`in the Example below.
`c. Other Laboratory Procedures
`Laboratory tests monitoring and measuring GR antagonist
`metabolite generation, plasma concentrations and clearance
`rates,
`including urine concentration of antagonist and
`metabolites, may also be useful in practicing the methods of
`the invention. For example, mifepri stone has two hydrophilic,
`N—monomethylated
`and N—dimethylated, metabolites.
`Plasma and urine concentrations of these metabolites (in
`addition to RU486) can be determined using, for example,
`thin layer chromatography, as described in Kawai Pharma—
`col. and Experimental Therapeutics 2412401-406, 1987.
`IV. Glucocorticoid Receptor Antagonists to Treat Migraine in
`a Subject
`The invention provides for methods for treating migraine a
`subject utilizing any composition or compoundthat can block
`a biological response associated with the binding of cortisol
`or a cortisol analogue to a GR. Antagonists of GR activity
`utilized in the methods of the invention are well described in
`the scientific and patent literature. A few illu strative examples
`are set forth below.
`A. Steroidal Anti—Glucocorticoids as GR Antagonists.
`Steroidal glucocorticoid antagonists are administered to
`treat migraine in various embodiments ofthe invention. Ste-
`roidal antiglucocorticoids can be obtained by modification of
`the basic structure of glucocorticoid agonists,
`i.e., varied
`forms ofthe steroid backbone. The structure of cortisol can be
`modified in a variety of ways. The two mo st commonly
`known classes of structural modifications of the cortisol ste-
`roid backbone to create glucocorticoid antagonists include
`modifications ofthe l l—beta hydroxy group and modification
`of the l7—beta side chain (see, e.g., Lefebvre, J. Steroid Bio—
`chem. 33:557-563, 1989).
`
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`US 8,450,379 B2
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`9
`Examples of steroidal GR antagonists include androgen—
`type steroid compounds as described in US. Pat. No. 5,929,
`058, and the compounds disclosed in U.S. Pat. Nos. 4,296,
`206; 4,386,085; 4,447,424; 4,477,445; 4,519,946; 4,540,686;
`4,547,493; 4,634,695; 4,634,696; 4,753,932; 4,774,236;
`4,808,710; 4,814,327; 4,829,060; 4,861,763; 4,912,097;
`4,921,638; 4,943,566; 4,954,490; 4,978,657; 5,006,518;
`5,043,332; 5,064,822; 5,073,548; 5,089,488; 5,089,635;
`5,093,507; 5,095,010; 5,095,129; 5,132,299; 5,166,146;
`5,166,199; 5,173,405; 5,276,023; 5,380,839; 5,348,729;
`5,426,102; 5,439,913; 5,616,458, 5,696,127, and 6,303,591.
`Such steroidal GR antagonists include cortexolone, dexam-
`ethasone-oxetanone,
`19-nordeoxycorticosterone,
`19-nor-
`progesterone, cortisol-2l-mcsylatc; dcxamcthasonc-2l-me-
`sylate, 1 1[3—(4—dimethylaminoethoxyphenyl)—1701—propynyl—
`17[3-hydroxy-4,9-estradien-3-one
`(RU009),
`and
`17B-
`hydroxy- 1 7(1— 1 9-(4-111ethylphenyl)androsta-4,9(l 1 )-dien-3 -
`one (RUO44).
`Other examples of