US20200306265A1 - Neuroactive steroids, compositions, and uses thereof - Google Patents

Neuroactive steroids, compositions, and uses thereof Download PDF

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US20200306265A1
US20200306265A1 US16/083,339 US201716083339A US2020306265A1 US 20200306265 A1 US20200306265 A1 US 20200306265A1 US 201716083339 A US201716083339 A US 201716083339A US 2020306265 A1 US2020306265 A1 US 2020306265A1
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subject
dose
depression
compound
neuroactive steroid
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Stephen Jay Kanes
Helen Colquhoun
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Sage Therapeutics Inc
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Sage Therapeutics Inc
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Assigned to SAGE THERAPEUTICS, INC. reassignment SAGE THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KANES, STEPHEN JAY
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • Progesterone and its metabolites have been demonstrated to have profound effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985); Pfaff, D. W and McEwen, B. S., Science 219:808-814 (1983); Gyermek et al., J Med Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987)).
  • the levels of progesterone and its metabolites vary with the phases of the menstrual cycle. It has been well documented that the levels of progesterone and its metabolites decrease prior to the onset of menses.
  • PMS premenstrual syndrome
  • PND postnatal depression
  • PPD postpartum depression
  • PND is also associated with severe anxiety and irritability.
  • PND-associated depression is not amenable to treatment by classic antidepressants, and women experiencing PND show an increased incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).
  • neuroactive steroids e.g., a neuroactive steroid as described herein, e.g., progesterone and its metabolites; in the treatment and prevention of tremor (e.g., essential tremor), depression (e.g., postpartum depression, major depressive disorder), and anxiety disorder.
  • tremor e.g., essential tremor
  • depression e.g., postpartum depression, major depressive disorder
  • anxiety disorder e.g., anxiety disorder.
  • the disclosure features, inter alia, a method, the method comprising administering a neuroactive steroid, e.g., a neuroactive steroid as described herein, e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, alphaxolone, or Compound 9 as described below, or a pharmaceutical composition comprising a neuroactive steroid (e.g., brexanolone) to a subject, for example to treat a CNS-related disorder such as tremor, depression (e.g., postpartum depression, major depressive disorder), or anxiety disorder.
  • a neuroactive steroid e.g., a neuroactive steroid as described herein, e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, alphaxolone, or Compound 9 as described below
  • a pharmaceutical composition comprising a neuro
  • the neuroactive steroid is formulated for parenteral delivery (e.g., intravenous delivery (IV)).
  • a CNS disorder e.g., tremor, e.g., essential tremor
  • depression e.g., postpartum depression
  • anxiety disorder the methods comprising administering to the subject a composition described herein, e.g., a neuroactive steroid, e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone, and optionally a cyclodextrin, e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl ether ⁇ -cyclodextrin, e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl
  • a cyclodextrin e.g
  • compositions comprising a neuroactive steroid, e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone; and optionally a cyclodextrin, e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl ether ⁇ -cyclodextrin, e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl ether ⁇ -cyclodextrin, e.g., CAPTISOL®.
  • a neuroactive steroid e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone
  • a cyclodextrin e.g., a ⁇ -cyclodextrin,
  • a method for treating a human subject comprising: identifying a subject at risk of suffering from depression (e.g., postpartum depression) or an anxiety disorder; and administering (e.g., orally, intravenously) to the subject a therapeutically effective amount of a therapeutic agent (e.g., a neuroactive steroid as described herein (e.g., allopregnanolone)) or a pharmaceutical composition comprising a therapeutic agent (e.g., a pharmaceutical composition as described herein, e.g., brexanolone).
  • the therapeutic agent is administered to the subject within 3 days, 2 days, 1 day, or 24 hours of delivery of a baby (e.g., within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, within 30 minutes).
  • the subject is identified to be at risk through a screening method (e.g., Edinburgh Postnatal Depression Scale (EPDS), e.g., a score of 10 or more on the EPDS, a score of 13 or more on the EPDS).
  • a screening method e.g., Edinburgh Postnatal Depression Scale (EPDS)
  • EPDS Edinburgh Postnatal Depression Scale
  • the subject is identified to be at risk through screening instruments such as Patient Health Questionnaire (PHQ) in various forms or the Hospital Anxiety and Depression Scales or Geriatric Depression Scale.
  • PHQ Patient Health Questionnaire
  • the subject has given birth. In some embodiments, the subject has given birth within 3, 2, or 1 days; 24, 20, 16, 12, 8, 6, 4, 3, 2, or 1 hours; or 60, 45, 30, 15, 10, or 5 minutes. In some embodiments, the subject is due to give birth. In some embodiments, the subject is due to give birth in 9, 8, 7, 6, 5, 4, 3, 2, or 1 months; 4, 3, 2, or 1 weeks; or 7, 6, 5, 4, 3, 2, or 1 days. In some embodiments, the subject is in her third trimester of pregnancy. In some embodiments, the subject has an attribute, characteristic, or exposure (that increases the likelihood of developing a disorder as described herein, e.g., neuroactive steroid deficiency).
  • the subject has a chronic illness (e.g., cancer or cardiovascular disease), other mental health disorders (including substance misuse), or a family history of psychiatric disorders.
  • the subject is disabled or has poor health status due to medical illness, complicated grief, chronic sleep disturbance, loneliness, or history of depression.
  • the subject has poor self-esteem, child-care stress, prenatal anxiety, life stress, decreased social support, single/unpartnered relationship status, history of depression, difficult infant temperament, previous postpartum depression, lower socioeconomic status, or unintended pregnancy.
  • the subject has hyperemesis gravidarum (e.g., severe form of morning sickness, e.g., preventing adequate intake of food and fluids).
  • the subject has had a complication in pregnancy (e.g., emergency C-sections, pre-eclampsia, hospitalization during pregnancy, concern about fetal distress and admission of the baby to special care (NICU), the baby was in the NICU).
  • the subject has had emotionally painful or stressful experiences around pregnancy, childbirth, or early parenting (e.g., the subject was treated for infertility, had a previous miscarriage or other pregnancy loss, delivery of multiples, special needs, colic or difficult temperament baby, had difficulty feeding).
  • the subject has had a history of domestic violence, sexual or other abuse (e.g., abused as a child or as an adult).
  • the subject has had a traumatic childhood (e.g., loss of a parent, troubling relationship with parent).
  • the subject has stress (e.g., loss of someone close, job loss, financial hardship, divorce, strain in a relationship, house move).
  • the subject has lack of social support.
  • the subject has a perfectionist or controlling personality.
  • the therapeutic agent is a Selective Serotonin Reuptake Inhibitor (SSRI).
  • SSRI Selective Serotonin Reuptake Inhibitor
  • the therapeutic agent is a neuroactive steroid described herein (e.g., a neuroactive steroid selected from pregnanolone, ganaxolone, alphadalone, alphaxalone, and allopregnanolone) or a pharmaceutically acceptable salt or isotopologue thereof).
  • the therapeutic agent is:
  • the pharmaceutical composition is brexanolone.
  • the therapeutic agent is Compound 9 or a pharmaceutically acceptable salt or isotopologue thereof.
  • the therapeutic agent or pharmaceutical composition comprising the therapeutic agent is administered parenterally, wherein administering occurs through an intermittent intravenous infusion or continuous intravenous infusion.
  • the therapeutic agent is Compound 9
  • the therapeutic agent or pharmaceutical composition comprising the therapeutic agent is administered orally.
  • the neuroactive steroid or pharmaceutical composition comprising the neuroactive steroid is administered chronically.
  • the neuroactive steroid or pharmaceutical composition comprising the neuroactive steroid is administered acutely.
  • a method for treating a human subject suffering from depression (e.g., postpartum depression or major depressive disorder) or an anxiety disorder comprising administering (e.g., orally, intravenously) to the subject a therapeutically effective amount of a neuroactive steroid (e.g., allopregnanolone) or pharmaceutically acceptable salt or isotopologue thereof or a pharmaceutical composition comprising a neuroactive steroid or pharmaceutically acceptable salt or isotopologue thereof (e.g., brexanolone).
  • a neuroactive steroid e.g., allopregnanolone
  • pharmaceutically acceptable salt or isotopologue thereof e.g., brexanolone
  • the depression is clinical depression (e.g., severe depression), postnatal or postpartum depression, atypical depression, melancholic depression, Psychotic Major Depression (PMD), catatonic depression, Seasonal Affective Disorder (SAD), dysthymia, double depression, Depressive Personality Disorder (DPD), Recurrent Brief Depression (RBD), minor depressive disorder, bipolar disorder or manic depressive disorder, post-traumatic stress disorders, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior.
  • the depression is severe depression.
  • the depression is postpartum depression.
  • the depression is major depressive disorder.
  • the method provides maintenance treatment or preventative treatment.
  • the method provides acute treatment of the depression (e.g., within 72 hours, 60 hours, 48 hours, 24 hours, 12 hours, or less). In some embodiments, the method provides acute treatment of the depression or anxiety disorder (e.g., provides relief from a symptom in less than 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours).
  • the method provides rapid onset of efficacy (e.g., rapid reduction in a symptom of depression or anxiety disorder; rapidly affective to reduce a symptom of depression or anxiety disorder, e.g., a subject experiences relief from a symptom of depression or anxiety disorder described herein within 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours)).
  • rapid onset of efficacy e.g., rapid reduction in a symptom of depression or anxiety disorder; rapidly affective to reduce a symptom of depression or anxiety disorder, e.g., a subject experiences relief from a symptom of depression or anxiety disorder described herein within 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours)).
  • the therapeutic effect is sustained (e.g., effectively treats a symptom of depression or anxiety disorder and the efficacy is maintained for at least 1 day (e.g., at least 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or more).
  • the efficacy is maintained after a single course of treatment (e.g., single dose, multiple doses, or cycle of treatment) of a compound described herein (e.g., allopregnanolone) or pharmaceutical composition described herein (e.g., brexanolone).
  • a single course of treatment e.g., single dose, multiple doses, or cycle of treatment
  • a compound described herein e.g., allopregnanolone
  • pharmaceutical composition described herein e.g., brexanolone
  • the therapeutic effect is does not cause an adverse event (e.g., does not cause a severe or moderate adverse event, e.g., during treatment or 3 days, 7 days, 10 days, 20 days, 30 days, 60 days, 90 days, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more after treatment).
  • an adverse event e.g., does not cause a severe or moderate adverse event, e.g., during treatment or 3 days, 7 days, 10 days, 20 days, 30 days, 60 days, 90 days, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more after treatment.
  • the method includes a course of treatment with multiple dosages or cycles of treatment (e.g., a first dose or cycle of treatment is a parenteral dose such as an i.v. dose, and a second dose or cycle of treatment is an oral dose).
  • a first dose or cycle of treatment is a parenteral dose such as an i.v. dose
  • a second dose or cycle of treatment is an oral dose
  • the first and second dose or cycle of treatment include the same compound.
  • the first dose or cycle of treatment includes a first compound (e.g., a first compound described herein such as allopregnanolone) and the second dose or cycle of treatment includes a second compound that is different from the first compound.
  • the subject is substantially relieved of at least one symptom within 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less of said administration. In some embodiments, the subject is substantially relieved of at least one symptom for 1, 2, 3, 4, 5, 6, or 7 days; 1, 2, 3, or 4 weeks; or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more.
  • the neuroactive steroid is selected from pregnanolone, ganaxolone, alphadalone, alphaxalone, and allopregnanolone. In some embodiments, the neuroactive steroid is deuterated allopregnanolone. In some embodiments, the neuroactive steroid is an estrol. In some embodiments, the neuroactive steroid is:
  • the pharmaceutical composition is brexanolone.
  • the neuroactive steroid is Compound 9 as described herein.
  • the neuroactive steroid or pharmaceutical composition comprising the neuroactive steroid is administered parenterally, wherein administering occurs through an intravenous intermittent infusion.
  • the neuroactive steroid is Compound 9
  • the neuroactive steroid or pharmaceutical composition comprising the neuroactive steroid is administered orally.
  • the neuroactive steroid or pharmaceutical composition comprising the neuroactive steroid is administered chronically.
  • the neuroactive steroid or pharmaceutical composition comprising the neuroactive steroid is administered acutely.
  • the neuroactive steroid or pharmaceutically acceptable salt thereof or pharmaceutical composition comprising a neuroactive steroid is administered to the subject within 3 days, 2 days, 1 day, or 24 hours of delivery of a baby (e.g., within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, within 30 minutes).
  • the subject is identified to be at risk through a screening method (e.g., Edinburgh Postnatal Depression Scale (EPDS), e.g., a score of 10 or more on the EPDS, a score of 13 or more on the EPDS).
  • a screening method e.g., Edinburgh Postnatal Depression Scale (EPDS)
  • EPDS Edinburgh Postnatal Depression Scale
  • the subject is identified to be at risk through screening instruments such as Patient Health Questionnaire (PHQ) in various forms or the Hospital Anxiety and Depression Scales or Geriatric Depression Scale.
  • PHQ Patient Health Questionnaire
  • the subject has given birth. In some embodiments, the subject has given birth within 3, 2, or 1 days; 24, 20, 16, 12, 8, 6, 4, 3, 2, or 1 hours; or 60, 45, 30, 15, 10, or 5 minutes. In some embodiments, the subject is due to give birth. In some embodiments, the subject is due to give birth in 9, 8, 7, 6, 5, 4, 3, 2, or 1 months; 4, 3, 2, or 1 weeks; or 7, 6, 5, 4, 3, 2, or 1 days.
  • the subject has an attribute, characteristic, or exposure (that increases the likelihood of developing a disorder as described herein, e.g., neuroactive steroid deficiency).
  • the subject has a chronic illness (e.g., cancer or cardiovascular disease), other mental health disorders (including substance misuse), or a family history of psychiatric disorders.
  • the subject is disabled or has poor health status due to medical illness, complicated grief, chronic sleep disturbance, loneliness, or history of depression.
  • the subject has poor self-esteem, child-care stress, prenatal anxiety, life stress, decreased social support, single/unpartnered relationship status, history of depression, difficult infant temperament, previous postpartum depression, lower socioeconomic status, or unintended pregnancy.
  • the subject has hyperemesis gravidarum (e.g., severe form of morning sickness, e.g., preventing adequate intake of food and fluids).
  • the subject has had a complication in pregnancy (e.g., emergency C-sections, pre-eclampsia, hospitalization during pregnancy, concern about fetal distress and admission of the baby to special care (NICU), the baby was in the NICU).
  • the subject has had emotionally painful or stressful experiences around pregnancy, childbirth, or early parenting (e.g., the subject was treated for infertility, had a previous miscarriage or other pregnancy loss, delivery of multiples, special needs, colic or difficult temperament baby, had difficulty feeding).
  • the subject has had a history of domestic violence, sexual or other abuse (e.g., abused as a child or as an adult).
  • the subject has had a traumatic childhood (e.g., loss of a parent, troubling relationship with parent).
  • the subject has stress (e.g., loss of someone close, job loss, financial hardship, divorce, strain in a relationship, house move).
  • the subject has lack of social support.
  • the subject has a perfectionist or controlling personality.
  • the subject is a female. In some embodiments, the female is not breast feeding.
  • the subject is an adult. In some embodiments, the subject is from 18 to 45 years of age.
  • the subject is suffering from (e.g., has been diagnosed with) postpartum depression (e.g., severe postpartum depression).
  • postpartum depression e.g., severe postpartum depression
  • the subject has experienced a Major Depressive Episode in the postpartum period.
  • the period begins within the first 4 weeks following delivery of a baby.
  • a method of treating a human subject suffering from tremor comprising administering a therapeutically effective amount of a neuroactive steroid.
  • the method does not result in sedation.
  • the tremor is essential tremor.
  • the administering is performed parenterally. In some embodiments, the administering is performed intravenously.
  • the administering is performed orally.
  • the administering comprises administering one or more cycles of treatment, a cycle of treatment comprising: administering a first dose of the neuroactive steroid; administering a second dose of the neuroactive steroid; and administering a third dose of the neuroactive steroid, said neuroactive steroid doses being sufficient to treat said subject.
  • the first dose is 20 to 40 ⁇ g/kg/hr (e.g., about 30 ⁇ g/kg/hr, 29 ⁇ g/kg/hr).
  • the second dose is 45 to 65 ⁇ g/kg/hr (e.g., about 60 ⁇ g/kg/hr, 58 ⁇ g/kg/hr).
  • the third dose is 80 to 100 ⁇ g/kg/hr (e.g., about 90 ⁇ g/kg/hr, 86 ⁇ g/kg/hr).
  • each of the first, second, and third doses are 2 to 6 hours (e.g., 4 hours) in duration.
  • each of the first, second, and third doses are 1, 2, 3, 4, 5, or 6 hours in duration.
  • each of the first, second, and third doses are administered for equal periods of duration.
  • the administering comprises administering two cycles of treatment.
  • a rest period follows (e.g., immediately follows, is less than 60, 30, 20, 10, 5, 2, or 1 minute after) the first cycle of treatment. In some embodiments, a rest period precedes the second cycle of treatment. In some embodiments, a rest period follows the first cycle of treatment and precedes the second cycle of treatment. In some embodiments, the rest period is 6 to 8 days (e.g., 7 days) in duration.
  • the amount of neuroactive steroid delivered/unit time in the second dose e.g., as measured in ⁇ g/kg/hour, is 1 to 2 times higher than that of the first dose. In some embodiments, the amount of neuroactive steroid delivered/unit time in the third dose, e.g., as measured in ⁇ g/kg/hour, is 2 to 4 times higher than that of the first dose.
  • said first dose results in a plasma concentration of 10 to 100 nM, 25 to 75 nM, 40 to 60, or 50 nM.
  • said second dose results in a plasma concentration of 20 to 200 nM, 50 to 150 nM, 80 to 120, or 100 nM.
  • said third dose results in a plasma concentration of 30 to 300 nM, 100 to 200 nM, 120 to 180, or 150 nM.
  • said first dose results in a plasma concentration of 50+/ ⁇ 10 nM, 50+/ ⁇ 5 nM, 50+/ ⁇ 2 nM, or 50 nM.
  • said second dose results in a plasma concentration of 100+/ ⁇ 20 nM, 100+/ ⁇ 10 nM, 100+/ ⁇ 5 nM, or 100 nM.
  • said third dose results in a plasma concentration of 150+/ ⁇ 30 nM, 150+/ ⁇ 20 nM, 150+/ ⁇ 10 nM, or 150 nM.
  • said first dose is administered over a period of time that is not longer than 6, 5, 4, or 3 hours. In some embodiments, said first dose is administered over a period of time that is at least 2, 3, or 4 hours in duration.
  • administration of the second dose occurs immediately after administration of the first dose.
  • administration of the third dose occurs immediately after administration of the second dose.
  • the duration of administration is at least 12, 24, 48, 72, or 96 hours in duration. In some embodiments, the duration of administration is about 40, 50, 60, or 70 hours. In some embodiments, the administration is performed continuously.
  • the administering comprises administering one or more cycles of treatment, a cycle of treatment comprising: providing a single infusion of the neuroactive steroid.
  • the administering comprises administering one or more cycles of treatment, a cycle of treatment comprising: administering a first infusion of the neuroactive steroid; and administering a second infusion of the neuroactive steroid; said neuroactive steroid infusions being sufficient to treat said subject.
  • the administration of the second infusion occurs immediately after administration of the first infusion.
  • the amount of neuroactive steroid delivered/unit time in the second infusion e.g., as measured in ⁇ g/kg/hour, is higher than that of the first infusion.
  • the amount of neuroactive steroid delivered/unit time in the second infusion e.g., as measured in ⁇ g/kg/hour, is at least 1 to 2 times higher than that of the first infusion.
  • the amount of neuroactive steroid delivered/unit time in the second infusion e.g., as measured in ⁇ g/kg/hour, is lower than that of the first infusion.
  • the amount of neuroactive steroid delivered/unit time in the second infusion e.g., as measured in ⁇ g/kg/hour, is at least 1 to 2 times lower than that of the first infusion.
  • the method comprises administering a plurality of infusions. In some embodiments, the method comprises administering a first and second infusion. In some embodiments, the administration of the second infusion begins no longer than 90, 60, 30, 10, or 5 minutes after the beginning or end of the administration of the first infusion. In some embodiments, the second infusion begins 0 to 90, 0 to 60, 0 to 30, 0 to 10, or 0 to 5 minutes after the beginning or end of the administration of the first infusion. In some embodiments, the second infusion begins no more than 60, 30, 20, 10, 5, 4, 3, 2, or 1 minute(s) after the end of administration of the first infusion. In some embodiments, the second infusion begins at the end of administration of the first infusion.
  • the first infusion and the initiation of the second infusion are performed with the same delivery device, e.g., with the same cannula or reservoir.
  • the amount of neuroactive steroid delivered/unit time varies during the first infusion.
  • the first (step-up) infusion delivers a smaller amount of neuroactive steroid/unit time than the second (maintenance) infusion. In some embodiments, the first (step-up) infusion comprises administering a plurality of step doses, wherein each subsequent step dose delivers a larger amount of neuroactive steroid/unit time than the step dose that precedes it.
  • the amount of neuroactive steroid delivered/unit time varies during the second (step-down) infusion.
  • the second (step-down) infusion delivers a smaller amount of neuroactive steroid/unit time than the first (maintenance) infusion.
  • the second (step-down) infusion comprises administering a plurality of step doses, wherein each subsequent step dose delivers a smaller amount of neuroactive steroid/unit time than the step dose that precedes it.
  • the subject is 35 to 75 years of age. In some embodiments, the subject has a TETRAS Performance Subscale score of 2 or greater for at least one maneuver selected from forward horizontal reach posture, lateral “wing beating” posture, or finger-nose-finger testing; in the ‘upper limb tremor’ test.
  • the method provides acute treatment of the tremor (e.g., provides relief from a symptom in less than 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours).
  • the method provides rapid onset of efficacy (e.g., rapid reduction in a symptom of tremor; rapidly affective to reduce a symptom of tremor, e.g., a subject experiences relief from a symptom of a tremor within 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours)).
  • rapid onset of efficacy e.g., rapid reduction in a symptom of tremor; rapidly affective to reduce a symptom of tremor, e.g., a subject experiences relief from a symptom of a tremor within 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours)).
  • the therapeutic effect is sustained (e.g., effectively treats a symptom of tremor and the efficacy is maintained for at least 1 day (e.g., at least 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months).
  • the efficacy is maintained after a single course of treatment (e.g., single dose, multiple doses, or cycle of treatment) of a compound described herein (e.g., allopregnanolone).
  • a single course of treatment e.g., single dose, multiple doses, or cycle of treatment
  • a compound described herein e.g., allopregnanolone
  • the therapeutic effect is does not cause an adverse event (e.g., does not cause a severe or moderate adverse event, e.g., during treatment or 3 days, 7 days, 10 days, 20 days, 30 days, 60 days, 90 days, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more after treatment).
  • an adverse event e.g., does not cause a severe or moderate adverse event, e.g., during treatment or 3 days, 7 days, 10 days, 20 days, 30 days, 60 days, 90 days, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more after treatment.
  • the method includes a course of treatment with multiple dosages or cycles of treatment (e.g., a first dose or cycle of treatment is a parenteral dose such as an i.v. dose, and a second dose or cycle of treatment is an oral dose).
  • a first dose or cycle of treatment is a parenteral dose such as an i.v. dose
  • a second dose or cycle of treatment is an oral dose
  • the first and second dose or cycle of treatment include the same compound.
  • the first dose or cycle of treatment includes a first compound (e.g., a first compound described herein such as allopregnanolone) and the second dose or cycle of treatment includes a second compound that is different from the first compound.
  • the subject has been diagnosed with essential tremor. In some embodiments, the subject has suffered from tremor for at least 2 years.
  • a method of treating a subject suffering from tremor comprising: administering a first dose, wherein administration of said first dose; and results in a plasma level of neuroactive steroid of 50 to 300 nM neuroactive steroid; a rest period comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days; and administering a second dose, wherein administration of said second dose; and results in a plasma level of neuroactive steroid of 50 to 300 nM neuroactive steroid; wherein, collectively, the administrations are provided in sufficient amount to treat said subject.
  • the method does not result in sedation.
  • a method of treating a subject suffering from tremor comprising: administering a first dose, wherein administration of said first dose lasts for at least 1 day; and results in a plasma level of neuroactive steroid of 100 to 200 nM neuroactive steroid; a rest period comprising at least 5, 6, or 7 days; and administering a second dose, wherein administration of said second dose lasts for at least 1 day; and results in a plasma level of neuroactive steroid of 100 to 200 nM neuroactive steroid; wherein, collectively, the administrations are provided in sufficient amount to treat said subject.
  • the method does not result in sedation.
  • a method of treating a subject suffering from tremor comprising: administering a first dose, wherein administration of said first dose lasts for 1 day; and results in a plasma level of neuroactive steroid of 150 nM neuroactive steroid; a rest period comprising 7 days; and administering a second dose, wherein administration of said second dose lasts for 1 day; and results in a plasma level of neuroactive steroid of 150 nM neuroactive steroid; wherein, collectively, the administrations are provided in sufficient amount to treat said subject.
  • the method does not result in sedation.
  • the administration of the second dose begins no longer than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 days after the beginning or end of the administration of the first dose. In some embodiments, the second dose begins 1 to 14, 3 to 12, 5 to 10, or 7 days after the beginning or end of the administration of the first dose. In some embodiments, the second dose begins no more than 14, 12, 10, 9, 8, 7, 6, 5, 3, 2, or 1 day after the end of administration of the first dose. In some embodiments, the first dose and the initiation of the second dose are performed with the same delivery device, e.g., with the same cannula or reservoir.
  • the plasma concentration of said third dose is measured at a preselected time, e.g., at 10, 15, 20, 30, 45, or 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, or 24 hours, or 2, 3, or 4 days after the initiation of said third dose.
  • said third dose results in a plasma concentration of 150 nM, e.g., as measured at a preselected time, e.g., at 10, 15, 20, 30, 45, or 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, or 24 hours, or 2, 3, or 4 days after the initiation of said third dose.
  • a method of treating a subject suffering from tremor comprising the steps of: a) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone or Compound 9) in reducing tremor (e.g., symptoms of tremor) in a subject treated with the neuroactive steroid (e.g., allopregnanolone or Compound 9); and b) administering to the subject a therapeutic agent (e.g., neuroactive steroid) if the information indicates that tremor (e.g., symptoms of tremor) is reduced in the subject as compared to the subject before having received the neuroactive steroid (e.g., allopregnanolone or Compound 9), thereby treating the subject.
  • a neuroactive steroid e.g., allopregnanolone or Compound 9
  • a method of selecting a therapeutic agent for treating tremor (e.g., essential tremor) in a human subject treated with a neuroactive steroid (e.g., allopregnanolone or Compound 9) comprising the steps of: a) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone or Compound 9) in reducing tremor (e.g., symptoms of tremor) in a subject; and b) selecting the therapeutic agent (e.g., neuroactive steroid) if the information indicates that tremor (e.g., symptoms of the depression or anxiety disorder) is reduced in the subject as compared to the subject before having received the neuroactive steroid (e.g., allopregnanolone or Compound 9).
  • tremor e.g., essential tremor
  • tremor e.g., essential tremor
  • tremor e.g., essential tremor
  • a method of evaluating e.g., diagnosing, prognosing, and determining a course of treatment in) a subject suffering from tremor (e.g., essential tremor) comprising the steps of: a) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone) in reducing tremor (e.g., symptoms of tremor) in a subject treated with the neuroactive steroid (e.g., allopregnanolone); and b) determining if tremor (e.g., symptoms of tremor) is reduced in the subject as compared to the subject before receiving the neuroactive steroid (e.g., allopregnanolone), thereby evaluating the subject.
  • tremor e.g., essential tremor
  • the information is received, e.g., about 1, 2, 3, 4, 5, or 6 days; about 1, 2, or 3 weeks; about 1, 2, or 3 months after administration of the neuroactive steroid (e.g., allopregnanolone).
  • the neuroactive steroid e.g., allopregnanolone
  • the subject has been administered the neuroactive steroid less than about 3 months (e.g., less than about 2 or 1 month; 3, 2, or 1 weeks; 6, 5, 4, 3, 2, or 1 days) prior to receiving the information.
  • the subject has been administered the neuroactive steroid (e.g., allopregnanolone) by intravenous infusion.
  • the therapeutic agent is administered by oral administration. In some embodiments, the therapeutic agent is administered as a solid composition (e.g., a solid dosage form).
  • a method of evaluating e.g., diagnosing, prognosing, or determining a course of treatment in) a subject suffering from tremor (e.g., essential tremor) comprising the steps of: a) administering to the subject a therapeutic agent (e.g., neuroactive steroid); and b) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone) in reducing tremor (e.g., symptoms of tremor) in a subject treated with the neuroactive steroid (e.g., allopregnanolone), thereby evaluating the subject.
  • the information is acquired by imaging the subject or a sample from the subject.
  • the information is acquired by fMRI.
  • the information is acquired by SPECT.
  • a method for treating a human subject suffering from depression (e.g., postpartum depression) or an anxiety disorder comprising: administering a first infusion of a neuroactive steroid, wherein said first/step-up infusion is administered for 8-16 hours (e.g., 12 hours); administering a second/maintenance infusion of a neuroactive steroid, wherein said second/maintenance infusion is administered for 24-48 hours (e.g., 36 hours); and administering a third infusion of a neuroactive steroid, wherein said third/downward taper infusion is administered for 8-16 hours (e.g., 12 hours); said neuroactive steroid doses being sufficient to treat said subject.
  • depression e.g., postpartum depression
  • an anxiety disorder comprising: administering a first infusion of a neuroactive steroid, wherein said first/step-up infusion is administered for 8-16 hours (e.g., 12 hours); administering a second/maintenance infusion of a neuroactive ste
  • the subject is identified to be at risk through a screening method (e.g., Edinburgh Postnatal Depression Scale (EPDS), e.g., a score of 10 or more on the EPDS, a score of 13 or more on the EPDS).
  • a screening method e.g., Edinburgh Postnatal Depression Scale (EPDS)
  • EPDS Edinburgh Postnatal Depression Scale
  • the subject is identified to be at risk through screening instruments such as Patient Health Questionnaire (PHQ) in various forms or the Hospital Anxiety and Depression Scales or Geriatric Depression Scale.
  • PHQ Patient Health Questionnaire
  • the subject has given birth. In some embodiments, the subject has given birth within 3, 2, 1 days; 24, 20, 16, 12, 8, 6, 4, 3, 2, 1 hours; 60, 45, 30, 15, 10, 5 minutes. In some embodiments, the subject is due to give birth. In some embodiments, the subject is due to give birth in 9, 8, 7, 6, 5, 4, 3, 2, 1 months; 4, 3, 2, 1 weeks; 7, 6, 5, 4, 3, 2, 1 days.
  • the subject has an attribute, characteristic, or exposure (that increases the likelihood of developing a disorder as described herein, e.g., neuroactive steroid deficiency).
  • the subject has a chronic illness (e.g., cancer or cardiovascular disease), other mental health disorders (including substance misuse), or a family history of psychiatric disorders.
  • the subject is disabled or has poor health status due to medical illness, complicated grief, chronic sleep disturbance, loneliness, or history of depression.
  • the subject has poor self-esteem, child-care stress, prenatal anxiety, life stress, decreased social support, single/unpartnered relationship status, history of depression, difficult infant temperament, previous postpartum depression, lower socioeconomic status, or unintended pregnancy.
  • the subject has hyperemesis gravidarum (e.g., severe form of morning sickness, e.g., preventing adequate intake of food and fluids).
  • the subject has had a complication in pregnancy (e.g., emergency C-sections, pre-eclampsia, hospitalization during pregnancy, concern about fetal distress and admission of the baby to special care (NICU), the baby was in the NICU).
  • the subject has had emotionally painful or stressful experiences around pregnancy, childbirth, or early parenting (e.g., the subject was treated for infertility, had a previous miscarriage or other pregnancy loss, delivery of multiples, special needs, colic or difficult temperament baby, had difficulty feeding).
  • the subject has had a history of domestic violence, sexual or other abuse (e.g., abused as a child or as an adult).
  • the subject has had a traumatic childhood (e.g., loss of a parent, troubling relationship with parent).
  • the subject has stress (e.g., loss of someone close, job loss, financial hardship, divorce, strain in a relationship, house move).
  • the subject has lack of social support.
  • the subject has a perfectionist or controlling personality.
  • a method for treating a human subject suffering from depression (e.g., postpartum depression or major depressive disorder) or an anxiety disorder comprising: administering a first infusion of a neuroactive steroid, said first/step-up infusion comprising administering a continuously increasing amount of neuroactive steroid at an amount of neuroactive steroid/unit time of 5-100 ⁇ g/kg/hour, 10-80 ⁇ g/kg/hour, 15-70 ⁇ g/kg/hour, or 30 ⁇ g/kg/hour; administering a second/maintenance infusion of a neuroactive steroid, said second/maintenance infusion comprising administering an amount of neuroactive steroid/unit time of 50-100 ⁇ g/kg/hour, 70-100 ⁇ g/kg/hour, 86 g ⁇ g/kg/hour, or 60 ⁇ g/kg/hour; and administering a third infusion of a neuroactive steroid, said third/downward taper infusion comprising administering administering
  • the method provides therapeutic effect (e.g., as measured by reduction in Hamilton Depression Score (HAM-D)) within 4, 3, 2, or 1 days; or 24, 20, 16, 12, 10, or 8 hours or less.
  • the therapeutic effect is a decrease from baseline in HAM-D score at the end of a treatment period (e.g., 12, 24, or 48 hours after administration; or 24, 48, 60, 72, or 96 hours or more).
  • the method provides therapeutic effect (e.g., as measured by reduction in Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, or 1 days; or 24, 20, 16, 12, 10, or 8 hours or less.
  • the therapeutic effect is a improvement measured by the EPDS.
  • the method provides therapeutic effect (e.g., as measured by reduction in Clinical Global Impression-Improvement Scale (CGI)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.
  • CGI Clinical Global Impression-Improvement Scale
  • the therapeutic effect is a CGI score of 2 or less.
  • the subject is identified to be at risk through a screening method (e.g., Edinburgh Postnatal Depression Scale (EPDS), e.g., a score of 10 or more on the EPDS, a score of 13 or more on the EPDS).
  • a screening method e.g., Edinburgh Postnatal Depression Scale (EPDS)
  • EPDS Edinburgh Postnatal Depression Scale
  • the subject is identified to be at risk through screening instruments such as Patient Health Questionnaire (PHQ) in various forms or the Hospital Anxiety and Depression Scales or Geriatric Depression Scale.
  • PHQ Patient Health Questionnaire
  • the subject has given birth (e.g., a live birth, stillbirth, miscarriage). In some embodiments, the subject has given birth within 3, 2, 1 days; 24, 20, 16, 12, 8, 6, 4, 3, 2, 1 hours; 60, 45, 30, 15, 10, 5 minutes. In some embodiments, the subject is due to give birth. In some embodiments, the subject is in her third trimester of pregnancy.
  • the subject has reached term pregnancy (e.g., early term (i.e., between 37 weeks and 38 weeks and 6 days); full term (i.e., between 39 weeks and 40 weeks and 6 days); late term (i.e., between 41 weeks and 41 weeks and 6 days); or postterm (i.e., 42 weeks and beyond)) or has given early term, full term, late term, or postterm birth.
  • the subject is due to give birth in 9, 8, 7, 6, 5, 4, 3, 2, 1 months; 4, 3, 2, 1 weeks; 7, 6, 5, 4, 3, 2, 1 days.
  • the subject has terminated her pregnancy.
  • the subject has had an abortion.
  • the subject has an attribute, characteristic, or exposure (that increases the likelihood of developing a disorder as described herein, e.g., neuroactive steroid deficiency).
  • the subject has a chronic illness (e.g., cancer or cardiovascular disease), other mental health disorders (including substance misuse), or a family history of psychiatric disorders.
  • the subject is disabled or has poor health status due to medical illness, complicated grief, chronic sleep disturbance, loneliness, or history of depression.
  • the subject has poor self-esteem, child-care stress, prenatal anxiety, life stress, decreased social support, single/unpartnered relationship status, history of depression, difficult infant temperament, previous postpartum depression, lower socioeconomic status, or unintended pregnancy.
  • the subject has hyperemesis gravidarum (e.g., severe form of morning sickness, e.g., preventing adequate intake of food and fluids).
  • the subject has had a complication in pregnancy (e.g., emergency C-sections, pre-eclampsia, hospitalization during pregnancy, concern about fetal distress and admission of the baby to special care (NICU), the baby was in the NICU).
  • the subject has had emotionally painful or stressful experiences around pregnancy, childbirth, or early parenting (e.g., the subject was treated for infertility, had a previous miscarriage or other pregnancy loss, delivery of multiples, special needs, colic or difficult temperament baby, had difficulty feeding).
  • the subject has had a history of domestic violence, sexual or other abuse (e.g., abused as a child or as an adult).
  • the subject has had a traumatic childhood (e.g., loss of a parent, troubling relationship with parent).
  • the subject has stress (e.g., loss of someone close, job loss, financial hardship, divorce, strain in a relationship, house move).
  • the subject has lack of social support.
  • the subject has a perfectionist or controlling personality.
  • a method of treating a subject suffering from depression or an anxiety disorder comprising the steps of: a) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone or Compound 9) in reducing the depression or anxiety disorder (e.g., symptoms of the depression or anxiety disorder) in a subject treated with the neuroactive steroid (e.g., allopregnanolone or Compound 9); and b) administering to the subject a therapeutic agent (e.g., a neuroactive steroid) if the information indicates that the depression or anxiety disorder (e.g., symptoms of the depression or anxiety disorder) is reduced in the subject as compared to the subject before having received the neuroactive steroid (e.g., allopregnanolone or Compound 9), thereby treating the subject.
  • the depression is major depressive disorder.
  • the depression is postpartum depression.
  • a method of selecting a therapeutic agent for treating depression or an anxiety disorder in a human subject treated with a neuroactive steroid (e.g., allopregnanolone or Compound 9) comprising the steps of: a) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone or Compound 9) in reducing the depression or anxiety disorder (e.g., symptoms of the depression or anxiety disorder) in a subject; and b) selecting the therapeutic agent (e.g., neuroactive steroid) if the information indicates that the depression or anxiety disorder (e.g., symptoms of the depression or anxiety disorder) is reduced in the subject as compared to the subject before having received the neuroactive steroid (e.g., allopregnanolone or Compound 9).
  • the depression is major depressive disorder.
  • the depression is postpartum depression.
  • a method of evaluating e.g., diagnosing, prognosing, and determining a course of treatment in) a subject suffering from depression or anxiety disorder, comprising the steps of: a) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone or Compound 9) in reducing depression or anxiety disorder (e.g., symptoms of the depression or anxiety disorder) in a subject treated with the neuroactive steroid (e.g., allopregnanolone or Compound 9); and b) determining if the depression or anxiety disorder (e.g., symptoms of the depression or anxiety disorder) is reduced in the subject as compared to the subject before receiving the neuroactive steroid (e.g., allopregnanolone), thereby evaluating the subject.
  • a neuroactive steroid e.g., allopregnanolone or Compound 9
  • the information is received, e.g., about 1, 2, 3, 4, 5, or 6 days; about 1, 2, or 3 weeks; about 1, 2, or 3 months after administration of the neuroactive steroid (e.g., allopregnanolone).
  • the subject has been administered the neuroactive steroid less than about 3 months (e.g., less than about 2 or 1 month; 3, 2, or 1 weeks; 6, 5, 4, 3, 2, or 1 days) prior to receiving the information.
  • the subject has been administered the neuroactive steroid (e.g., allopregnanolone) by intravenous infusion.
  • the therapeutic agent is administered by oral administration.
  • the therapeutic agent is administered as a solid composition (e.g., a solid dosage form).
  • a method of evaluating e.g., diagnosing, prognosing, or determining a course of treatment in) a subject suffering from depression or anxiety disorder, comprising the steps of: a) administering to the subject a therapeutic agent (e.g., neuroactive steroid or Compound 9); and b) receiving information related to the therapeutic effect of a neuroactive steroid (e.g., allopregnanolone or Compound 9) in reducing the depression or anxiety disorder (e.g., symptoms of the depression or anxiety disorder) in a subject treated with the neuroactive steroid (e.g., allopregnanolone or Compound 9), thereby evaluating the subject.
  • the information is acquired by imaging the subject or a sample from the subject.
  • the information is acquired by fMRI.
  • the information is acquired by SPECT.
  • a method of treating a subject suffering from a neuroendocrine disease comprising: intravenously administering to the subject a therapeutically effective amount of a neuroactive steroid (e.g., allopregnanolone), wherein administering occurs by continuous intravenous infusion or intermittent intravenous infusion.
  • a neuroactive steroid e.g., allopregnanolone
  • administering occurs by continuous intravenous infusion or intermittent intravenous infusion.
  • the concentrations of allopregnanolone in plasma is greater than that in a normal subject.
  • the concentrations of allopregnanolone in plasma is 10 nM in plasma or less.
  • a method of treating a symptom of a neuroendocrine diseases comprising: intravenously administering to the subject a therapeutically effective amount of a neuroactive steroid (e.g., allopregnanolone), wherein administering occurs by continuous intravenous infusion.
  • a neuroactive steroid e.g., allopregnanolone
  • the symptom is reduced at a magnitude or rate different from that observed in a subject without having received treatment.
  • a method of increasing allopregnanolone levels in a subject comprising: intravenously administering to the subject a therapeutically effective amount of a neuroactive steroid (e.g., allopregnanolone), wherein administering occurs by continuous intravenous infusion or intermittent infusion.
  • a neuroactive steroid e.g., allopregnanolone
  • provided herein are methods for treating a disease or disorder described herein, comprising administering to a subject a therapeutically effective amount of Compound 9
  • a method for treating or preventing a disorder described herein comprising orally administering a total daily dose of Compound 9, or pharmaceutically acceptable salt or isotopologue thereof, or pharmaceutical composition thereof of about 10 mg to about 100 mg to a subject in need thereof.
  • Compound 9, or a pharmaceutically acceptable salt or isotopologue thereof, or pharmaceutical composition thereof is administered chronically. In some embodiments, Compound 9, or pharmaceutically acceptable salt or isotopologue thereof, or pharmaceutical composition thereof is administered acutely.
  • the disease or disorder is a GABA-related disease or disorder.
  • the GABA receptor is modulated (e.g., as determined by assessment of electrical activity in the brain using an electroencephalogram (EEG)).
  • EEG electroencephalogram
  • the GABA receptor is modulated (e.g., as determined by assessment of electrical activity in the brain by beta-band EEG).
  • the subject is administered about 10 mg to about 80 mg (e.g., about 10 mg to about 60 mg) of the compound. In some embodiments, the subject is administered about 10 mg to about 50 mg (e.g., about 35 mg) of the compound. In some embodiments, the subject is administered less than about 100 mg, less than about 80 mg, less than about 60 mg, less than about 50, less than about 40, less than about 20 mg.
  • the subject is administered at least once a day. In some embodiments, the subject is administered once a day.
  • the subject is administered for at least 1, 2, 3, 4, 5, 6, 7 days. In some embodiments, the subject is administered for 1, 2, 3, 4, 5, 6, 7 days.
  • the subject has not had food for 1, 2, 4, 6, 8, 12, 24 hours. In some embodiments, the subject has had food within 1, 2, 4, 6, 8, 12, 24 hours of administration.
  • the subject is administered as a pharmaceutical composition. In some embodiments, the subject is administered a solution formulation. In some embodiments, the subject is administered a suspension formulation. In some embodiments, the subject is administered a solid dosage formulation.
  • the composition comprises a cyclodextrin (e.g., sulfoalkyl ether ⁇ -cyclodextrin (SAEBCD) or hydroxypropyl ⁇ -cyclodextrin (HPBCD)).
  • SAEBCD sulfoalkyl ether ⁇ -cyclodextrin
  • HPBCD hydroxypropyl ⁇ -cyclodextrin
  • the disorder is a seizure or epilepsy disorder (e.g., orphan epilepsies (e.g., Dravet syndrome, Lennox-Gastaut syndrome, Tuberous sclerosis complex, Rett syndrome, PCDH19 epilepsy), seizure associated with a neurological disorder).
  • a seizure or epilepsy disorder e.g., orphan epilepsies (e.g., Dravet syndrome, Lennox-Gastaut syndrome, Tuberous sclerosis complex, Rett syndrome, PCDH19 epilepsy), seizure associated with a neurological disorder).
  • the disorder is depression (e.g., postpartum depression).
  • the subject does not experience an adverse effect (e.g., a serious adverse event or severe adverse event as described herein).
  • the subject does not experience an increase from pre-dose supine blood pressure (e.g., systolic, diastolic) 1, 2, 4, 8, 12, 24 hours or more after administration.
  • the subject does not experience an increase in heart rate from 1, 2, 4, 8, 12, 24 hours or more after administration.
  • the subject experiences sedation (e.g., mild, transient, and associated with daily peak exposure).
  • the subject does not experience sedation (e.g., rate of moderate to deep sedation as defined by a structured rating scale (e.g., MOAA/S) is comparable to placebo (e.g., MOAA/S is less than 3, MOAA/S is less than 2).
  • the subject is not sedated relative to a reference standard.
  • the reference standard is the amount of sedation relative to a subject administered a placebo.
  • the subject does not experience sedation, as measured in a score of 3 or less as measured by MOAA/S (e.g., as measured in a score of 2 or less as measured by MOAA/S.
  • the subject does not experience sedation e.g., as measured by a score of 5 or higher as measured by SSS.
  • the subject does not experience impact on cognition e.g., as measured by testing of psychomotor function, attention, visual learning, or executive function.
  • the method further comprises administering an additional therapeutic agent.
  • a method for treating a human subject comprising: identifying a subject at risk of suffering from depression (e.g., postpartum depression) or an anxiety disorder; and administering (e.g., orally, intravenously) to the subject a therapeutically effective amount of Compound 9.
  • the therapeutic agent is administered to the subject within 3 days, 2 days, 1 day, 24 hours of delivery of a baby (e.g., within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, within 30 minutes).
  • Compound 9 or a composition comprising Compound 9 is administered orally.
  • the subject is identified to be at risk through a screening method (e.g., Edinburgh Postnatal Depression Scale (EPDS), e.g., a score of 10 or more on the EPDS, a score of 13 or more on the EPDS).
  • EPDS Edinburgh Postnatal Depression Scale
  • the subject has given birth (e.g., the subject has given birth within 3, 2, 1 days; 24, 20, 16, 12, 8, 6, 4, 3, 2, 1 hours; 60, 45, 30, 15, 10, 5 minutes).
  • the subject is due to give birth.
  • the subject is due to give birth in 9, 8, 7, 6, 5, 4, 3, 2, 1 months; 4, 3, 2, 1 weeks; 7, 6, 5, 4, 3, 2, 1 days.
  • the subject has an attribute, characteristic, or exposure (that increases the likelihood of developing a disorder as described herein, e.g., neuroactive steroid deficiency).
  • the subject has hyperemesis gravidarum (e.g., severe form of morning sickness, e.g., preventing adequate intake of food and fluids).
  • the subject has had a complication in pregnancy (e.g., emergency C-sections, pre-eclampsia, hospitalization during pregnancy, concern about fetal distress and admission of the baby to special care (NICU), the baby was in the NICU).
  • the subject has had emotionally painful or stressful experiences around pregnancy, childbirth, or early parenting (e.g., the subject was treated for infertility, had a previous miscarriage or other pregnancy loss, delivery of multiples, special needs, colic or difficult temperament baby, had difficulty feeding).
  • the subject has had a history of domestic violence, sexual or other abuse (e.g., abused as a child or as an adult).
  • the subject has had a traumatic childhood (e.g., loss of a parent, troubling relationship with parent).
  • the subject has stress (e.g., loss of someone close, job loss, financial hardship, divorce, strain in a relationship, house move).
  • the subject has lack of social support.
  • the subject has a perfectionist or controlling personality.
  • the therapeutic agent is a Selective Serotonin Reuptake Inhibitor (SSRI).
  • a method for treating a human subject suffering from major depressive disorder (e.g., postpartum depression) or an anxiety disorder comprising administering (e.g., orally, intravenously) to the subject a therapeutically effective amount of Compound 9.
  • a method for treating a human subject suffering from depression (e.g., postpartum depression) or an anxiety disorder comprising administering (e.g., orally, intravenously) to the subject a therapeutically effective amount of Compound 9.
  • the depression is clinical depression (e.g., severe depression), postnatal or postpartum depression, atypical depression, melancholic depression, Psychotic Major Depression (PMD), catatonic depression, Seasonal Affective Disorder (SAD), dysthymia, double depression, Depressive Personality Disorder (DPD), Recurrent Brief Depression (RBD), minor depressive disorder, bipolar disorder or manic depressive disorder, post-traumatic stress disorders, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior.
  • the depression is severe depression.
  • the depression is postpartum depression.
  • the depression is major depressive disorder.
  • the method provides acute treatment of the depression (e.g., within 72 hours, 48 hours, 24 hours, 12 hours, or less). In some embodiments, the method provides maintenance treatment or preventative treatment. In some embodiments, the method provides acute treatment of the depression or anxiety disorder (e.g., provides relief from a symptom in less than 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours).
  • the method provides rapid onset of efficacy (e.g., rapid reduction in a symptom of depression or anxiety disorder; rapidly affective to reduce a symptom of depression or anxiety disorder, e.g., a subject experiences relief from a symptom of depression or anxiety disorder described herein within 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours)).
  • rapid onset of efficacy e.g., rapid reduction in a symptom of depression or anxiety disorder; rapidly affective to reduce a symptom of depression or anxiety disorder, e.g., a subject experiences relief from a symptom of depression or anxiety disorder described herein within 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours)).
  • the therapeutic effect is sustained (e.g., effectively treats a symptom of depression or anxiety disorder and the efficacy is maintained for at least 1 day (e.g., at least 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, or more).
  • the efficacy is maintained after a single course of treatment (e.g., single dose, multiple doses, or cycle of treatment) of Compound 9.
  • the therapeutic effect is does not cause an adverse event (e.g., does not cause a severe or moderate adverse event, e.g., during treatment or 3 days, 7 days, 10 days, 20 days, 30 days, 60 days, 90 days, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more after treatment).
  • an adverse event e.g., does not cause a severe or moderate adverse event, e.g., during treatment or 3 days, 7 days, 10 days, 20 days, 30 days, 60 days, 90 days, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more after treatment.
  • the subject is substantially relieved of at least one symptom within 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less of said administration. In some embodiments, the subject is substantially relieved of at least one symptom for 1, 2, 3, 4, 5, 6, 7 days; 1, 2, 3, 4 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or more.
  • Compound 9 is administered to a pregnant subject. In some embodiments, the subject is pregnant. In some embodiments, Compound 9 is administered to the subject in a pregnant subject in the third trimester of the pregnancy.
  • Compound 9 is administered to the subject within 3 days, 2 days, 1 day, 24 hours of delivery of a baby (e.g., within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, within 30 minutes).
  • the subject is identified to be at risk through a screening method (e.g., Edinburgh Postnatal Depression Scale (EPDS), e.g., a score of 10 or more on the EPDS, a score of 13 or more on the EPDS).
  • EPDS Edinburgh Postnatal Depression Scale
  • the subject has given birth (e.g., the subject has given birth within 3, 2, 1 days; 24, 20, 16, 12, 8, 6, 4, 3, 2, 1 hours; 60, 45, 30, 15, 10, 5 minutes).
  • the subject is due to give birth.
  • the subject is due to give birth in 9, 8, 7, 6, 5, 4, 3, 2, 1 months; 4, 3, 2, 1 weeks; 7, 6, 5, 4, 3, 2, 1 days.
  • the subject has an attribute, characteristic, or exposure (that increases the likelihood of developing a disorder as described herein, e.g., neuroactive steroid deficiency).
  • the subject has hyperemesis gravidarum (e.g., severe form of morning sickness, e.g., preventing adequate intake of food and fluids).
  • the subject has had a complication in pregnancy (e.g., emergency C-sections, pre-eclampsia, hospitalization during pregnancy, concern about fetal distress and admission of the baby to special care (NICU), the baby was in the NICU).
  • the subject has had emotionally painful or stressful experiences around pregnancy, childbirth, or early parenting (e.g., the subject was treated for infertility, had a previous miscarriage or other pregnancy loss, delivery of multiples, special needs, colic or difficult temperament baby, had difficulty feeding)
  • the subject has had a history of domestic violence, sexual or other abuse (e.g., abused as a child or as an adult).
  • the subject has had a traumatic childhood (e.g., loss of a parent, troubling relationship with parent).
  • the subject has stress (e.g., loss of someone close, job loss, financial hardship, divorce, strain in a relationship, house move).
  • the subject has lack of social support.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high pressure liquid chromatography
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound.
  • the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound.
  • the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient or carrier.
  • analogue means one analogue or more than one analogue.
  • modulation refers to the inhibition or potentiation of GABA receptor function.
  • a “modulator” e.g., a modulator compound
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci . (1977) 66(1): 1-79.
  • Solvate refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • solvents include water, ethanol, acetic acid, and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • Stepoisomers It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of t electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • “Brexanolone” refers to a sterile solution of 5 mg/mL allopregnanolone in 250 mg/mL sulfobutylether- ⁇ -cyclodextrin (SBECD) buffered with citrate, which is diluted with sterile water for injection to render it isotonic for IV infusion.
  • SBECD sulfobutylether- ⁇ -cyclodextrin
  • a “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g. infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms “human,” “patient,” and “subject” are used interchangeably herein.
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).
  • a “cycle of treatment” comprises administering a first dose of a neuroactive steroid, administering a second dose of the neuroactive steroid, and administering a third dose of the neuroactive steroid, said neuroactive steroid doses being sufficient to treat said subject.
  • the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, e.g., a disorder as described herein (e.g., tremor (e.g., essential tremor); depression (e.g., postpartum depression); or an anxiety disorder).
  • a CNS-related disorder e.g., a disorder as described herein (e.g., tremor (e.g., essential tremor); depression (e.g., postpartum depression); or an anxiety disorder).
  • a CNS-related disorder e.g., a disorder as described herein (e.g., tremor (e.g., essential tremor); depression (e.g., postpartum depression); or an anxiety disorder).
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • FIG. 1 depicts an exemplary effect of Compound 9 and diazepam on (A) extrasynaptic or (B) synaptic electrical activity in the brain.
  • FIG. 2 depicts an exemplary comparative effect of Compound 9 and diazepam.
  • A PTZ threshold following subchronic dosing for 7d; and
  • B Pharmaco-resistant SE model.
  • FIG. 3 depicts exemplary preclinical anticonvulsant efficacy in rodents.
  • FIG. 4 depicts exemplary PK/PD Profile and Brain Exposure for Compound 9.
  • A Exposure levels of allopregnanolone and Compound 9 following a single oral dose in rat;
  • B Exposure levels of Compound 9 in the plasma and brain of rat.
  • FIG. 5 shows exemplary pharmacokinetics of Compound 9 during Single Ascending Dose Study.
  • FIG. 6 shows exemplary pharmacokinetics of Compound 9 during Multiple Ascending Dose Study.
  • FIG. 7 shows exemplary dose linearity over the Multiple Dose Range Studied.
  • FIG. 8 shows exemplary MOAA/S Mean Score for Single Ascending Dose Study.
  • FIG. 9 shows exemplary MOAA/S Mean Score for Multiple Ascending Dose Study.
  • FIG. 10 shows an outline of an exemplary double-blind, randomized, placebo-controlled, Phase 2 registration study of brexanolone in 21 hospital inpatient women with severe PPD.
  • FIG. 11A shows effects of brexanolone or placebo on mean HAM-D total score over time in 21 hospital inpatient women with severe PPD participating in an exemplary double-blind, randomized, placebo-controlled, Phase 2 registration study of brexanolone.
  • FIG. 11B shows effects of brexanolone or placebo on mean MADRS total score over time in 21 hospital inpatient women with severe PPD participating in an exemplary double-blind, randomized, placebo-controlled, Phase 2 registration study of brexanolone.
  • FIG. 12 shows exemplary HAM-D Remission Rates Over Time in 21 hospital inpatient women with severe PPD participating in an exemplary double-blind, randomized, placebo-controlled, Phase 2 registration study of brexanolone.
  • the present invention is directed to neuroactive steroids that may act, for example, as GABA modulators.
  • such compounds are envisioned to be useful as therapeutic agents for treating a disorder described herein, e.g., tremor (e.g., essential tremor); depression (e.g., postpartum depression, major depressive disorder); an anxiety disorder, comprising administering to the subject an effective amount of a compound of the present invention or a composition thereof.
  • the compound is administered by intravenous administration.
  • the compound is administered orally.
  • a compound disclosed herein for example, a neuroactive steroid described herein such as allopregnanolone or Compound 9, can be administered as a hormone or steroid replacement therapy in a subject.
  • a subject described herein has experienced a decrease in a steroid or hormone level prior to treatment with a compound described herein.
  • a subject generally experiences a decrease in allopregnanolone subsequent to delivery of an infant.
  • the neuroactive steroid is administered to the subject within 3 days, 2 days, 1 day, or 24 hours of delivery of a baby (e.g., within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, or within 30 minutes).
  • a subject can be administered a compound described herein (e.g., allopregnanolone) after experiencing a decrease in steroid or hormone level.
  • the decrease in hormone or steroid level is at least by a factor of 2 (e.g., at least a factor of 3, 4, 5, 10 or 100).
  • Also provided herein is a method for treating or preventing a disorder described herein, comprising orally administering a total daily dose of Compound 9,
  • Compounds of the present invention can modulate GABA function, and therefore can act as neuroactive steroids for the treatment and prevention of CNS-related conditions in a subject.
  • Modulation refers to the inhibition or potentiation of GABA receptor function.
  • the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating CNS conditions in mammals including humans and non-human mammals.
  • the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.
  • Exemplary neuroactive steroid compounds include:
  • Exemplary CNS conditions related to GABA-modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression such as PND, major depressive disorder, or perinatal depression, dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), compulsive disorders (e.g., obsessive compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], disorders of memory and/or cognition [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular type dementia], movement disorders [e.g.,
  • a combination of a compound of the present invention and another pharmacologically active agent is provided.
  • the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a condition associated with brain excitability comprising administering to the subject an effective amount of a compound of the present invention to the subject.
  • a method of treating or preventing tremor in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.
  • the tremor is essential tremor.
  • a method of treating or preventing mood disorders in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.
  • the mood disorder is depression.
  • the mood disorder is postpartum depression.
  • the mood disorder is major depressive disorder.
  • a method of alleviating or preventing PMS, PND, major depressive disorder, or perinatal depression in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.
  • a method of treating or preventing stress or anxiety in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
  • a method of alleviating or preventing insomnia in a subject comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.
  • a method of inducing sleep and maintaining substantially the level of REM sleep that is found in normal sleep, wherein substantial rebound insomnia is not induced comprising administering an effective amount of a compound of the present invention.
  • a method of cognition enhancement or treating memory disorder by administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the disorder is Alzheimer's disease.
  • the disorder is Rett syndrome.
  • a method of treating attention disorders by administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the attention disorder is ADHD.
  • the therapeutic agent e.g., a neuroactive steroid or compound described herein
  • the subject is administered to the subject within 3 days, 2 days, 1 day, 24 hours of delivery of a baby (e.g., within 12 hours, within 6 hours, within 3 hours, within 2 hours, within 1 hour, within 30 minutes).
  • the method includes acute treatment of a disorder described herein.
  • a method described herein provides relief from a symptom described herein in less than 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours).
  • the subject experiences, upon administration of a compound described herein (e.g., allopregnanolone) rapid onset of efficacy of the compound.
  • a subject experiences relief from a symptom of a disorder described herein within 1 week (e.g., within 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or 12 hours).
  • a method described herein provides for sustained efficacy upon treatment with a compound described herein.
  • a subject is treated with a compound described herein, wherein the treatment effectively treats a symptom of a disorder described herein and the efficacy is maintained for at least 1 day (e.g., at least 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months).
  • the efficacy is maintained after a single course of treatment of a compound described herein (e.g., allopregnanolone).
  • Course of treatment is a treatment regimen administered to a subject so as to provide efficacy of a symptom of a disorder to the subject.
  • a course of treatment is a single dose.
  • a course of treatment includes multiple doses of a compound described herein.
  • a course of treatment includes a cycle of treatment of a compound described herein.
  • a method described herein can include a course of treatment with multiple dosages or cycles of treatment, for example, where a first dose or cycle of treatment is a parenteral dose such as an intravenous dose, and a second dose or cycle of treatment is an oral dose.
  • the first and second dose or cycle of treatment include the same compound described herein.
  • the first dose or cycle of treatment includes a first compound (e.g., a first compound described herein such as allopregnanolone) and the second dose or cycle of treatment includes a second compound that is different from the first compound.
  • a method described herein provides effective treatment without causing a severe adverse event. In an embodiment, a method described herein provides effective treatment without causing a moderate or severe adverse event. In an embodiment, a method described herein provides effective treatment without causing an adverse event.
  • the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly, or intravenously.
  • neuroendocrine disorder or “neuroendocrine dysfunction” refers to a variety of conditions caused by imbalances in the body's hormone production directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and the pituitary gland are two areas of the brain that regulate the production of hormones, damage to the hypothalamus or pituitary gland, e.g., by traumatic brain injury, may impact the production of hormones and other neuroendocrine functions of the brain.
  • the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., a women's health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition is polycystic ovary syndrome.
  • Symptoms of neuroendocrine disorder include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, and somatic symptoms; including but not limited to fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, attention difficulties, loss of lipido, infertility, amenorrhea, loss of muscle mass, increased belly body fat, low blood pressure, reduced heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.
  • neurodegenerative disease includes diseases and disorders that are associated with the progressive loss of structure or function of neurons, or death of neurons.
  • Neurodegenerative diseases and disorders include, but are not limited to, Alzheimer's disease (including the associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injuries; ataxia and convulsion (including for the treatment and prevention and prevention of seizures that are caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign forgetfulness; brain edema; cerebellar ataxia including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusive injuries (e.g., spinal cord injury and head injury); dementias including multi-infarct dementia and senile dementia; disturbances of consciousness; Down syndrome; drug-induced or medication-induced Parkinsonism (such as neuroleptic-induced acute akathisia, acute dystonia, Parkinson
  • Neurodegenerative diseases also include, but are not limited to, neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest.
  • Methods of treating or preventing a neurodegenerative disease also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.
  • the compounds described herein e.g., the compound of Compound 9, or pharmaceutically acceptable salt, or a pharmaceutically acceptable composition thereof, can be used in a method described herein, for example in the treatment of a disorder described herein such as epilepsy, status epilepticus, or seizure, for example as described in WO2013/112605 and WO/2014/031792, the contents of which are incorporated herein in their entirety.
  • a disorder described herein such as epilepsy, status epilepticus, or seizure, for example as described in WO2013/112605 and WO/2014/031792, the contents of which are incorporated herein in their entirety.
  • Epilepsy is a brain disorder characterized by repeated seizures over time.
  • Types of epilepsy can include, but are not limited to generalized epilepsy, e.g., childhood absence epilepsy, juvenile nyoclonic epilepsy, epilepsy with grand-mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, e.g., temporal lobe epilepsy, frontal lobe epilepsy, benign focal epilepsy of childhood.
  • Status epilepticus can include, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges.
  • Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures, and can include early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus.
  • Early status epilepticus is treated with a first line therapy.
  • Established status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, and a second line therapy is administered.
  • Refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line and a second line therapy, and a general anesthetic is generally administered.
  • Super refractory status epilepticus is characterized by status epileptic seizures which persist despite treatment with a first line therapy, a second line therapy, and a general anesthetic for 24 hours or more.
  • Non-convulsive status epilepticus can include, e.g., focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.
  • focal non-convulsive status epilepticus e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus
  • generalized non-convulsive status epilepticus e.g., late onset absence non-convulsive status epilepticus, atypical absence non-convulsive
  • the compounds described herein can also be administered as a prophylactic to a subject having a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges; prior to the onset of a seizure.
  • a CNS disorder e.g., a traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus;
  • a seizure is the physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain.
  • the term “seizure” is often used interchangeably with “convulsion.” Convulsions are when a person's body shakes rapidly and uncontrollably. During convulsions, the person's muscles contract and relax repeatedly.
  • seizures are divided into two broad categories: generalized and partial (also called local or focal). Classifying the type of seizure helps doctors diagnose whether or not a patient has epilepsy.
  • Generalized seizures are produced by electrical impulses from throughout the entire brain, whereas partial seizures are produced (at least initially) by electrical impulses in a relatively small part of the brain.
  • the part of the brain generating the seizures is sometimes called the focus.
  • Absence seizures cause a short loss of consciousness (just a few seconds) with few or no symptoms.
  • the patient most often a child, typically interrupts an activity and stares blankly. These seizures begin and end abruptly and may occur several times a day. Patients are usually not aware that they are having a seizure, except that they may be aware of “losing time.”
  • Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients sometimes describe the jerks as brief electrical shocks. When violent, these seizures may result in dropping or involuntarily throwing objects.
  • Clonic seizures are repetitive, rhythmic jerks that involve both sides of the body at the same time.
  • Tonic seizures are characterized by stiffening of the muscles.
  • Atonic seizures consist of a sudden and general loss of muscle tone, particularly in the arms and legs, which often results in a fall.
  • Seizures described herein can include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; unremitting seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign Rolandic seizures; febrile seizures; emotional seizures; focal seizures; gelastic seizures; generalized onset seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post traumatic seizures; subtle seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures.
  • the seizure is a generalized seizure associated with Dravet Syndrome, Lennox-G
  • movement disorders refers to a variety of diseases and disorders that are associated with hyperkinetic movement disorders and related abnormalities in muscle control.
  • exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (defined particularly by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle, tics and Tourette syndrome, Restless legs syndrome, stiff person syndrome, and gait disorders.
  • tremor for example cerebellar tremor or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, parkinsonian tremor, physiological tremor, psychogenic tremor, or rubral tremor.
  • Tremor includes hereditary, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyoid-parathyroid-, liver disease and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellitus, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, Manganese, arsenic, toluene); drug-induced (narcoleptics, tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders.
  • metabolic diseases e.g., thyoid-parathyroid-, liver disease and hypoglycemia
  • peripheral neuropathies associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes mellit
  • Clinical tremor can be classified into physiologic tremor, enhanced physiologic tremor, essential tremor syndromes (including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor), dystonic tremor, parkinsonian tremor, cerebellar tremor, Holmes' tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.
  • essential tremor syndromes including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • dystonic tremor including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • dystonic tremor including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • dystonic tremor including classical essential tremor, primary orthostatic tremor, and task- and position-specific tremor
  • Tremor is an involuntary, at times rhythmic, muscle contraction and relaxation that can involve oscillations or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs).
  • body parts e.g., hands, arms, eyes, face, head, vocal folds, trunk, legs.
  • Cerebellar tremor or intention tremor is a slow, broad tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions in or damage to the cerebellum resulting from, e.g., tumor, stroke, disease (e.g., multiple sclerosis, an inherited degenerative disorder).
  • Dystonic tremor occurs in individuals affected by dystonia, a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive motions and/or painful and abnormal postures or positions.
  • Dystonic tremor may affect any muscle in the body.
  • Dystonic tremors occurs irregularly and often can be relieved by complete rest.
  • Essential tremor or benign essential tremor is the most common type of tremor.
  • Essential tremor may be mild and nonprogressive in some, and may be slowly progressive, starting on one side of the body but affect both sides within 3 years. The hands are most often affected, but the head, voice, tongue, legs, and trunk may also be involved.
  • Tremor frequency may decrease as the person ages, but severity may increase. Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase their severity. Symptoms generally evolve over time and can be both visible and persistent following onset.
  • Orthostatic tremor is characterized by fast (e.g., greater than 12 Hz) rhythmic muscle contractions that occurs in the legs and trunk immediately after standing. Cramps are felt in the thighs and legs and the patient may shake uncontrollably when asked to stand in one spot. Orthostatic tremor may occurs in patients with essential tremor.
  • Parkinsonian tremor is caused by damage to structures within the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a “pill-rolling” action of the hands that may also affect the chin, lips, legs, and trunk. Onset of parkinsonian tremor typically begins after age 60. Movement starts in one limb or on one side of the body and can progress to include the other side.
  • Physiological tremor can occur in normal individuals and have no clinical significance. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. The tremor classically has a frequency of about 10 Hz.
  • Psychogenic tremor or hysterical tremor can occur at rest or during postural or kinetic movement.
  • Patient with psychogenic tremor may have a conversion disorder or another psychiatric disease.
  • Rubral tremor is characterized by coarse slow tremor which can be present at rest, at posture, and with intention.
  • the tremor is associated with conditions that affect the red nucleus in the midbrain, classical unusual strokes.
  • Parkinson's Disease affects nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremors, and changes in speech and gait. Parkinsonism is characterized by tremor, bradykinesia, rigidity, and postural instability. Parkinsonism shares symptoms found in Parkinson's Disease, but is a symptom complex rather than a progressive neurodegenerative disease.
  • Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures.
  • Dystonic movements can be patterned, twisting, and may be tremulous.
  • Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation.
  • Chorea is a neurological disorder characterized by jerky involuntary movements typically affecting the shoulders, hips, and face. Huntington's Disease is an inherited disease that causes nerve cells in the brain to waste away. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can hinder walk, talk, and swallowing.
  • Ataxia refers to the loss of full control of bodily movements, and may affect the fingers, hands, arms, legs, body, speech, and eye movements.
  • Myloclonus and Startle is a response to a sudden and unexpected stimulus, which can be acoustic, tactile, visual, or vestibular.
  • Tics are an involuntary movement usually onset suddenly, brief, repetitive, but non-rhythmical, typically imitating normal behavior and often occurring out of a background of normal activity. Tics can be classified as motor or vocal, motor tics associated with movements while vocal tics associated with sound. Tics can be characterized as simple or complex. For example simple motor tics involve only a few muscles restricted to a specific body part. Tourette Syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple motor tics and at least one vocal tic.
  • Restless Legs Syndrome is a neurologic sensorimotor disorder characterized by an overwhelming urge to move the legs when at rest.
  • Stiff Person Syndrome is a progressive movement disorder characterized by involuntary painful spasms and rigidity of muscles, usually involving the lower back and legs. Stiff-legged gait with exaggerated lumbar hyperlordosis typically results. Characteristic abnormality on EMG recordings with continuous motor unit activity of the paraspinal axial muscles is typically observed. Variants include “stiff-limb syndrome” producing focal stiffness typically affecting distal legs and feet.
  • Gait disorders refer to an abnormality in the manner or style of walking, which results from neuromuscular, arthritic, or other body changes. Gait is classified according to the system responsible for abnormal locomotion, and include hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.
  • a mood disorder for example clinical depression, postnatal depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, cationic depression, seasonal affective disorder, dysthymia, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic depressive disorder, depression caused by chronic medical conditions, treatment-resistant depression, refractory depression, suicidality, suicidal ideation, or suicidal behavior.
  • the method described herein provides therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression).
  • the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson's Disease), women's health disorders or conditions).
  • a disease or disorder described herein e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson's Disease), women's health disorders or conditions).
  • Clinical depression is also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, and refers to a mental disorder characterized by pervasive and persistent low mood that is accompanied by low self-esteem and loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression have trouble sleeping, lose weight, and generally feel agitated and irritable. Clinical depression affects how an individual feels, thinks, and behaves and may lead to a variety of emotional and physical problems. Individuals with clinical depression may have trouble doing day-to-day activities and make an individual feel as if life is not worth living.
  • MDD major depressive disorder
  • Peripartum depression refers to depression in pregnancy. Symptoms include irritability, crying, feeling restless, trouble sleeping, extreme exhaustion (emotional and/or physical), changes in appetite, difficulty focusing, increased anxiety and/or worry, disconnected feeling from baby and/or fetus, and losing interest in formerly pleasurable activities.
  • Postnatal depression is also referred to as postpartum depression (PPD), and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, reduced sexual desire, crying episodes, anxiety, and irritability.
  • the PND is a treatment-resistant depression (e.g., a treatment-resistant depression as described herein).
  • the PND is refractory depression (e.g., a refractory depression as described herein).
  • a subject having PND also experienced depression, or a symptom of depression during pregnancy. This depression is referred to herein as) perinatal depression.
  • a subject experiencing perinatal depression is at increased risk of experiencing PND.
  • AD Atypical depression
  • Patients suffering from AD also may have excessive sleep or somnolence (hypersomnia), a sensation of limb heaviness, and significant social impairment as a consequence of hypersensitivity to perceived interpersonal rejection.
  • Melancholic depression is characterized by loss of pleasure (anhedonia) in most or all activities, failures to react to pleasurable stimuli, depressed mood more pronounced than that of grief or loss, excessive weight loss, or excessive guilt.
  • PMD Psychitic major depression
  • psychotic depression refers to a major depressive episode, in particular of melancholic nature, where the individual experiences psychotic symptoms such as delusions and hallucinations.
  • Catatonic depression refers to major depression involving disturbances of motor behavior and other symptoms. An individual may become mute and stuporose, and either is immobile or exhibits purposeless or playful movements.
  • SAD Seasonal affective disorder
  • Dysthymia refers to a condition related to unipolar depression, where the same physical and cognitive problems are evident. They are not as severe and tend to last longer (e.g., at least 2 years).
  • Double depression refers to fairly depressed mood (dysthymia) that lasts for at least 2 years and is punctuated by periods of major depression.
  • DPD Depressive Personality Disorder
  • RBD Recurrent Brief Depression
  • Minor depressive disorder or minor depression refers to a depression in which at least 2 symptoms are present for 2 weeks.
  • Bipolar disorder or manic depressive disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression).
  • emotional highs mania or hypomania
  • lows depression
  • mania the individual may feel or act abnormally happy, energetic, or irritable. They often make poorly thought out decisions with little regard to the consequences.
  • the need for sleep is usually reduced.
  • depression there may be crying, poor eye contact with others, and a negative outlook on life.
  • the risk of suicide among those with the disorder is high at greater than 6% over 20 years, while self harm occurs in 30-40%.
  • Other mental health issues such as anxiety disorder and substance use disorder are commonly associated with bipolar disorder.
  • Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, chronic stress.
  • Treatment-resistant depression refers to a condition where the individuals have been treated for depression, but the symptoms do not improve.
  • antidepressants or physchological counseling do not ease depression symptoms for individuals with treatment-resistant depression.
  • individuals with treatment-resistant depression improve symptoms, but come back.
  • Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and/or anxiolytic drugs, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation and/or transcranial magnetic stimulation).
  • Post-surgical depression refers to feelings of depression that follow a surgical procedure (e.g., as a result of having to confront one's mortality). For example, individuals may feel sadness or empty mood persistently, a loss of pleasure or interest in hobbies and activities normally enjoyed, or a persistent felling of worthlessness or hopelessness.
  • Mood disorder associated with conditions or disorders of women's health refers to mood disorders (e.g., depression) associated with (e.g., resulting from) a condition or disorder of women's health (e.g., as described herein).
  • mood disorders e.g., depression
  • a condition or disorder of women's health e.g., as described herein.
  • Suicidality, suicidal ideation, suicidal behavior refers to the tendency of an individual to commit suicide.
  • Suicidal ideation concerns thoughts about or an unusual preoccupation with suicide.
  • the range of suicidal ideation varies greatly, from e.g., fleeting thoughts to extensive thoughts, detailed planning, role playing, incomplete attempts. Symptoms include talking about suicide, getting the means to commit suicide, withdrawing from social contact, being preoccupied with death, feeling trapped or hopeless about a situation, increasing use of alcohol or drugs, doing risky or self-destructive things, saying goodbye to people as if they won't be seen again.
  • Symptoms of depression include persistent anxious or sad feelings, feelings of helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, sleeplessness, irritability, fatigue, motor challenges, loss of interest in pleasurable activities or hobbies, loss of concentration, loss of energy, poor self-esteem, absence of positive thoughts or plans, excessive sleeping, overeating, appetite loss, insomnia, self-harm, thoughts of suicide, and suicide attempts.
  • the presence, severity, frequency, and duration of symptoms may vary on a case to case basis. Symptoms of depression, and relief of the same, may be ascertained by a physician or psychologist (e.g., by a mental state examination).
  • the method provides therapeutic effect (e.g., as measured by reduction in Hamilton Depression Score (HAM-D)) within 4, 3, 2, 1 days; 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less.
  • the therapeutic effect is a decrease from baseline in HAM-D score at the end of a treatment period (e.g., 12, 24, 48 hours after administration; 24, 48, 72, 96 hours or more).
  • the decrease from baseline in HAM-D score is from severe (e.g., HAM-D score of 24 or greater) to symptom-free (e.g., HAM-D score of 7 or lower).
  • the baseline score is about 10 to 52 (e.g., more than 10, 15, or 20; 10 to 52, 12 to 52, 15 to 52, 17 to 52, 20 to 52, 22 to 52). In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the HAM-D score at the end of the treatment period is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, 1.8). In some embodiments, the HAM-D score at the end of the treatment period is less than 10, 7, 5, or 3.
  • the decrease in HAM-D score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D score at the end of the treatment period is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, 1.8).
  • the decrease in the baseline HAM-D score to HAM-D score at the end of the treatment period is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 fold).
  • the percentage decrease in the baseline HAM-D score to HAM-D score at the end of the treatment period is at least 50% (e.g., 60%, 70%, 80%, 90%).
  • the therapeutic effect is a decrease from baseline in HAM-D score at the end of a treatment period (e.g., 12, 24, 48 hours after administration; 24, 48, 72, 96 hours or more) at least 10, 15, or 20 points.
  • the therapeutic effect is a decrease from baseline in HAM-D score at the end of a treatment period (e.g., 12, 24, 48 hours after administration; 24, 48, 72, 96 hours or more) at least 5, 7, or 10 points more relative to the therapeutic effect provided by a placebo treatment.
  • the method provides therapeutic effect (e.g., as measured by reduction in Montgomery-Asberg Depression Rating Scale (MADRS)) within 4, 3, 2, 1 days; 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less.
  • the Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts) which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. 0-6 indicates normal/symptom absent; 7-19 indicates mild depression; 20-34 indicates moderate depression; and >34 indicates severe depression.
  • the therapeutic effect is a decrease from baseline in MADRS score at the end of a treatment period (e.g., 12, 24, 48 hours after administration; 24, 48, 60, 72, 96 hours or more).
  • the decrease from baseline in MADRS score is from severe (e.g., MADRS score of 30 or greater) to symptom-free (e.g., MADRS score of 20 or lower).
  • the mean change from baseline in MADRS total score from treatment with a compound described herein is about ⁇ 15, ⁇ 20, ⁇ 25, ⁇ 30, while the mean change from baseline in MADRS total score from treatment with placebo is about ⁇ 15, ⁇ 10, ⁇ 5.
  • the method provides therapeutic effect (e.g., as measured by reduction in Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.
  • the therapeutic effect is a improvement measured by the EPDS.
  • the method provides therapeutic effect (e.g., as measured by reduction in Clinical Global Impression-Improvement Scale (CGI)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.
  • CGI Clinical Global Impression-Improvement Scale
  • the therapeutic effect is a CGI score of 2 or less.
  • the method provides therapeutic effect (e.g., as measured by reduction in Generalized Anxiety Disorder 7-Item Scale (GAD-7)) within 4, 3, 2, 1 days; 24, 20, 16, 12, 10, 8 hours or less.
  • GID-7 Generalized Anxiety Disorder 7-Item Scale
  • anxiety disorders e.g., generalized anxiety disorder, panic disorder, obsessive compulsive disorder, phobia, post-traumatic stress disorder.
  • Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety.
  • Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders.
  • Generalized anxiety disorder is a common chronic disorder characterized by long-lasting anxiety that is not focused on any one object or situation. Those suffering from generalized anxiety experience non-specific persistent fear and worry and become overly concerned with everyday matters. Generalized anxiety disorder is the most common anxiety disorder to affect older adults.
  • panic disorder a person suffers from brief attacks of intense terror and apprehension, often marked by trembling, shaking, confusion, dizziness, nausea, difficulty breathing.
  • panic attacks defined by the APA as fear or discomfort that abruptly arises and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; although the specific cause is not always apparent.
  • a diagnosis of panic disorder also requires that said attacks have chronic consequences: either worry over the attacks' potential implications, persistent fear of future attacks, or significant changes in behavior related to the attacks. Accordingly, those suffering from panic disorder experience symptoms even outside of specific panic episodes.
  • Obsessive compulsive disorder is a type of anxiety disorder primarily characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (urges to perform specific acts or rituals).
  • the OCD thought pattern may be likened to superstitions insofar as it involves a belief in a causative relationship where, in reality, one does not exist.
  • the process is entirely illogical; for example, the compulsion of walking in a certain pattern may be employed to alleviate the obsession of impending harm.
  • the compulsion is entirely inexplicable, simply an urge to complete a ritual triggered by nervousness.
  • sufferers of OCD may only experience obsessions, with no overt compulsions; a much smaller number of sufferers experience only compulsions.
  • the single largest category of anxiety disorders is that of phobia, which includes all cases in which fear and anxiety is triggered by a specific stimulus or situation. Sufferers typically anticipate cosmic consequences from encountering the object of their fear, which can be anything from an animal to a location to a bodily fluid.
  • Post-traumatic stress disorder or PTSD is an anxiety disorder which results from a traumatic experience.
  • Post-traumatic stress can result from an extreme situation, such as combat, rape, hostage situations, or even serious accident. It can also result from long term (chronic) exposure to a severe stressor, for example soldiers who endure individual battles but cannot cope with continuous combat. Common symptoms include flashbacks, avoidant behaviors, and depression.
  • Conditions or disorders related to women's health include, but are not limited to, Gynecological health and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women's overall health and wellness (e.g., menopause).
  • PMS premenstrual syndrome
  • PMDD premenstrual dysphoric disorder
  • PCOS polycystic ovary syndrome
  • Gynecological health and disorders affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and such disorders as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.
  • PMS Premenstrual syndrome
  • PMDD Premenstrual dysphoric disorder
  • the symptoms of PMDD are similar to PMS but more severe and may interfere with work, social activity, and relationships.
  • PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflicts, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, change in appetite, feeling out of control or overwhelmed, sleep problems, physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).
  • Pregnancy issues include preconception care and prenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and premature birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.
  • Miscarriage refers to a pregnancy that ends on its own, within the first 20 weeks of gestation.
  • Abortion referse to the deliberate termination of a pregnancy, which can be performed during the first 28 weeks of pregnancy.
  • Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.
  • PCOS Polycystic ovary syndrome
  • PCOS Polycystic ovary syndrome
  • Symptoms of PCOS include irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, darker, velvety skin.
  • PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.
  • Menopause refers to the 12 months after a woman's last menstrual period and marks the end of menstrual cycles. Menopause typically occurs in a woman's 40 s or 50 s. Physical symptoms such as hot flashes and emotional symptoms of menopause may disrupt sleep, lower energy, or trigger anxiety or feelings of sadness or loss. Menopause includes nautral menopause and surgical menopause, which is a type of induced menopause due to an event such as surgery (e.g., hysterectomy, oophorectomy; cancer).
  • Neuroactive steroids are natural, synthetic, or semi-synthetic steroids that rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. Neuroactive steroids effect binding to membrane-bound receptors such as those for inhibitory and (or) excitatory neurotransmitters including GABA A , NMDA, and sigma receptors.
  • the steroids that may be classified into functional groups according to chemical structure and physiological activity and include estrogenic hormones, progestational hormones, and androgenic hormones.
  • progestational hormones referred to herein as “progestins” or “progestogens”, and their derivatives and bioactive metabolites.
  • progestins e.g., progesterone
  • progestin metabolites such as progesterone.
  • progesterone refers to a member of the progestin family and includes a 21 carbon steroid hormone. Progesterone is also known as D4-pregnene-3,20-dione; ⁇ 4-pregnene-3,20-dione; or pregn-4-ene-3,20-dione. As used herein a “synthetic progestin” is a molecule whose structure is related to that of progesterone, is synthetically derived, and retains the biological activity of progesterone.
  • Representative synthetic progestins include, but are not limited to, substitutions at the 17-position of the progesterone ring to introduce a hydroxyl, acetyl, hydroxyl acetyl, aliphatic, nitro, or heterocyclic group, modifications to produce 17 ⁇ -OH esters (e.g., 17 ⁇ -hydroxyprogesterone caproate), as well as modifications that introduce 6-methyl, 6-ene, and 6-chloro substituents onto progesterone (e.g., medroxyprogesterone acetate, megestrol acetate, and chlormadinone acetate), and which retains the biological activity of progesterone.
  • substitutions at the 17-position of the progesterone ring to introduce a hydroxyl, acetyl, hydroxyl acetyl, aliphatic, nitro, or heterocyclic group
  • modifications to produce 17 ⁇ -OH esters e.g., 17 ⁇ -hydroxyprogesterone caproate
  • progestin derivatives include 5-dehydroprogesterone, 6-dehydro-retroprogesterone (dydrogesterone), allopregnanolone (allopregnane-3 ⁇ , or 30-ol-20-one), ethynodiol diacetate, hydroxyprogesterone caproate (pregn-4-ene-3,20-dione, 17-(1-oxohexy)oxy); levonorgestrel, norethindrone, norethindrone acetate (19-norpregn-4-en-20-yn-3-one, 17-(acetyloxy)-, (17 ⁇ )-); norethynodrel, norgestrel, pregnenolone, ganaxolone (also referred to as CCD-1042 or INN), and megestrol acetate.
  • the neuroactive steroid is ganaxolone.
  • Useful progestins also can include allopregnone-3 ⁇ or 3 ⁇ , 20 ⁇ or 20 ⁇ -diol (see Merck Index 258-261); allopregnane-3 ⁇ ,21-diol-11,20-dione; allopregnane-3 ⁇ ,17 ⁇ -diol-20-one; 3,20-allopregnanedione, allopregnane, 3 ⁇ ,11 ⁇ ,17 ⁇ ,20 ⁇ ,21-pentol; allopregnane-3 ⁇ ,17 ⁇ ,20 ⁇ ,21-tetrol; allopregnane-3 ⁇ or 3 ⁇ ,11 ⁇ ,17 ⁇ ,21-tetrol-20-one, allopregnane-3 ⁇ ,17 ⁇ or 20 ⁇ -triol; allopregnane-3 ⁇ ,17 ⁇ ,21-triol-11,20-dione; allopregnane-3 ⁇ ,11 ⁇ ,21-triol-20-one; allopregnane-3 ⁇ ,17 ⁇ ,21-triol-20-one; all
  • progestin derivatives include esters with non-toxic organic acids such as acetic acid, benzoic acid, maleic acid, malic acid, caproic acid, and citric acid and inorganic salts such as hydrochloride, sulfate, nitrate, bicarbonate and carbonate salts.
  • suitable progestins include alphaxalone (also referred to as INN, alfaxolone, and alphaxolone), alphadolone (also referred to as alfadolone), hydroxydione, and minaxolone.
  • the neuroactive steroid is alphaxolone.
  • Additional suitable neuroactive steroids are disclosed in WIPO Publication Nos. WO2013/188792, WO 2013/056181, WO2015/010054, WO2014/169832, WO2014/169836, WO2014/169833, WO2014/169831, WO2015/027227, WO 2014/100228, U.S. Pat. Nos. 5,232,917, 8,575,375 and 8,759,330, which are incorporated herein by reference for the neuroactive steroids described therein.
  • the therapeutic agent is a neuroactive steroid (e.g., a neuroactive steroid selected from pregnanolone, ganaxolone, alphadalone, alphaxalone, and allopregnanolone).
  • a neuroactive steroid selected from pregnanolone, ganaxolone, alphadalone, alphaxalone, and allopregnanolone.
  • Exemplary neuroactive steroid compounds include:
  • the steroids are one or more of a series of sedative-hypnotic 3 alpha-hydroxy ring A-reduced pregnane steroids that include the major metabolites of progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC), respectively.
  • These 3 alpha-hydroxysteroids do not interact with classical intracellular steroid receptors but bind stereoselectively and with high affinity to receptors for the major inhibitory neurotransmitter in the brain, gamma-amino-butyric acid (GABA).
  • the neuroactive steroids are progesterone, pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone or other progesterone analogs.
  • the neuroactive steroid is allopregnanolone or a derivative thereof.
  • the neuroactive steroid is allopregnanolone.
  • Exemplary derivatives include, but are not limited to, (20R)-17beta-(1-hydroxy-2,3-butadienyl)-5alpha-androstane-3alpha-ol (HBAO). Additional derivatives are described in WO 2012/127176.
  • the neuroactive steroid is allopregnanolone. In some embodiments, the neuroactive steroid is ganaxolone. In some embodiments, the neuroactive steroid is alphaxolone.
  • the neuroactive steroids described herein e.g., “allopregnanolone,” “ganaxolone,” and “alphaxolone,” also encompasses pharmaceutically acceptable, pharmacologically active derivatives including individual enantiomers (dextrogyral and levrogyral enantiomers) and their pharmaceutically acceptable salts, mixtures of enantiomers and their pharmaceutically acceptable salts, and active metabolites and their pharmaceutically acceptable salts, unless otherwise noted.
  • dosages of enantiomers, derivatives, and metabolites may need to be adjusted based on relative activity of the racemic mixture of the neuroactive steroid, e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone.
  • the lipophilic nature of the neuroactive steroid can make it different to formulate for in vivo administration.
  • the neuroactive steroid e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone
  • the neuroactive steroid can be formulated with a host, such as a cyclodextrin to improve the solubility.
  • the neuroactive steroid e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone
  • the neuroactive steroid can be modified in an attempt to improve the solubility.
  • polar groups can be introduced onto position 16 ⁇ with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids as described in Kasal et al., J. Med. Chem., 52(7), 2119-215 (2009).
  • a variety of methods can be employed to enhance the solubility and bioavailability of neuroactive steroids. See, for example, “Water-Insoluble Drug Formulation”, 2nd Edition, edited by Rong Liu (CRC Press, Boca Raton, Fla., 2008). Using the techniques described below, a solubilized formulation of one or more neuroactive steroids can be prepared.
  • the solubility of neuroactive steroids can be improved by inclusion complexation (e.g., host-guest formulations).
  • Inclusion complexes are formed when a nonpolar molecule (i.e., the guest, such as a drug with poor aqueous stability) or portion of a molecule inserts into a nonpolar cavity of another molecule or group of molecules (i.e., the host). If the host molecule or molecules exhibit water good solubility, the solubility of the host-guest complex will be greater than the solubility of the guest alone.
  • Inclusion complexes containing or comprising one or more neuroactive steroids can be formed using any suitable host molecule or molecules.
  • the water solubility of neuroactive steroids can be increased by inclusion complexation with cyclodextrins.
  • Steroid-cyclodextrin complexes are known in the art. See, for example, U.S. Pat. No. 7,569,557 to Backensfeld, et al., and U.S. Patent Application Publication No. US 2006/0058262 to Zoppetti, et al.
  • Dextrans are soluble polysaccharides produced by bacteria and yeasts. They are characterized by a predominance (>95%) of ⁇ (1-6) backbone linkages and varying proportions of ⁇ (1-2), ⁇ (1-3) and ⁇ (1-4) linkages typically at branch points 1, 2. Dextrins are partially hydrolyzed glucose homopolymers composed exclusively of ⁇ (1-4) backbone linkages.
  • Cyclodextrins are cyclic oligosaccharides containing or comprising six ( ⁇ -cyclodextrin), seven ( ⁇ -cyclodextrin), eight ( ⁇ -cyclodextrin), or more ⁇ -(1,4)-linked glucose residues.
  • the hydroxyl groups of the cyclodextrins are oriented to the outside of the ring while the glucosidic oxygen and two rings of the non-exchangeable hydrogen atoms are directed towards the interior of the cavity.
  • cyclodextrins possess a hydrophobic inner cavity combined with a hydrophilic exterior which conveys water solubility.
  • the neuroactive steroid i.e., the guest
  • the hydrophobic interior of the cyclodextrin i.e., the host
  • the host-guest complex retains water solubility as a consequence of the hydrophobic exterior of the cyclodextrin ring.
  • Neuroactive steroid-cyclodextrin complexes can, as solubility permits, be incorporated into any of the parenteral and non-parenteral formulations described below. If desired, the aqueous solubility of solid neuoractive steroid-cyclodextrin complexes can be further enhanced by isolating the neuoractive steroid-cyclodextrin complex as a solid via lyophilization and/or via micronizing the solid neuoractive steroid-cyclodextrin complex.
  • This cyclic orientation provides a truncated cone structure that is hydrophilic on the exterior and lipophilic on the interior. Cyclodextrin complexes are formed when a guest molecule is partially or fully contained in the interior of the cavity.
  • the parent ⁇ -, ⁇ -, and ⁇ -cyclodextrins (particularly 3 ) have limited aqueous solubility and show toxicity when given parenterally. Therefore, the parent cyclodextrin structure can be chemically modified to generate a parenterally safe CD-derivative. The modifications are typically made at one or more of the 2, 3, or 6 position hydroxyls.
  • Neuroactive steroid-cyclodextrin complexes are preferably formed from a cyclodextrin selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, and derivatives thereof.
  • the cyclodextrin may be chemically modified such that some or all of the primary or secondary hydroxyl groups of the macrocycle, or both, are functionalized with a pendant group.
  • Suitable pendant groups include, but are not limited to, sulfinyl, sulfonyl, phosphate, acyl, and C 1 -C 12 alkyl groups optionally substituted with one or more (e.g., 1, 2, 3, or 4) hydroxy, carboxy, carbonyl, acyl, oxy, oxo; or a combination thereof.
  • Methods of modifying these alcohol residues are known in the art, and many cyclodextrin derivatives are commercially available, including sulfo butyl ether ⁇ -cyclodextrins available under the trade name CAPTISOL® from Ligand Pharmaceuticals (La Jolla, Calif.).
  • Suitable cyclodextrins for use in neuroactive steroid e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone formulations
  • cyclodextrins disclosed in U.S. Pat. Nos. 5,874,418; 6,046,177; and 7,635,733, which are herein incorporated by reference.
  • Suitable cyclodextrins for use in neuroactive steroid formulations non-exclusively include ⁇ -cyclodextrin; ⁇ -cyclodextrin; ⁇ -cyclodextrin; methyl ⁇ -cyclodextrin; methyl ⁇ -cyclodextrin; methyl ⁇ -cyclodextrin; ethyl ⁇ -cyclodextrin; butyl ⁇ -cyclodextrin; butyl ⁇ -cyclodextrin; butyl ⁇ -cyclodextrin; pentyl ⁇ -cyclodextrin; hydroxyethyl ⁇ -cyclodextrin; hydroxyethyl ⁇ -cyclodextrin; 2-hydroxypropyl ⁇ -cyclodextrin; 2-hydroxypropyl ⁇ -cyclodextrin; 2-hydroxypropyl ⁇ -cyclodextrin; 2-hydroxypropyl ⁇ -cyclodextrin; 2-hydroxybut
  • Preferred cyclodextrins include, but are not limited to, alkyl cyclodextrins, hydroxy alkyl cyclodextrins, such as hydroxy propyl ⁇ -cyclodextrin, carboxy alkyl cyclodextrins and sulfoalkyl ether cyclodextrins, such as sulfo butyl ether ⁇ -cyclodextrin.
  • the cyclodextrin is a alpha, beta, or gamma cyclodextrin having a plurality of charges (e.g., negative or positive) on the surface.
  • the cyclodextrin is a ⁇ -cyclodextrin containing or comprising a plurality of functional groups that are negatively charged at physiological pH. Examples of such functional groups include, but are not limited to, carboxylic acid (carboxylate) groups, sulfonate (RSO 3 ⁇ ), phosphonate groups, phosphinate groups, and amino acids that are negatively charged at physiological pH.
  • the charged functional groups can be bound directly to the cyclodextrins or can be linked by a spacer, such as an alkylene chain.
  • the number of carbon atoms in the alkylene chain can be varied, but is generally between about 1 and 10 carbons, preferably 1-6 carbons, more preferably 1-4 carbons.
  • Highly sulfated cyclodextrins are described in U.S. Pat. No. 6,316,613.
  • the cyclodextrins is a ⁇ -cyclodextrin functionalized with a plurality of sulfobutyl ether groups.
  • a cyclodextrins is sold under the trade name CAPTISOL®.
  • CAPTISOL® is a polyanionic beta-cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, or sulfobutylether (SBE).
  • CAPTISOL® is not a single chemical species, but comprised of a multitude of polymeric structures of varying degrees of substitution and positional/regional isomers dictated and controlled to a uniform pattern by a patented manufacturing process consistently practiced and improved to control impurities.
  • CAPTISOL® contains six to seven sulfobutyl ether groups per cyclodextrin molecule. Because of the very low pKa of the sulfonic acid groups, CAPTISOL® carries multiple negative charges at physiologically compatible pH values. The four-carbon butyl chain coupled with repulsion of the end group negative charges allows for an “extension” of the cyclodextrin cavity. This often results in stronger binding to drug candidates than can be achieved using other modified cyclodextrins. It also provides a potential for ionic charge interactions between the cyclodextrin and a positively charged drug molecule. In addition, these derivatives impart exceptional solubility and parenteral safety to the molecule. Relative to beta-cyclodextrin, CAPTISOL® provides higher interaction characteristics and superior water solubility in excess of 100 grams/100 ml, a 50-fold improvement.
  • the cyclodextrins has plurality of functional groups that are negatively charged at physiological pH. Suitable positively charged groups include, but are not limited to, quaternary ammonium groups. Exemplary cyclodextrins include, but are not limited to, mono-6(A)-butylammonium-6(A)-deoxy-beta-cyclodextrin tosylate (BuAM-beta-CD) and Amine- and guanidine-derivatised ⁇ -cyclodextrin ( ⁇ CD).
  • BuAM-beta-CD mono-6(A)-butylammonium-6(A)-deoxy-beta-cyclodextrin tosylate
  • ⁇ CD Amine- and guanidine-derivatised ⁇ -cyclodextrin
  • the cyclodextrin is present in an amount of from about 0.1% to about 40% w/w of the overall formulation, preferably from about 5% to about 40% w/w, more preferably about 10% to about 40% w/w, most preferably about 10% to about 35% w/w.
  • the concentration of the cyclodextrins is from about 15% to about 35% w/w, preferably from about 20% to about 35% w/w, more preferably about 30% to about 35% w/w.
  • the formulation contains about 1 to about 2, preferably about 1.5 mg neuroactive steroid (e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, alphaxolone) per mL of cyclodextrin, e.g., CAPTISOL®.
  • neuroactive steroid e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, alphaxolone
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention (also referred to as the “active ingredient”) and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.
  • compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • the compounds provided herein are administered in an effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the compounds provided herein When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”).
  • Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject's life.
  • the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.
  • the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level.
  • the placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject's body.
  • the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s).
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention.
  • the acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.
  • a non-toxic acid addition salt i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluen
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration.
  • a pharmaceutically acceptable excipient e.g., a composition suitable for injection, such as for intravenous (IV) administration.
  • compositions agents include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection.
  • General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences , Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005).
  • injectable preparations such as sterile injectable aqueous suspensions
  • suitable dispersing or wetting agents and suspending agents exemplary excipients that can be employed include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.
  • the pharmaceutical composition further comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins consisting of 6, 7 and 8 ⁇ -1, 4-linked glucose units, respectively, optionally comprising one or more substituents on the linked sugar moieties, which include, but are not limited to, substituted or unsubstituted methylated, hydroxyalkylated, acylated, and sulfoalkylether substitution.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, e.g., for example, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No. 5,376,645.
  • the composition comprises hexapropyl- ⁇ -cyclodextrin. In a more particular embodiment, the composition comprises hexapropyl- ⁇ -cyclodextrin (10-50% in water).
  • the injectable composition can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the compounds provided herein are administered in an effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include pre-filled, pre-measured ampules or syringes of the liquid compositions.
  • the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • the compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents.
  • the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.
  • compositions described herein can comprise a buffer (e.g., a buffer at a pH of between about 3 and about 8 (e.g., between about 5 and about 7, between about 5.5 and about 6.5, between about 5.9 and about 6.1).
  • a buffer e.g., a buffer at a pH of between about 3 and about 8 (e.g., between about 5 and about 7, between about 5.5 and about 6.5, between about 5.9 and about 6.1).
  • buffer refers to a compound that, usually in combination with at least one other compound, provides a chemical system in solution that exhibits buffering capacity, that is, the capacity to neutralize, within limits, the pH lowering or raising effects of either strong acids or bases (alkali), respectively, with relatively little or no change in the original pH (e.g., the pH before being affected by, e.g., strong acid or base).
  • buffering capacity that is, the capacity to neutralize, within limits, the pH lowering or raising effects of either strong acids or bases (alkali), respectively, with relatively little or no change in the original pH (e.g., the pH before being affected by, e.g., strong acid or base).
  • alkali strong acids or bases
  • buffering capacity can refer to the millimoles (mM) of strong acid or base (or respectively, hydrogen or hydroxide ions) required to change the pH by one unit when added to one liter (a standard unit) of the buffer solution. From this definition, it is apparent that the smaller the pH change in a solution caused by the addition of a specified quantity of acid or alkali, the greater the buffer capacity of the solution. See, for example, Remington: The Science and Practice of Pharmacy , Mack Publishing Co., Easton, Pa. (19 th Edition, 1995), Chapter 17, pages 225-227. The buffer capacity will depend on the kind and concentration of the buffer components.
  • the buffering components are present from 1 mM, 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 75 mM, 100 mM, 150 mM, 200 mM, 250 mM or more in solution.
  • Preferred buffers include 4-2-hydroxyethyl-1-piperazineethanesulfonic acid (HEPES), 2- ⁇ [tris(hydroxymethyl)methyl]amino ⁇ ethanesulfonic acid (TES), 3-(N-morpholino)propanesulfonic acid (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES), dimethylarsinic acid (cacodylate), citrate (e.g., saline sodium citrate, potassium citrate, ammonium citrate), 2-(N-morpholino)ethanesulfonic acid (MES), phosphate (e.g., PBS, D-PBS), succinate (i.e., 2(R)-2-(methylamino)succinic acid), acetate, dimethylglutarate, maleate, imidazole, N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), N,N-bis(2-
  • the buffer comprises a monoprotic acid.
  • the buffer comprises a polyprotic acid (e.g., citrate or phosphate).
  • the buffer is a solution of one or more substances (e.g., a salt of a weak acid and a weak base; a mixture of a weak acid and a salt of the weak acid with a strong base).
  • the buffer comprises a piperazine (e.g., PIPES, HEPES, POPSO, EPPS).
  • the buffer comprises a non-metal complexing compound (e.g., MES, MOPS, PIPES).
  • a non-metal complexing compound e.g., MES, MOPS, PIPES.
  • the buffer comprises a metal complexing compound (i.e., a metal chelating agent).
  • a metal chelating agent is citrate.
  • the buffer is citrate buffer. In some embodiments, the buffer is phosphate buffer. In some embodiments, the buffer is histidine buffer.
  • the buffer is present at a concentration of about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 20, 50, 100, 200, 250, 500 mM or more. In some embodiments, the buffer is present at a concentration of about 1 to about 500 mM, about 1 to about 300 mM, about 1 to about 200 mM, about 1 to about 100 mM, about 1 to about 50 mM, about 10 to about 500 mM, about 10 to about 300 mM, about 10 to about 200 mM, about 10 to about 100 mM, about 10 to about 50 mM.
  • the buffer is present at a concentration of about 0.01 to about 10 mM, about 0.05 to about 5 mM, about 0.05 to about 5 mM, about 0.1 to about 5 mM, about 0.1 to about 3.5 mM.
  • the pH of the aqueous solution is at or near physiological pH.
  • the pH of the aqueous solution is between about 3 to about 8 (e.g., between about 5 and about 7, between about 5.5 and about 6.5, between about 5.9 and about 6.1), or any specific value within said range.
  • the pH of the aqueous solution is between about 5 to about 6.5, or any specific value within said range (e.g., 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4).
  • the pH of the aqueous solution is about 6.
  • the pH may be adjusted to a more optimal pH depending on the stability of the neuroactive steroids and sulfoalkylether- ⁇ -cyclodextrin included in the solution.
  • the pH can be adjusted, for example, with hydrochloric, phosphoric acid or organic acids, such as citric acid, lactic acid, malic acid, tartaric acid, acetic acid, gluconic acid, succinic acid, and combinations thereof.
  • the pH is adjusted with base (e.g., 1 N sodium hydroxide) or acid (e.g., 1 N hydrochloric acid).
  • the buffer is citrate buffer and the pH is between about 3 to about 8. In some embodiments, the buffer is citrate buffer and the pH is between about 3 to about 7.4. In some embodiments, the buffer is citrate buffer and the pH is between about 5.5 to about 6.2.
  • the buffer is phosphate buffer and the pH is between about 3 to about 9. In some embodiments, the buffer is phosphate buffer and the pH is between about 6.2 to about 8.2. In some embodiments, the buffer is phosphate buffer and the pH is about 7.4.
  • Formulations for Administration e.g., Parenteral Administration
  • Compounds (e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, alphaxolone) described herein can be formulated for parenteral administration.
  • Preferred doses, dosage forms, or modes of administration are parenteral, e.g., intranasally, buccally, intravenous, intramuscular, subcutaneous, intraparenteral, bucosal, sublingual, intraocular, and topical (e.g., intravenous or intramuscular).
  • the informational material can include instructions to administer the compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein.
  • the neuroactive steroid is formulated for parenteral administration.
  • Parenteral formulations can be prepared as aqueous compositions using techniques known in the art.
  • such compositions can be prepared as injectable formulations, for example, solutions or suspensions; solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection; emulsions, such as water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.
  • injectable formulations for example, solutions or suspensions
  • solid forms suitable for using to prepare solutions or suspensions upon the addition of a reconstitution medium prior to injection emulsions, such as water-in-oil (w/o) emulsions, oil-in-water (o/w) emulsions, and microemulsions thereof, liposomes, or emulsomes.
  • emulsions such as water-in-oil (w/o) emulsions,
  • the parenteral formulations are prepared as an injectable formulation, e.g., for intravenous administration.
  • the parenteral formulation comprises a compound (e.g., a neuroactive steroid as described herein, e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, alphaxolone), and a cyclodextrin, e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl ether J-cyclodextrin, e.g., CAPTISOL®).
  • a compound e.g., a neuroactive steroid as described herein, e.g., pregnanolone, allopregnanolone, alphadalone, ganaxolone, alphaxolone
  • a cyclodextrin e.g., a ⁇ -cycl
  • the parenteral formulation comprises pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone and a sulfo butyl ether J-cyclodextrin, e.g., CAPTISOL®.
  • the carrier can be a solvent or dispersion medium containing or comprising, for example, water (e.g., Water for Injection, USP), ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof.
  • water e.g., Water for Injection, USP
  • ethanol e.g., ethanol
  • polyols e.g., glycerol, propylene glycol, and liquid polyethylene glycol
  • oils such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sugars or sodium chloride.
  • Solutions and dispersions of the active compounds as the free acid or base or pharmacologically acceptable salts thereof can be prepared in water or another solvent or dispersing medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, and combination thereof.
  • Suitable surfactants may be anionic, cationic, amphoteric or nonionic surface active agents.
  • Suitable anionic surfactants include, but are not limited to, those containing or comprising carboxylate, sulfonate and sulfate ions.
  • anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate.
  • Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine.
  • nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide.
  • amphoteric surfactants include sodium N-dodecyl- ⁇ -alanine, sodium N-lauryl- ⁇ -iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
  • the formulation can contain a preservative to prevent the growth of microorganisms. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.
  • the formulation may also contain an antioxidant to prevent degradation of the active agent(s).
  • a formulation is typically buffered to a pH of 3-9 for parenteral administration upon reconstitution.
  • Suitable buffers include, but are not limited to, phosphate buffers, acetate buffers, citrate buffers, or others described herein.
  • Water soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.
  • Sterile injectable solutions can be prepared by incorporating the active compounds in the required amount in the appropriate solvent or dispersion medium with one or more of the excipients listed above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those listed above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the powders can be prepared in such a manner that the particles are porous in nature, which can increase dissolution of the particles. Methods for making porous particles are well known in the art.
  • the parenteral formulations described herein can be formulated for controlled release including immediate release, delayed release, extended release, pulsatile release, and combinations thereof.
  • the neuroactive steroid is provided in a composition comprising a cyclodextrin, e.g., ⁇ -cyclodextrin, e.g., sulfo butyl ether ⁇ -cyclodextrin, e.g., CAPTISOL®.
  • the neuroactive steroid is provided at a concentration of 0.1 to 10 mg/mL neuroactive steroid. In some embodiments, the neuroactive steroid is provided at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL neuroactive steroid. In some embodiments, the neuroactive steroid is provided at a concentration of 1.25 mg/mL neuroactive steroid. In some embodiments, the neuroactive steroid is provided at a concentration of 2.5 mg/mL neuroactive steroid. In some embodiments, the neuroactive steroid is provided at a concentration of 3.75 mg/mL neuroactive steroid. In some embodiments, the neuroactive steroid is provided at a concentration of 5 mg/mL neuroactive steroid.
  • the cyclodextrin is present in the composition at 1-30%, 2-18%, 10-15% by weight of cyclodextrin per volume of composition. In some embodiments, the cyclodextrin is present in the composition at 1, 2.5, 5, 10, 12, 13, 15, 25, or 30% by weight of cyclodextrin per volume of composition. In some embodiments, the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition. In some embodiments, the cyclodextrin is present in the composition at 25% by weight of cyclodextrin per volume of composition.
  • the cyclodextrin is present in the composition at 1-30%, 2-18%, 10-15%, or 20-30% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL neuroactive steroid.
  • the cyclodextrin is present in the composition at 1, 2.5, 5, 10, 12, 13, 15, 25, or 30% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 0.1, 0.5, 1, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8, 9, or 10 mg/mL neuroactive steroid.
  • the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 5 mg/mL neuroactive steroid. In some embodiments, the cyclodextrin is present in the composition at 25% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 5 mg/mL neuroactive steroid. In some embodiments, the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 3.75 mg/mL neuroactive steroid.
  • the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 2.5 mg/mL neuroactive steroid. In some embodiments, the cyclodextrin is present in the composition at 12% by weight of cyclodextrin per volume of composition and the neuroactive steroid is provided at a concentration of 1.25 mg/mL neuroactive steroid.
  • compositions described herein include a therapeutically effective amount of a neuroactive steroid, such as pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone; and a cyclodextrin, e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl ether ⁇ -cyclodextrin, e.g., CAPTISOL®) provided in a dosage form suitable for parenteral administration.
  • a neuroactive steroid such as pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone
  • a cyclodextrin e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl ether ⁇ -cyclodextrin, e.g.,
  • compositions described herein include a therapeutically effective amount of a neuroactive steroid, such as pregnanolone, allopregnanolone, alphadalone, ganaxolone, or alphaxolone; and a cyclodextrin, e.g., a ⁇ -cyclodextrin, e.g., a sulfo butyl ether ⁇ -cyclodextrin, e.g., CAPTISOL®) provided in a dosage form suitable for oral administration.
  • the neuroactive steroid is allopregnanolone.
  • the neuroactive steroid is deuterated allopregnanolone.
  • the neuroactive steroid is an estrol. In some embodiments, the neuroactive steroid is selected from neuroactive steroids that are disclosed in WIPO Publication Nos. WO2013/188792, WO 2013/056181, WO2015/010054, WO2014/169832, WO2014/169836, WO2014/169833, WO2014/169831, WO2015/027227, WO 2014/100228, U.S. Pat. Nos. 5,232,917, 8,575,375 and 8,759,330.
  • AUC Area under the curve
  • reference neuroactive steroid refers to the area under the curve that tracks the serum concentration (nmol/L) of neuroactive steroid over a given time following the IV administration of the reference neuroactive steroid standard.
  • reference neuroactive steroid is intended the formulation of neuroactive steroid that serves as the basis for determination of the total hourly neuroactive steroid dose to be administered to a human subject with tremor (e.g., essential tremor), depression (e.g., postpartum depression), or an anxiety disorder to achieve the desired positive effect, i.e., a positive therapeutic response that is improved with respect to that observed without administration of neuroactive steroid.
  • tremor e.g., essential tremor
  • depression e.g., postpartum depression
  • an anxiety disorder to achieve the desired positive effect, i.e., a positive therapeutic response that is improved with respect to that observed without administration of neuroactive steroid.
  • the dose of neuroactive steroid to be administered provides a final serum level of neuroactive steroid of about 100 ng/mL to about 1000 ng/mL, about 1100 ng/mL to about 1450 ng/mL, 100 ng/mL to about 250 ng/mL, about 200 ng/mL to about 350 ng/mL, about 300 ng/mL to about 450 ng/mL, about 350 ng/mL to about 450 ng/mL, about 400 ng/mL to about 550 ng/mL, about 500 ng/mL to about 650 ng/mL, about 600 ng/mL to about 750 ng/mL, about 700 ng/mL to about 850 ng/mL, about 800 ng/mL to about 950 ng/mL, about 900 ng/mL to about 1050 ng/mL, about 1000 ng/mL to about 1150 ng/mL, about 100 ng/mL to
  • the serum level of neuroactive steroid is about 100 ng/mL, 250 ng/mL, 300 ng/mL, 350 ng/mL, 360 ng/mL, 370 ng/mL, 380 ng/mL, 390 ng/mL, 400 ng/mL, 410 ng/mL, 420 ng/mL, 430 ng/mL, 440 ng/mL, 450 ng/mL, 500 ng/mL, 750 ng/mL, 900 ng/mL, 1200 ng/mL, 1400 ng/mL, or 1600 ng/mL.
  • the dose of neuroactive steroid to be administered provides a final serum level of neuroactive steroid of about 100 nmoles/L to about 5000 nmoles/L, about 100 nmoles/L to about 2500 nmoles/L, about 100 nmoles/L to about 1000 nmoles/L, 100 nmoles/L to about 500 nmoles/L, about 100 nmoles/L to about 250 nmoles/L, about 100 nmoles/L to about 200 nmoles/L, about 125 nmoles/L to about 175 nmoles/L. or about 140 nmoles/L to about 160 nmoles/L.
  • the serum level of neuroactive steroid is about 100 nmoles/L, 125 nmoles/L, 150 nmoles/L, 175 nmoles/L, 200 nmoles/L, 250 nmoles/L, 300 nmoles/L, 350 nmoles/L, 500 nmoles/L, 750 nmoles/L, 1000 nmoles/L, 1500 nmoles/L, 2000 nmoles/L, 2500 nmoles/L, or 5000 nmoles/L.
  • a therapeutic agent e.g., a neuroactive steroid described herein
  • composition comprising a therapeutic agent
  • the infusion occurs over at least 1, 2, 3, 4, 5, 6, or 7 days. In an embodiment, the infusion occurs over the course of 1, 2, 3, 4, 5, 6, or 7 days.
  • the infusion is bolus infusion (e.g., single dose, single infusion).
  • the infusion is a plurality of bolus infusions (e.g., multiple bolus infusions, e.g., more than one bolus infusions, e.g., 2, 3, 4, 5 or more bolus infusions).
  • the plurality of bolus infusions is administered in 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more.
  • the infusion is an intermittent infusion (e.g., an infusion that occurs at irregular intervals).
  • the infusion is a continuous infusion.
  • the method comprises administering a plurality of infusions.
  • the method comprises administering a first, second, and third infusion.
  • the administration of the second infusion begins no longer than 90, 60, 30, 10, or 5 minutes after the beginning or end of the administration of the first infusion.
  • the second infusion begins 0 to 90, 0 to 60, 0 to 30, 0 to 10, or 0 to 5 minutes after the beginning or end of the administration of the first infusion.
  • the second infusion begins no more than 60, 30, 20, 10, 5, 4, 3, 2, or 1 minute(s) after the end of administration of the first infusion.
  • the second infusion begins at the end of administration of the first infusion.
  • the first infusion and the initiation of the second infusion are performed with the same delivery device, e.g., with the same cannula or reservoir.
  • the amount of neuroactive steroid delivered/unit time varies during the first infusion.
  • the first (step-up) infusion delivers a smaller amount of neuroactive steroid/unit time than the second (maintenance) infusion.
  • the first (step-up) infusion comprises administering a plurality of step doses, wherein each subsequent step dose delivers a larger amount of neuroactive steroid/unit time than the step dose that precedes it.
  • said third infusion is administered for a period of time that is between 5 and 20 hours, 8 and 16 hours, 10 and 15 hours, or 10 and 13 hours. In an embodiment, said first infusion is administered for 12+/ ⁇ 2 hours. In an embodiment, said first infusion is administered for 12 hours.
  • the amount of neuroactive steroid delivered/unit time varies during the first infusion.
  • administering said step-up dose comprises administering a continuously increasing amount of neuroactive steroid or a composition comprising a neuroactive steroid. In an embodiment, administering said step-up dose comprises administering a continuously increasing amount of neuroactive steroid/unit time.
  • the method comprises a first, second, and third step dose.
  • said first step dose is administered at an amount of neuroactive steroid/unit time of 5-50 ⁇ g/kg/hour (e.g., 21.5 ⁇ g/kg/hour). In an embodiment, said first step dose is administered at an amount of neuroactive steroid/unit time of 5-50 ⁇ g/kg/hour, 10-40 ⁇ g/kg/hour, 20-30 ⁇ g/kg/hour, ⁇ g/kg/hour, 21 ⁇ g/kg/hour, 22 ⁇ g/kg/hour, or 21.5 ⁇ g/kg/hour. In an embodiment, said first step dose is administered at an amount of neuroactive steroid/unit time of 30 ⁇ g/kg/hour.
  • said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 ⁇ g/kg/hour (e.g., 43 ⁇ g/kg/hour). In an embodiment, said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 ⁇ g/kg/hour, 20-70 ⁇ g/kg/hour, 30-50 ⁇ g/kg/hour, 42 ⁇ g/kg/hour, 43 ⁇ g/kg/hour, or 44 ⁇ g/kg/hour. In an embodiment, said second step dose is administered at an amount of neuroactive steroid/unit time of 60 ⁇ g/kg/hour.
  • said third step dose is administered at an amount of neuroactive steroid/unit time of 25-150 ⁇ g/kg/hour. In an embodiment, said third step dose is administered at an amount of neuroactive steroid/unit time of 25-150 ⁇ g/kg/hour, 40-100 ⁇ g/kg/hour, 60-70 ⁇ g/kg/hour, 63 ⁇ g/kg/hour, 64 ⁇ g/kg/hour, 65 ⁇ g/kg/hour, or 64.5 ⁇ g/kg/hour. In an embodiment, said third step dose is administered at an amount of neuroactive steroid/unit time of 90 ⁇ g/kg/hour.
  • a first step dose, second step dose, and third step dose are administered by intermittent infusion, wherein said first step dose is administered at an amount of neuroactive steroid/unit time of 30 ⁇ g/kg/hour, said second step dose is administered at an amount of neuroactive steroid/unit time of 60 ⁇ g/kg/hour, and said third step dose is administered at an amount of neuroactive steroid/unit time of 90 ⁇ g/kg/hour.
  • a first step dose and second step dose are administered by intermittent infusion, wherein said first step dose is administered at an amount of neuroactive steroid/unit time of 30 ⁇ g/kg/hour and said second step dose is administered at an amount of neuroactive steroid/unit time of 60 ⁇ g/kg/hour.
  • the third (step-down/downward taper) infusion delivers a smaller amount of neuroactive steroid/unit time than the second (maintenance) infusion.
  • the third (step-down/downward taper) infusion comprises administering a plurality of step doses, wherein each subsequent step dose delivers a lower amount of neuroactive steroid/unit time than the step dose that precedes it.
  • said third infusion is administered for a period of time that is between 5 and 20 hours, 8 and 16 hours, 10 and 15 hours, or 10 and 13 hours.
  • said third infusion is administered for 12+/ ⁇ 2 hours.
  • said third infusion is administered for 12 hours.
  • administering said downward taper dose comprises administering a continuously decreasing amount of neuroactive steroid. In an embodiment, administering said downward taper dose comprises administering a continuously decreasing amount of neuroactive steroid/unit time.
  • the method comprises a first, second, and third step dose.
  • said first step dose is administered at an amount of neuroactive steroid/unit time of 25-150 ⁇ g/kg/hour (e.g., 30 ⁇ g/kg/hour). In an embodiment, said first step dose is administered at an amount of neuroactive steroid/unit time of 25-150 ⁇ g/kg/hour, 40-100 ⁇ g/kg/hour, 60-70 ⁇ g/kg/hour, 63 ⁇ g/kg/hour, 64 ⁇ g/kg/hour, 65 ⁇ g/kg/hour, or 64.5 ⁇ g/kg/hour. In an embodiment, said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 ⁇ g/kg/hour (e.g., 43 ⁇ g/kg/hour).
  • said second step dose is administered at an amount of neuroactive steroid/unit time of 10-100 ⁇ g/kg/hour, 20-70 ⁇ g/kg/hour, 30-50 ⁇ g/kg/hour, 42 ⁇ g/kg/hour, 43 ⁇ g/kg/hour, or 44 ⁇ g/kg/hour.
  • said third step dose is administered at an amount of neuroactive steroid/unit time of 5-50 ⁇ g/kg/hour (e.g., 21.5 ⁇ g/kg/hour).
  • said third step dose is administered at an amount of neuroactive steroid/unit time of 5-50 ⁇ g/kg/hour, 10-40 ⁇ g/kg/hour, 20-30 ⁇ g/kg/hour, 20 ⁇ g/kg/hour, 21 ⁇ g/kg/hour, 22 ⁇ g/kg/hour, or 21.5 ⁇ g/kg/hour.
  • the method comprises administering a second/maintenance infusion of 50-150 ⁇ g/kg/hour (e.g., 86 ⁇ g/kg/hour or 60 ⁇ g/kg/hour) of the neuroactive steroid.
  • the second/maintenance infusion is 50-150 ⁇ g/kg/hour, 60-100 ⁇ g/kg/hour, 70-90 ⁇ g/kg/hour, 85 ⁇ g/kg/hour, 86 ⁇ g/kg/hour, or 87 ⁇ g/kg/hour.
  • said second/maintenance infusion is administered for a period of time that is between 5 and 80 hours, 10 and 70 hours, 20 and 50 hours, or 30 and 40 hours.
  • said second/maintenance infusion is administered for 36+/ ⁇ 5 hours. In an embodiment, said second/maintenance infusion is administered for 36 hours. In an embodiment, the plasma concentration of said second/maintenance infusion is measured at a preselected time, e.g., at 10, 15, 20, 30, 45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, 2, 3, 4 days after the initiation of said second/maintenance infusion.
  • said second/maintenance infusion results in a plasma concentration of 150 nM, e.g., as measured at a preselected time, e.g., at 10, 15, 20, 30, 45, 60 minutes, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours, 2, 3, 4 days after the initiation of said second/maintenance infusion.
  • said second/maintenance infusion is administered at the same amount of neuroactive steroid/unit time over the entire second/maintenance infusion.
  • said first step dose is 10 to 40% (e.g., 25%) of the second/maintenance infusion; said second step dose is 30 to 70% (e.g., 50%) of the second/maintenance infusion; and said third step dose is 60 to 90% (e.g., 75%) of the second/maintenance infusion.
  • said first step dose is 60 to 90% (e.g., 75%) of the second/maintenance infusion; said second step dose is 30 to 70% (e.g., 50%) of the second/maintenance infusion; and said third step dose is 10 to 40% (e.g., 25%) of the second/maintenance infusion.
  • the amount of neuroactive steroid delivered/unit time in said first step dose is 10 to 40% (e.g., 25%) of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion; the amount of neuroactive steroid delivered/unit time in said second step dose is 30 to 70% (e.g., 50%) of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion; and the amount of neuroactive steroid delivered/unit time in said third step dose is 60 to 90% (e.g., 75%) of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion.
  • the amount of neuroactive steroid delivered/unit time in said first step dose is 60 to 90% (e.g., 75%) of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion; the amount of neuroactive steroid delivered/unit time in said second step dose is 30 to 70% (e.g., 50%) of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion; and the amount of neuroactive steroid delivered/unit time in said third step dose is 10 to 40% (e.g., 25%) of the amount of neuroactive steroid delivered/unit time in said second/maintenance infusion.
  • the GABAA positive allosteric modulator Compound 9 was orally active in preclinical anticonvulsant models, and suppressed seizures arising from a variety of stimuli, including chemoconvulsants, proconvulsant stimuli, and genetic predisposition.
  • Compound 9 caused sedation and ataxia as manifestations of exaggerated pharmacology.
  • the compound was assessed in 14-day rat and dog toxicology studies with daily administration of Compound 9 as a solution in HPBCD in dogs and Labrasol® in rats.
  • the NOAEL in rats was 3 mg/kg (females) and 22.5 mg/kg (males), and was 2.5 mg/kg in dogs. There were no adverse effects in dogs or rats in the main toxicology studies. A single observation of mortality occurred in one female rat at the high dose in a toxicokinetic study which was suspected to have been related to exaggerated pharmacology.
  • Example 2 A Phase I, Double-Blind, Placebo-Controlled, Single Ascending Dose Study to Determine the Maximum Tolerated Dose (MTD), Pharmacokinetics and Pharmacodynamics of Compound 9 Oral Solution in Healthy Volunteers and the Safety, Tolerability, and Pharmacokinetics of Compound 9 in Subjects with Essential Tremor
  • MTD maximum tolerated dose
  • Compound 9 Oral Solution was prepared as 1 mg/mL and 6 mg/mL stock aqueous solutions of Compound 9 Drug Substance containing 40% HPBCD and 0.0025% sucralose.
  • the 1 mg/mL and 6 mg/mL stock Compound 9 Oral Solutions were compounded from Compound 9 Drug Substance Powder in the Bottle and Excipient(s) in the Bottle (manufactured under cGMP conditions) and further admixed at the clinical site in preparation for dosing. Placebo will be matched to study drug at each dose cohort.
  • Subject doses will be prepared as an approximate 40 mL oral solution to be swallowed all at once, followed by approximately 200 mL of water that has been used to rinse the dosing bottle.
  • the start time of swallowing the approximate 40 mL oral solution is time zero for all assessments.
  • SAD Cohorts In each of the SAD cohorts, subjects will be randomly assigned to receive either Compound 9 (six subjects) or placebo (two subjects) in a blinded manner. Cohort 1 will receive Dose 1, Cohort 2 will receive Dose 2, and so on.
  • the maximum recommended starting dose for this Phase I study is 0.25 mg. Doses will be prepared for each cohort based on the dose escalation scheme shown below which may be amended depending on Safety Review Committee (SRC) dose escalation decisions described in the section below.
  • SRC Safety Review Committee
  • This four-part study will assess the effects of a single dose of Compound 9.
  • the initial part of the study is a double-blind, placebo-controlled single ascending dose (SAD) design in healthy, adult volunteers with the objective of identifying the maximum tolerated dose (MTD) and pharmacokinetic (PK) profiles of Compound 9 Oral Solution. Escalation to the next dose will be undertaken only after safety and PK data have been reviewed by the Safety Review Committee (SRC) and agreement reached that it is safe to increase the dose.
  • SRC Safety Review Committee
  • the SRC will not receive any unblinded PK data unless it is agreed upon by the SRC to unblind a subject and/or cohort based on the completed safety review.
  • the second part of the study will assess food effect by observing the PK profile of the single dose that best approximates 50% of the MTD after consumption of a standard meal in the same cohort that originally tested this dose; this dose level may be adjusted for safety reasons.
  • the pharmacodynamic effects of Compound 9 on the central nervous system will be assessed in two cohorts of fasted subjects using electroencephalograph (EEG) and other testing indicative of CNS effects.
  • EEG electroencephalograph
  • subjects will receive either the MTD or placebo then return to the clinic to receive the other treatment in crossover fashion.
  • the second EEG cohort will receive either the dose that best approximates 50% of the MTD or placebo, and then return to the clinic to receive the other treatment in crossover fashion.
  • the two EEG cohorts will have approximately one week between crossover periods.
  • the fourth part of the study will assess the safety, tolerability and pharmacokinetics of a single dose of Compound 9 in an open label fashion in one cohort of 6 subjects with essential tremor who are otherwise healthy. Subjects will eat a standard clinic breakfast prior to dosing. Enrollment into this cohort will continue until 6 subjects have been dosed.
  • the SAD and EEG cohorts will consist of eight subjects randomly assigned to active or placebo treatment. Sentinel dosing will be employed for the first SAD cohort, with one subject randomized to receive Compound 9 and the other placebo on the first day. The other six subjects in the first cohort will be dosed approximately 24 hours later.
  • the food effect cohort will be comprised of up to six subjects, all of whom will receive active treatment. Sentinel dosing will be employed for the first cohort, with one subject randomized to receive Compound 9 and the other placebo on the first day. The other six subjects in the first cohort will be dosed approximately 24 hours later. Each cohort will be dosed at approximately weekly intervals in order to allow adequate time for collection and review of safety and PK data.
  • the Essential Tremor cohort will be comprised of 6 subjects assigned to receive a dose approximating the SAD MTD in an open-label fashion.
  • the pharmacodynamic (PD) effects of the Compound 9 Oral Solution MTD will be assessed via EEG, eye tracking, mood, psychomotor testing and subjective drug effects.
  • the dosing schedule for subjects participating in the EEG portion of the study will be determined in the manner described below.
  • the last two cohorts of subjects will be randomly assigned in a blinded manner to receive treatments as shown in Table 2 (Cohorts EEG-A and EEG-B, eight subjects in each cohort).
  • Subjects in Cohort EEG-A will be randomized to either the dose from the SAD that best approximates 50% of MTD or placebo and then crossover to the other treatment after a one-week washout.
  • EEG-B Subjects in Cohort EEG-B will be randomized to either the MTD or placebo and then crossover to the other treatment after a one-week washout. Subjects in this part of the study will have continuous EEG collected for approximately 24 hours after the start of dosing; standardized eye tracking and psychomotor tests will also be performed (Table 8).
  • the safety, tolerability and pharmacokinetics of Compound 9 will be assessed in six subjects with essential tremor who are otherwise healthy. All six subjects will be assigned to receive a dose approximating the SAD MTD in an open-label manner (Table 9). Subjects in this cohort will perform the clinician-rated TETRAS (Performance subscale) and the accelerometer based Kinesia measure (Great Lakes NeuroTechnologies, Valley View, Ohio) to generate exploratory tremor amplitude data which will be used to inform the design of possible Phase 2 studies in essential tremor. Subjects in the Essential Tremor cohort will be dosed after eating a standard breakfast.
  • AEs will be coded using MedDRATM with the version used specified in the clinical study report.
  • SOC System Organ Class
  • preferred term preferred term
  • dose group preferred term
  • cohort preferred term
  • C-SSRS C-SSRS
  • Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum and maximum.
  • change from baseline values will be calculated at each time point and will be summarized using the same summary statistics.
  • Out-of-range safety endpoints may be categorized as low or high where applicable.
  • summaries will include counts and percentages.
  • Derived PK parameters will include area under the plasma concentration curve (AUCO-inf), the distributional half-life and terminal half-life (t1 ⁇ 2), the maximum concentration (Cmax), the time to reach maximum concentration (Tmax), and the clearance (CL) and urine excretion.
  • PK parameters will be summarized using appropriate descriptive statistics. Time to reach maximum concentration (Tmax) will be summarized using n, mean, standard deviation, median, minimum, and maximum. All other PK parameters will be summarized using n, geometric mean, coefficient of variation, median, minimum, and maximum.
  • Dose proportionality will be analyzed using an ANCOVA model using the logarithm of PK parameter (AUC and Cmax) as the dependent variable and the logarithm of the dose as the independent variable. Point estimates and the corresponding CIs will be estimated for both AUC and Cmax. For the food effect analysis, the log-transformed AUC and Cmax will be compared across food conditions using a paired t-test. Additional statistical testing may be performed according to the bioanalytical statistical analysis plan.
  • EEG endpoints The pharmacodynamics analysis of EEG endpoints and their relationship to psychomotor testing and eye tracking measures will be described in a separate analysis plan.
  • PK/PD exploratory analyses will be performed utilizing sedation, mood, EEG and psychomotor data.
  • the secondary endpoints of SSS, MOAA/S, BL-VAS, and DEQ-5 values will be summarized using the same descriptive statistics described above for the safety variables.
  • Additional cohorts may be considered to accommodate dose repetition or slower dose escalation than planned in the SAD part of the study.
  • Subjects participating in the double-blind, randomized portions of the study will be randomly assigned to either placebo or active treatment with Compound 9 Oral Solution according to a randomization schedule prepared by an independent statistician.
  • the Food cohort subjects will receive study drug at the dose that best approximates 50% of the MTD in an open-label manner once MTD has been determined.
  • the EEG cohort subjects will initially receive either Compound 9
  • the Essential Tremor cohort subjects will be assigned to receive a dose approximating the SAD MTD in an open-label manner.
  • Subjects in each of the SAD cohorts will receive a single dose of study drug, either Compound 9 Oral Solution (6 subjects) or placebo (2 subjects).
  • the proposed dose escalation scheme for the SAD part of the study is presented in Table 3.
  • 6 subjects who received the dose that best approximates 50% of the MTD will receive this dose a second time after ingestion of a standard meal.
  • two cohorts of 8 subjects each will be tested using two dosing periods.
  • One EEG cohort will receive the MTD; the other EEG cohort will receive the dose that best approximates 50% of the MTD.
  • subjects will receive either a single dose of Compound 9 or matching placebo (4 subjects per active and placebo treatments). These subjects will return after an approximate one-week washout period to receive the MTD or placebo (Cohort EEG-A) OR the dose that best approximates 50% of the MTD or placebo (Cohort EEG-B) within their cohort in crossover fashion. All 8 subjects will receive active treatment in each of the two EEG cohorts during either the first or second dosing period.
  • the appropriate dose of Compound 9 Oral Solution or placebo will be administered according to the randomization schedule available to the pharmacist.
  • the dose escalation pattern may be modified by the Safety Review Committee.
  • Subjects in the Essential Tremor cohort will receive a single dose of study drug with Compound 9 Oral Solution at a dose approximating the SAD MTD in an open-label manner.
  • Doses will be prepared as an approximate 40 mL oral solution to be swallowed all at once, followed by approximately 200 mL of water which has been used to rinse the dosing bottle.
  • the start time of swallowing the approximately 40 mL oral solution is time zero for all assessments.
  • Subjects in the Essential Tremor cohort may have assistance from the clinic staff when taking the study medication. Subjects in this cohort will be dosed following consumption of a standard clinic breakfast.
  • Additional dosing may be permitted by dosing Compound 9 at a lower dose or by repeating the dose at which these events occurred depending on the extent and duration of the sedation and the dose(s) at which the sedation occurred.
  • the Safety Review Committee will consider MOAA/S scores as qualifying for stopping criteria only when the confirmation score is equal to or lower than the first assessment and when there is congruence with the SSS score at the same time point.
  • the SRC will choose the dose for the food effect cohort based on the doses that have been tolerated within the SAD phase; the dose best approximating 50% of the MTD will be utilized for the Food portion of the study.
  • One cohort will receive the maximum tolerated dose (MTD) or placebo (EEG-A); the other cohort will receive the dose best approximating 50% of the MTD or placebo (EEG-B).
  • MTD maximum tolerated dose
  • EEG-A placebo
  • EEG-B placebo
  • Each cohort will return in approximately one week to cross over to the other treatment within that cohort.
  • Subjects in the Essential Tremor cohort will receive a single dose of study drug of Compound 9 Oral Solution at the dose best approximating the SAD MTD.
  • the Sponsor PK lead will review the plasma PK data for the first 24 hours post-dose from each dose to determine whether the results indicate a linear increase from the previous dose that is proportionate to the increased dose and whether there are any indications of a compartment syndrome or threshold effect. The Sponsor PK lead will then provide feedback to the Sponsor Study Physician regarding the overall PK results, and the SRC will discuss accordingly. The SRC will not receive any unblinded PK data unless it is agreed upon by the SRC to unblind a subject and/or cohort based on the completed safety review for that cohort.
  • the SRC will not allow escalation of doses beyond those predicted to result in an AUC above the lowest NOAEL exposure in toxicology studies (male rat 14-day toxicology, AUC 5,050 ng ⁇ h/mL). Based on the plasma concentration information from previous cohorts, the SRC will consider adjusting the dose (dose reduction, dose repetition, or reduced dose escalation) for the next cohort if the Cmax of >50% of the next cohort is expected to exceed 400 ng/mL (the estimated human Cmax based on the lowest NOAEL Day 14 Cmax in female rats).
  • Subjects participating in the double-blind, randomized portions of the study will be randomly assigned to either placebo or active treatment with Compound 9 Oral Solution according to a randomization schedule prepared by an independent statistician.
  • the Food cohort subjects will receive study drug at the dose that best approximates 50% of the MTD in an open-label manner once MTD has been determined.
  • the EEG cohort subjects will initially receive either Compound 9 (MTD or the dose that best approximates 50% of the MTD) or placebo in a 1:1, double-blind fashion and return for the crossover portion of the study to receive the other treatment for that cohort.
  • Subjects in each of the SAD cohorts will receive a single dose of study drug, either Compound 9 Oral Solution (6 subjects) or placebo (2 subjects).
  • subjects will receive either a single dose of Compound 9 or matching placebo (4 subjects per active and placebo treatments). These subjects will return after an approximate one week washout period to receive the MTD or placebo (Cohort EEG-A) OR the dose that best approximates 50% of the MTD or placebo (Cohort EEG-B) within their cohort in crossover fashion. All 8 subjects will receive active treatment in each of the two EEG cohorts during either the first or second dosing period.
  • subjects with essential tremor may fail to qualify on the TETRAS after Admission and be withdrawn from the study prior to dosing. These subjects will be replaced to ensure there are 6 subjects dosed in this cohort.
  • the appropriate dose of Compound 9 Oral Solution or placebo will be administered according to the randomization schedule available to the pharmacist.
  • the dose escalation pattern may be modified by the Safety Review Committee.
  • the SAD cohorts will consist of up to 6 visits over a period of up to 28 days prior to dosing and 14 days after dosing.
  • the Food Effect cohort will consist of 9 visits over a period of up to 28 days prior to dosing and 21 days after initial dosing. This cohort will be administered a repeat of the dose that best approximates 50% of the MTD.
  • the EEG cohorts will consist of 9 visits over a period of up to 28 days prior to dosing and 21 days after initial dosing.
  • the Essential Tremor cohort will consist of up to 5 visits over a period of up to 28 days prior to dosing and approximately 14 days after dosing.
  • subjects will be admitted to the unit approximately 24 hours prior to the expected time of dosing.
  • subjects will be confined to the unit for approximately 72 hours after each dose.
  • subjects will be confined to the unit for approximately 48 hours after dosing; subjects may be released sooner if it is predicted that plasma concentrations of drug will be below the level of quantification earlier than 48 hours after dosing.
  • subjects in the Essential Tremor cohort are confined to the unit for 24 hours after dosing.
  • SSS Stanford Sleepiness Scale
  • MOAA/S Modified Observer's Assessment of Alertness/Sedation Scale
  • Bond-Lader VAS will assess different aspects of self-reported mood
  • DEQ-5 will assess whether the subject “liked” the drug and/or felt “high”.
  • Psychomotor testing will be undertaken during the EEG cohorts to assess cognitive function in a variety of domains such as attention, working memory, episodic secondary memory, executive function, and motor skills. A reduced battery of cognitive tests will be applied to subjects in the SAD cohorts.
  • An EEG with at least 24 channels set for continuous recording will be applied two hours prior to dosing and kept in place for approximately 36 hours after dosing in the EEG phase only.
  • Five-minute relaxation epochs will be conducted during the 36 hours as follows: V2 and V5: ⁇ 20 to ⁇ 15 minutes before dosing; post-dose 60 (+1 hour) to 65 minutes; 120 (2 hours) to 125 minutes; 420 (7 hours) to 425 minutes; 1,380 to 1,385 minutes (23 hours) after dosing.
  • a relaxation epoch may be added or the timing of the relaxation epochs adjusted based on Tmax or other findings observed during the SAD part of the study.
  • SRC Safety Review Committee
  • the SRC may stop the study for safety reasons at any time and will determine when the MTD has been reached using the pre-defined stopping rules.
  • the committee may overrule these stopping criteria by being more conservative, i.e., next dose lower than planned, but may not rule that the next dose should be higher than planned.
  • the SRC will not receive any unblinded PK data unless it is agreed upon by the SRC to unblind a subject and/or cohort based on the completed safety review.
  • Pharmacokinetic blood samples will be taken and processed for analysis for concentrations of Compound 9. Selected samples may also be analyzed for concentrations of Compound 9 metabolites; urine samples will also be tested for concentrations of Compound 9.
  • Plasma samples for PK analysis will be collected according to the sampling collection times specified in Table 4 for the SAD, Food and Essential Tremor cohorts and Table 5 for the EEG cohorts.
  • the start time of study drug administration is time zero and all postdosing sampling times are relative to this time.
  • the Investigator or designee will arrange to have the plasma samples transported as directed for bioanalysis.
  • Selected samples may also be analyzed for concentrations of metabolites of Compound 9.
  • An additional PK sample may be collected at any time if clinically indicated and at the discretion of the Investigator (e.g. for unusual or severe AEs). Each sample will be marked with unique identifiers with at least the study number, subject number, and the nominal sample time. The date and actual time that the blood sample was taken will be recorded on the case report form or equivalent.
  • the plasma and urine samples should be kept frozen at approximately ⁇ 70 to ⁇ 80° C. until analyzed. They should be packed as directed to avoid breakage during transit and with sufficient dry ice to prevent thawing for at least 72 hours.
  • a specimen-identification form or equivalent must be completed and sent to the laboratory with each set of samples. The clinical site will arrange to have the plasma and urine samples transported as directed for bioanalysis as detailed in the PK instructions.
  • Bioanalysis of plasma samples for the determination of Compound 9 levels will be conducted utilizing a validated LC-MS/MS method at Agilux Laboratories, Worcester, Mass.
  • the methodology for urine bioanalysis is in development and will be conducted at a later time by Agilux using the stored samples.
  • a supine 12-lead ECG will be performed at the times specified below and the standard intervals recorded as well as any abnormalities.
  • the 12-lead ECG will be assessed at SAD V1 (Screening and Day ⁇ 1 [Admission]), SAD V5, Food V1 and V8, EEG V1 and EEG V8. All time points are relative to the time of dosing. If the ECG planned time point is between the hours of ⁇ 22.00 h and ⁇ 08.00 h each day or if the subject has been discharged before the +72 hour time point during the Food and EEG phases of the study, the assessment need not be conducted at that time point.
  • Continuous pulse oximetry will be recorded at the same time points as the vital signs in all cohorts beginning 30 minutes prior to dosing and continuing for the first 24 h post dose. A pulse oximetry reading will also be taken at V1 (Screening). Continuous pulse oximetry will not be cancelled during the sleeping hours and will continue to be collected at all scheduled time points.
  • Continuous ECG monitoring will be conducted from approximately 1 hour pre-dose up to the last assessment time point on discharge days; subjects will have continuous ECG monitoring (telemetry) in order to detect any cardiac rhythm abnormalities. Any such clinically significant
  • C-SSRS Columbia—Suicide Severity Rating Scale
  • the “Baseline/Screening” C-SSRS form will be completed during the Admission visit (lifetime history and past 24 months).
  • the “Since Last Visit” C-SSRS form will be completed at all subsequent scheduled time points as detailed below.
  • the C-SSRS is provided in Appendix 4.
  • the SSS will be administered at the time points shown below for each cohort. All time points are relative to the time of dosing. If the planned time point is between the hours of ⁇ 22.00 h and ⁇ 08.00 h each day or if the subject has been discharged before the +72 hour time point during the Food and EEG phases of the study, the assessment need not be conducted at that time point.
  • the SSS is provided in Appendix 5. The SSS should be performed prior to the MOAA/S score.
  • MOAA/S Modified Observer's Assessment of Alertness/Sedation Scale
  • the MOAA/S allows exploration of deeper sedation states than the SSS.
  • the MOAA/S will be administered at the time points shown below for each cohort. All time points are relative to the time of dosing. If the planned time point is between the hours of ⁇ 22.00 h and ⁇ 08.00 h each day or if the subject has been discharged before the +72 hour time point during the Food and EEG phases of the study, the assessment need not be conducted at that time point. If a MOAA/S score of 3 or less ( ⁇ 3) is observed, confirm the score by waiting approximately 10 minutes and readministering the MOAA/S assessment. Record both the scheduled and unscheduled assessments.
  • Bond-Lader VAS (Mood Rating Scale) (BL-VAS)
  • Mood will be assessed using the Bond-Lader Mood Rating Scale during the EEG and Essential Tremor cohorts only. This is a 16-part self-administered questionnaire that employs 100 mm visual analogue scales to explore different aspects of self-reported mood. If the planned time point is between the hours of ⁇ 22.00 h and ⁇ 08.00 h each day or if the subject has been discharged before the +72 hour time point during the Food and EEG phases of the study, the assessment need not be conducted at that time point.
  • the BL-VAS is provided in Appendix 7.
  • the mood scale will be administered at the following time points: EEG: V2—pre-dose and post-dose 2, 12 and 24 hours; V3—post-dose 36 and 48 hours; V4—postdose 72 hours; V5 (crossover)—pre-dose and post-dose 2, 12 and 24 hours after dosing; V6—postdose 36 and 48 hours; V7—post-dose 72 hours; V8.
  • DEQ-5 A Drug Effects Questionnaire (DEQ-5) will be administered as follows:
  • the answers are recorded on a 100 mm visual analogue scale with the answer for each being “Not at all” and “Extremely” at the extremes. There will be options to record “Not applicable” for questions 3 and 4 if no drug effects are felt and for question 5 prior to administration of study medication. If the planned time point is between the hours of ⁇ 22.00 h and ⁇ 08.00 h each day or if the subject has been discharged before the +72 hour time point during the Food and EEG phases of the study, the assessment need not be conducted at that time point.
  • the DEQ5 will be administered at the following time points in all cohorts except the Food cohort:
  • Psychomotor tests will be conducted to assess cognitive function in a variety of domains such as attention, working memory, episodic secondary memory, executive function, and motor skills. If the planned time point is between the hours of ⁇ 22.00 h and ⁇ 08.00 h each day or if the subject has been discharged before the +72 hour time point during the Food and EEG phases of the study, the assessment need not be conducted at that time point.
  • SAD Cohorts V2—pre-dose and post-dose 3, 8 and 24 hours. A reduced battery of cognitive tests will be applied to subjects in the SAD cohorts. EEG Cohorts: V2—pre-dose and post-dose 3, 8 and 24 hours after dosing; V3 post-dose 48 hours; V4—post-dose 72 hours; V5 (crossover)—pre-dose and post-dose 3, 8 and 24 hours; V6—post-dose 48 hours; V7—post-dose 72 hours. Subjects will complete a practice session at admission on Day ⁇ 1 or at any time prior to the first scheduled time point.
  • an EEG with a minimum of 24 channels set for continuous recording will be applied approximately two hours prior to dosing and kept in place for approximately 36 hours after dosing.
  • Five-minute relaxation epochs will be conducted at the time points listed below. During these epochs subjects are asked to close their eyes, relax and empty their minds of thoughts. If the relaxation epoch is scheduled at the same time as another assessment, the relaxation epoch takes precedence. If a PK sample is due, the sample should be taken just prior to beginning the relaxation epoch.
  • EEG relaxation epochs A five-minute relaxation epoch will be undertaken at V2 and V5: ⁇ 20 to ⁇ 15 minutes before dosing; post-dose 60 (+1 hour) to 65 minutes; 120 (+2 hours) to 125 minutes (+2 hours); 420 (+7 hours) to 425 minutes; 1,380 to 1,385 minutes (+23 hours) after dosing.
  • a relaxation epoch may be added or the timing of the relaxation epochs adjusted based on Tmax or other findings observed during the SAD part of the study.
  • eye tracking will be assessed at the following time points. If the planned time point is between the hours of ⁇ 22.00 h and ⁇ 08.00 h each day or if the subject has been discharged before the +72 hour time point during the Food and EEG phases of the study, the assessment need not be conducted at that time point.
  • V2 and V5 pre-dose and post-dose 2.5, 7.5, 9.5 and 23.5 hours.
  • TRG Essential Tremor Rating Assessment Scale (TETRAS) performance subscale (Appendix 12) and the accelerometer-based Kinesia assessments will be administered at the time points shown below.
  • TETRAS score for the test conducted during Visit 1 (Admission) will be used to determine eligibility and must be ⁇ 8. The testing performed at Visit 2 just prior to dosing will not disqualify the subject even if any result is ⁇ 8.
  • An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered casually related to the product.
  • an AE can include an undesirable medical condition occurring at any time, including baseline or washout periods, even if no study treatment has been administered.
  • a serious adverse event is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), and at any dose of the investigational product, comparator or placebo, that fulfils one or more of the following:
  • Sedation will be assessed using specific rating scales in this study. In order to apply consistency to adverse event reports of sedation, Investigators will not record sedation as an adverse event unless there is a score of ⁇ 5 on the SSS and/or a score of ⁇ 2 on the MOAA/S. Consideration should be given to the most appropriate term to describe the sedation characteristics.
  • An Investigator who is qualified in medicine must make the determination of relationship to the investigational product for each AE (Unrelated, Possibly Related or Probably Related). The Investigator should decide whether, in his or her medical judgment, there is a reasonable possibility that the event may have been caused by the investigational product. If no valid reason exists for suggesting a relationship, then the AE should be classified as “unrelated.” If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship between the investigational product and the occurrence of the AE, then the AE should be considered “related.”
  • AEs Adverse events that occur after the first administration of study drug will be denoted Treatment Emergent Adverse Events. All AEs will be followed until they are resolved or have reached a clinical plateau with no expectation of future change.
  • the AE term should be reported in standard medical terminology when possible. For each AE, the investigator will evaluate and report the onset (date and time), resolution or clinical plateau (date and time), intensity, causality, action taken, serious outcome (if applicable), and whether or not it caused the subject to discontinue the study.
  • All SAEs (related and unrelated) will be recorded from the signing of the consent form until 28 days following the last dose of study drug. Any SAEs considered possibly or probably related to the investigational product and discovered by the Investigator at any time after the study should be reported. All SAEs must be reported to the Sponsor or Sponsor's designee immediately or as soon as possible, but no later than 6 hours by phone and in writing within 24 hours of the first awareness of the event. The Investigator must complete, sign and date the SAE pages, verify the accuracy of the information recorded on the SAE pages with the corresponding source documents to Designee.
  • AEs will be coded using MedDRATM with the version used specified in the clinical study report.
  • SOC System Organ Class
  • preferred term preferred term
  • dose group preferred term
  • cohort preferred term
  • Incidence of AEs will also be presented by maximum severity and relationship to study drug.
  • Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using descriptive statistics by dose group and cohort, where applicable.
  • Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum and maximum.
  • change from baseline values will be calculated at each time point and will be summarized using the same summary statistics.
  • Out-of-range safety endpoints may be categorized as low or high, where applicable. For all categorical endpoints, summaries will include counts and percentages.
  • Derived PK parameters will include area under the plasma concentration curve (AUCO-inf), the distributional half-life and terminal half-life (t1 ⁇ 2), the maximum concentration (Cmax), the time to reach maximum concentration (Tmax), and the clearance (CL) and urine excretion. PK parameters will be summarized using appropriate descriptive statistics. Time to reach maximum concentration (Tmax) will be summarized using n, mean, standard deviation, median, minimum, and maximum.
  • PK parameters will be summarized using n, geometric mean, coefficient of variation, median, minimum, and maximum.
  • Dose proportionality will be analyzed using an ANCOVA model using the logarithm of PK parameter (AUC and Cmax) as the dependent variable and the logarithm of the dose as the independent variable. Point estimates and the corresponding CIs will be estimated for both AUC and Cmax.
  • the secondary endpoints of SSS, MOAA/S, BL-VAS, and DEQ-5 values will be summarized using the same descriptive statistics described above for the safety variables.
  • the pharmacodynamics analysis of EEG endpoints and their relationship to psychomotor testing and eye tracking measures will be described in a separate analysis plan.
  • PK/PD exploratory analyses will be performed utilizing sedation, mood, EEG and psychomotor data.
  • TTRAS Activity Scale
  • accelerometer-based Kinesia scores will be summarized as described for safety and secondary endpoints.
  • the Safety Population is defined as all subjects who are administered study drug.
  • the Pharmacokinetic (PK) Population is defined as all subjects who are administered Compound 9 and have at least one bioanalysis result for the plasma concentration of Compound 9.
  • AEs will be coded using MedDRATM with the version used specified in the clinical study report.
  • SOC System Organ Class
  • preferred term preferred term
  • dose group preferred term
  • cohort preferred term
  • Incidence of AEs will also be presented by maximum severity and relationship to study drug.
  • Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using descriptive statistics by dose group and cohort, where applicable.
  • Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum and maximum.
  • change from baseline values will be calculated at each time point and will be summarized using the same summary statistics.
  • Out-of-range safety endpoints may be categorized as low or high, where applicable.
  • summaries will include counts and percentages.
  • PK parameters will be summarized using appropriate descriptive statistics.
  • Dose proportionality will be analyzed using an ANCOVA model using the logarithm of PK parameter (AUC and Cmax) as the dependent variable and the logarithm of the dose as the independent variable. Point estimates and the corresponding CIs will be estimated for both AUC and Cmax. For the food effect analysis, the log-transformed AUC and Cmax will be compared across food conditions using a paired t-test. Additional statistical testing may be performed according to the bioanalytical statistical analysis plan.
  • the secondary endpoints of SSS, MOAA/S, BL-VAS, and DEQ-5 values will be summarized using the same descriptive statistics described above for the safety variables.
  • the pharmacodynamics analysis of EEG endpoints and their relationship to psychomotor testing and eye tracking measures will be described in a separate analysis plan.
  • PK/PD exploratory analyses will be performed utilizing sedation, mood, EEG and psychomotor data.
  • V1 V1 Screening and Day ⁇ 1 (Admission), pre-dose and post-dose 1, 2, 3, 4, 8, 12, 24, 36, 48, and 72 hours.
  • 4 C-SSRS SAD Cohorts Screening Day ⁇ 1 (Admission), V4 post-dose 72 h, and V5.
  • MOAA/S SAD Cohorts V2—pre-dose and post dose 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 22 and 24 hours; V3—post-dose 28, 32, 36, 40 and 48 hours; V4—post-dose 60 and 72 hours.
  • DEQ5 SAD Cohorts V2—pre-dose and post-dose 2, 12 and 24 hours.
  • Phychomotor testing SAD Cohorts V2—pre-dose and post-dose 3, 8 and 24 hours. Subjects will complete a practice session during Screening prior to their Day ⁇ 1 (Admission) assessment.
  • V1 (Admission for Food cohort); V5 pre-dose and post-dose 1, 2, 4, 8, 12, 24; V6 36, 48; V7 72 hours; V8. 4 C-SSRS Food Cohort: V1 Administration for Food; V7 post-dose 72 h, and V8. 5 SSS Food Cohorts: V5—pre-dose and post-dose 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 22 and 24 hours; V6—post-dose 28, 32, 36, 40, and 48 hours; V7—post-dose 60 and 72 hours.
  • V5 pre-dose and post-dose 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 22 and 24 hours
  • V6 post-dose 28, 32, 36, 40 and 48 hours
  • V7 post-dose 60 and 72 hours. 7 See Appendix 2
  • V1 (Screening and Day ⁇ 1 [Admission]); V2—pre-dose; post-dose 4, 8, 24; V5 48 and Visit 7 72 hours after dosing.
  • C-SSRS EEG Cohorts V1 (Day ⁇ 1 [Admission]); V4 post-dose 72 h, V5 (crossover) pre-dose, V7 post-dose 72 h, and V8.
  • V2 pre-dose and post-dose 2, 4, 6, 8, 10, 12, 14, 16, 22 and 24 hours
  • V3 post-dose 36 and 48 hours
  • V4 post-dose 60 and 72 hours
  • V5 crossover
  • pre-dose and post-dose 2 4, 6, 8, 10, 12, 14, 16, 22 and 24 hours
  • V6 post-dose 36 and 48 hours
  • V7 post-dose 60 and 72 hours.
  • V2 pre-dose and post-dose 2, 4, 6, 8, 10, 12, 14, 16 and 24 hours
  • V3 post-dose 36 and 48 hours
  • V4 post-dose 60 and 72 hours
  • V5 crossover
  • pre-dose and post-dose 2 4, 6, 8, 10, 12, 14, 16, 22 and 24 hours
  • V6 post-dose 36 and 48 hours
  • V7 post-dose 60 and 72 hours.
  • V2 pre-dose and post-dose 2, 12 and 24 hours after dosing
  • V3 post-dose 36 and 48 hours
  • V4 post-dose 72 hours
  • V5 crossover
  • pre-dose 2 12, and 24 hours after dosing
  • V6 post-dose 36 and 48 hours
  • V7 post-dose 72 hours
  • EEG Cohorts V2—pre-dose and post-dose 3, 8 and 24 hours after dosing; V3 post-dose 48 hours; V4—post-dose 72 hours; V5 (crossover)—pre-dose and post-dose 3, 8 and 24 hours; V6—post-dose 48 hours; V7—post-dose 72 hours. Subjects will complete a practice session during Screening and on Day ⁇ 1 (Admission). 10 EEG relaxation epochs EEG Cohorts: V2 and V5: ⁇ 20 to ⁇ 15 minutes before dosing; post-dose 60 (1 hour) to 65 minutes; 120 (2 hours) to 125 minutes; 420 (7 hours) to 425 minutes; 1,380 to 1,385 minutes (23 hours) after dosing.
  • a relaxation epoch may be added or the timing of the relaxation epochs adjusted based on T max or other findings observed during the SAD part of the study.
  • V1 (Screening and Day ⁇ 1 [Admission]). V2 pre-dose and post-dose 1, 2, 3, 4, 6, 8, 12, 14, 16 and 24 hours; V3 48 hours after dosing; V4. Continuous pulse oximetry beginning 30 minutes pre-dose and through 24 h post-dose.
  • 3 12-Lead ECG V1 (screening and Day ⁇ 1 [Admission]; V2 pre-dose; post-dose 4, 8, 24; V3 48; V4.
  • 4 C-SSRS Essential Tremor Cohort V1 (Day ⁇ 1 [Admission]; V2 post-dose 24 h; V3 post-dose 48 h; V4.
  • a Safety Review Committee will be employed to review available data from each cohort and to determine the dose selection for the subsequent cohort, not to exceed the maximum proposed dose for each cohort.
  • the protocol also includes clear stopping rules with regard to sedation and other medical events of interest, as well as seriousness and severity of adverse events.
  • MOAA/S ⁇ 2 was one of the stopping criteria for dose escalation. 2 subjects in the 66 mg dose of SAD (stopping criteria met); 2 subjects in the 55 mg dose of SAD (stopping criteria not met). 2 subjects had a MOAA/S score of ⁇ 2, which upon repeat one subject had a value of >2.
  • MOAA/S Scale 0, No response after painful trapezius squeeze; 1, Responds only after painful trapezius squeeze; 2, Responds only after mild prodding or shaking; 3, Responds only after name is called loudly and/or repeatedly; 4, Lethargic response to name spoken in normal tone; 5, Responds readily to name spoken in normal tone.
  • Scores of 1 or 2 only observed for two subjects in 35 mg group; all occurred at 1 hour post-dose. By 4 hours post-dose, mean MOAA/S approached baseline values.
  • Compound 9 Oral Solution is available as 1 mg/mL and 6 mg/mL stock aqueous solutions of Compound 9 Drug Substance containing 40% HPBCD (Kleptose®) and 0.0025% sucralose which is further diluted with Sterile Water for Injection to achieve the selected dosages.
  • HPBCD Kerptose®
  • sucralose aqueous solution of Compound 9 Drug Substance containing 40% HPBCD (Kleptose®) and 0.0025% sucralose which is further diluted with Sterile Water for Injection to achieve the selected dosages.
  • the 1 mg/mL and 6 mg/mL stock Compound 9 Oral Solutions will be compounded from Compound 9 Drug Substance Powder in the Bottle and Excipient (s) in the Bottle (manufactured under cGMP conditions at Pharmatek) and further admixed at the clinical site in preparation for dosing. Placebo will be matched to study drug at each dose cohort. Detailed instructions for study drug preparation will be provided in the Pharmacy
  • the PAREXEL clinical Phase I unit will be responsible for procuring the CYP induction drugs (bupropion and simvastatin).
  • the CYP induction drugs bupropion and simvastatin.
  • Wellbutrin IR® is preferred but a generic may be substituted with permission from the Sponsor.
  • Zocor® is acceptable for simvastatin.
  • composition and pharmaceutical quality of the investigational product will be maintained according to the current Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines and available for review in the study medication documentation.
  • Compound 9 will be provided to the Phase 1 unit as powder in the bottle and excipient (s) in the bottle units and compounded in the pharmacy at a volume of 125 mL of either a 1 mg/mL or 6 mg/mL stock solution and then further diluted to approximately 40 mL at the identified doses.
  • Study drug labels with all required information and conforming to all applicable CFR and GMP/GCP guidelines will be prepared by the Phase I unit.
  • the study medication must be carefully stored at the temperature specified in the pharmacy manual (e.g., clinical dosing solutions stored at approximately 2-8° C. or room temperature for up to 24 hours after preparation), safely and separately from other drugs.
  • This study comprises a double blind, placebo-controlled multiple ascending dose (MAD) study followed by an open-label drug-drug interaction study (DDI) without placebo in healthy, adult volunteers.
  • MAD multiple-ascending-dose
  • DAI drug-drug-interaction
  • the objective of the MAD part of the study is to determine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) profile of seven days of dosing with Compound 9 Oral Solution (henceforth referred to as Compound 9).
  • Safety will be assessed utilizing physical examination, vital sign measurements, safety laboratory testing, 12-lead ECGs, sedation scores (the Stanford Sleepiness Scale (SSS) and Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S), and the Columbia-Suicide Severity Rating Scale (C-SSRS). Tolerability will be assessed by spontaneously reported adverse events.
  • SSS Stanford Sleepiness Scale
  • MOAA/S Modified Observer's Assessment of Alertness/Sedation Scale
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • PD pharmacodynamic effects of multiple days of dosing with Compound 9 will be assessed in Cohorts 1-3.
  • Pharmacodynamic effects on the central nervous system (CNS) will be assessed using psychomotor testing (Cogstate Early Phase Battery or similar consisting of Detection Task, Identification Task, One Card Learning Task, and Groton Maze Learning Test), mood, anxiety and depression (the Bond-Lader VAS for self-reported mood assessment and the Hospital Depression and Anxiety Scale [HADS]), a drug likeability questionnaire (Drug Effects Questionnaire [DEQ-5[), and electroencephalography (EEG) with eye tracking. Sleep quality will be assessed via a subject-rated questionnaire in Cohort 3 Part 2 (nighttime dosing).
  • the planned total daily dose for each MAD cohort is based on information obtained during the ongoing single, ascending dose (SAD) study (Example 2). Information such as the half-life of a single dose of Compound 9 will be reviewed to determine whether to dose once-daily (QD) or twice-daily (BID) dosing.
  • SAD single, ascending dose
  • QD once-daily
  • BID twice-daily
  • dosing is twice daily (BID)
  • BID dosing is twice daily
  • the total daily dose will be equally divided and 50% administered in the morning and 50% in the evening for six days; 50% of the total daily dose will be administered in the morning only on Day 7 to allow for a full PK profile.
  • Morning dosing will be between the hours of approximately 08:00 h and 09:00 h and evening dosing will be between the hours of approximately 19:00 h and 20:00 h.
  • Compound 9 will be administered in the morning to fasted subjects after a minimum of an 8 hour fast with a standard diet beginning approximately 4 hours after dosing.
  • Cohort 3 will not return for a second period of dosing, unless the Safety Review Committee decides to utilize Cohort 3 Part 2 to explore a lower dose than that administered in the first part of Cohort 3, or to evaluate a different dosing regimen.
  • the total daily dose will not exceed those evaluated during the earlier parts of the MAD part of the study.
  • Concentrations of Compound 9 in plasma and urine will be assessed after multiple days of oral dosing. Pharmacokinetics will be assessed based on parameters derived from frequent sampling for bioanalysis of Compound 9 concentrations. Metabolite concentrations of Compound 9 in plasma and in urine will also be investigated.
  • the DDI part of the study (Cohort 4) will investigate whether multiple dosing with Compound 9 induces the metabolism of either the CYP3A4 or CYP2B6 enzyme. All 12 subjects in the DDI part of the study will receive Compound 9 in an open-label fashion with the total daily dose of Compound 9 approximating the maximum well-tolerated single dose administered in the MAD part of the study.
  • Compound 9 may be required to administer Compound 9 using a BID regimen.
  • the DDI cohort dosing schedule is provided below.
  • Compound 9 dosing is with subjects in fasted state unless it is decided to administer Compound 9 BID in which case only the morning dose would be administered with subjects in a fasted state; subjects may have a standard breakfast prior to dosing with bupropion or simvastatin.
  • the dosing regimen for the DDI part of the study is presented below:
  • Plasma samples will be obtained to fully characterize the concentrations of simvastatin, bupropion, and Compound 9 and comparisons made for simvastatin and bupropion concentrations before and after Compound 9 administration.
  • Additional dosing may be permitted by dosing Compound 9 at a lower dose or by repeating the dose at which these events occurred depending on the extent and duration of the sedation and the dose(s) at which the sedation occurred.
  • the Safety Review Committee will consider MOAA/S scores as qualifying for stopping criteria only when the confirmation score is equal to or lower than the first assessment and when there is congruence with the SSS score at the same time point.
  • the Safety Population is defined as all subjects who are administered study drug.
  • the Pharmacokinetic (PK) Population is defined as all subjects who are administered Compound 9 and have at least one bioanalysis result for the plasma concentration of Compound 9. No formal sample size calculations have been undertaken for this safety and tolerability study. The number of subjects in each cohort and at each dose level is thought to be sufficient to assess preliminary safety and tolerability following multiple doses of Compound 9. No efficacy parameters are being collected or analyzed for this Phase I study.
  • AEs will be coded using MedDRATM with the version used specified in the clinical study report.
  • SOC System Organ Class
  • preferred term preferred term
  • dose group preferred term
  • cohort preferred term
  • Incidence of AEs will also be presented by maximum severity and relationship to study drug.
  • Data from vital signs, clinical laboratory measures, ECG, and C-SSRS will be summarized using descriptive statistics by dose group and cohort, where applicable.
  • Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum and maximum.
  • change from baseline values will be calculated at each time point and will be summarized using the same summary statistics.
  • Out-of-range safety endpoints may be categorized as low or high, where applicable. For all categorical endpoints, summaries will include counts and percentages.
  • PK parameters will be summarized using appropriate descriptive statistics. Time to reach maximum concentration (Tmax) will be summarized using n, mean, standard deviation, median, minimum, and maximum. All other PK parameters will be summarized using n, geometric mean, coefficient of variation, median, minimum, and maximum.
  • Dose proportionality will be analyzed using an ANCOVA model using the logarithm of PK parameter (AUC and Cmax) as the dependent variable and the logarithm of the dose as the independent variable. Point estimates and the corresponding CIs will be estimated for both AUC and Cmax.
  • PK parameters for AUC and Cmax for simvastatin and bupropion will be natural log-transformed and evaluated using a linear mixed effects model with fixed effects terms for treatment.
  • An unstructured covariance matrix will be used to allow for unequal treatment variances and to model the correlation between the treatment measurements within each subject via the REPEATED statement in SAS PEOC MIXED.
  • a ninety percent (90%) confidence interval (CI) will be constructed for the difference in least squares means on the log scale for each of AUC and Cmax.
  • Exponentiating the log-scale 90% CI will provide a 90% CI for the geometric mean ratios (simvastatin+Compound 9/simvastatin alone or bupropion+Compound 9/bupropion alone).
  • the secondary endpoints of SSS, MOAA/S, BL-VAS, HADS and DEQ-5 values will be summarized using the same descriptive statistics described above for the safety variables.
  • the pharmacodynamics analysis of EEG endpoints and their relationship to psychomotor testing and eye tracking measures will be described in a separate analysis plan.
  • PK/PD exploratory analyses will be performed utilizing sedation, mood, anxiety, depression, EEG and psychomotor data. Further details of the above analyses will be provided in the statistical analysis plan.
  • Placebo will be matched to study drug for each multiple ascending dose (MAD) cohort.
  • the drug-drug interaction (DDI) part of the study will be conducted in an open-label manner with Compound 9, bupropion and simvastatin.
  • Cohorts 1 and 2 of the MAD part of the study will consist of up to 14 visits over a period of up to 28 days prior to dosing, approximately 11 days confined to unit (admission, 7 days of dosing with Compound 9 and up to 3 days of follow up) and approximately 14 days after the last dose of Compound 9.
  • Cohort 3 (Parts 1 and 2 assuming QD dosing) will consist of up to 25 visits over a period of up to 28 days prior to dosing, approximately 22 days confined to unit (two 11-day periods of [admission 7 days of dosing with Compound 9 and up to 3 days of follow up with each Compound 9 dosing period]separated by approximately 7 days) and approximately 14 days after the last dose of Compound 9. If MAD dosing is determined to be BID, Cohort 3 will either not take place or will have a dosing regimen determined by the SRC with total daily dose not exceeding the maximum total daily dose tested during the previous cohorts.
  • the DDI cohort will consist of up to 16 visits over a period of up to 28 days prior to CYP-induction drug dosing, approximately 13 days confined to the unit (admission, 2 days of CYP-induction drug dosing, 7 days of dosing with Compound 9, a 3-day in-house follow up after last dose of Compound 9 (which includes 2 days of CYP-induction drug dosing) and 14 days after the last dose of Compound 9.
  • subjects will be admitted to the unit approximately 24 hours prior to the first dose of study drug (either Compound 9 [Cohorts 1, 2 and 3] or CYP-induction drug [Cohort 4]).
  • subjects will be confined to the unit for approximately 72 hours after the last dose of Compound 9 (or placebo in the MAD part of the study); subjects may be released sooner if it is predicted that plasma concentrations of Compound 9 will be below the level of quantification earlier than 72 hours after dosing. No subject may be discharged from the unit until the Investigator is satisfied that it is safe for the subject to be discharged from the unit.
  • SSS Stanford Sleepiness Scale
  • MOAA/S Modified Observer's Assessment of Alertness/Sedation Scale
  • DEQ-5 Drug Effects Questionnaire
  • An EEG with at least 24 channels set for continuous recording will be applied approximately 1 hour prior to dosing and kept in place for approximately 9 hours after Compound 9/placebo dosing for Cohorts 1, 2 and 3 Part 1 on Days 1 and 7.
  • EEG relaxation epochs and eye tracking will be completed at approximately 30 minutes pre-dose and at approximately 2 and 8 hours post-dose.
  • Pharmacokinetic blood samples will be taken and processed for analysis for concentrations of Compound 9 at the time points described. Selected samples may also be analyzed for concentrations of Compound 9 metabolites; urine samples will also be tested for concentrations of Compound 9. Samples from subjects participating in Cohort 4 will also be tested for concentrations of simvastatin, simvastatin acid, bupropion and hydroxyl-bupropion.
  • Plasma samples for PK analysis will be collected according to the sampling collection times specified for the MAD and the DDI cohorts.
  • the time of study drug administration is time zero and all post-dosing sampling times are relative to this time.
  • the Investigator or designee will arrange to have the plasma samples processed, stored and transported as directed for bioanalysis.
  • Selected samples may also be analyzed for concentrations of metabolites of Compound 9.
  • An additional PK sample may be collected at any time if clinically indicated and at the discretion of the Investigator (e.g. for unusual or severe AEs).
  • Each sample will be marked with unique identifiers such as the study number, subject number, and the nominal sample time. The date and actual time that the blood sample was taken
  • the plasma and urine samples should be kept frozen at approximately ⁇ 70° C. to ⁇ 80° C. until analyzed. They should be packed as directed to avoid breakage during transit and with sufficient dry ice to prevent thawing for at least 72 hours.
  • a specimen-identification form must be completed and sent to the laboratory with each set of samples. The clinical site will arrange to have the plasma and urine samples transported as directed for bioanalysis as detailed in the PK instructions.
  • Plasma samples will be taken from consenting participants in all cohorts on Day ⁇ 1 (Admission) (timing on Day 1 is flexible and will be determined by PAREXEL) and retained for possible future genomics studies.
  • the genomics samples will be stored at PAREXEL until the Sponsor identifies a suitable laboratory. Note that providing this sample is optional for subjects under a separate consent form.
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • subjects will be admitted to the unit approximately 24 hours prior to the expected time of dosing with Compound 9/placebo or CYP-interaction drug.
  • Subjects will be confined to the unit for approximately 72 hours after completion of the Compound 9 7-day dosing period for all cohorts; subjects may be released sooner if it is predicted that plasma concentrations of drug will be below the level of quantification earlier than 72 hours after Compound 9 dosing. No subjects may be discharged from the unit until the Investigator is satisfied that it is safe for the subject to be discharged from the unit.
  • PK samples and safety and pharmacodynamic assessments are currently planned to coincide with Tmax, but sample timing may be adjusted depending on the PK data observed earlier in the clinical development program.
  • the 12-lead ECG assessments will be performed after the subject has been supine for at least approximately 5 minutes and the standard intervals recorded as well as any abnormalities. All time points are relative to the time of dosing. If the ECG planned time point is between the hours of approximately ⁇ 22:00 h and ⁇ 08:00 h each day or if the subject has been discharged before the last time point, the assessment need not be conducted at that time point. Timing for this assessment may be adjusted depending on Tmax timing observed in the Example 2 SAD study. Timing is presented below.
  • On daytime PK frequent sampling days (relative days 1 and 7): if once daily dosing obtain predose and 2, 4, 8 and 12 hours post dose, or if twice daily dosing obtain pre-dose and 2, 4, 8, 12 hours post the morning dose, and 2 hours after the evening dose.
  • C-SSRS Columbia—Suicide Severity Rating Scale
  • MOAA/S Modified Observer's Assessment of Alertness/Sedation Scale
  • the MOAA/S allows exploration of deeper sedation states than the SSS. All time points are relative to the time of dosing. If the planned time point is between the hours of 22:00 h and 08:00 h each day or if the subject has been discharged before the +72 hour time point, the assessment need not be conducted at that time point. If a subject is difficult to awaken, an additional MOAA/S assessment may be performed at the discretion of the PI. Any MOAA score of 3 or less must be repeated. The MOAA/S assessment should be conducted after other assessments that are scheduled at the same time point. All time points relate to the administration of study drug.
  • Mood will be assessed using the Bond-Lader Mood Rating Scale (Appendix 7). This is a 16-part self-administered questionnaire that employs 100 mm visual analogue scales to explore different aspects of self-reported mood.
  • the mood scale will be administered at the following time points:
  • Compound 9/placebo dosing On the first and last daytime Compound 9/placebo dosing (relative Days 1 and 7): if once daily dosing obtain pre-dose, and at approximately 2, 4 and 12 hours post-dose; or if twice daily dosing obtain pre-dose, and at approximately 2, 4, 8 and 12 hours post the morning dose, and 2 hours post the evening dose (post-dose assessment timing may be adjusted depending on Example 2 SAD Tmax).
  • HADS Hospital Anxiety and Depression Scale
  • Compound 9/placebo dosing On the first and last daytime Compound 9/placebo dosing (relative Days 1 and 7): if once daily dosing obtain pre-dose, and at approximately 2, 4 and 12 hours post-dose; or if twice daily dosing obtain pre-dose, and at approximately 2, 4, 8 and 12 hours post the morning dose and 2 hours post the evening dose (post-dose assessment timing may be adjusted depending on Example 2 SAD Tmax).
  • Plasma samples for analysis of Compound 9 concentrations will be collected at the time points relative to dosing as shown.
  • the time of study drug administration is time zero and all post-dosing sampling times are relative to dosing time.
  • the investigator will arrange to have the plasma samples processed and transported as directed for bioanalysis as directed by the Sponsor. Selected samples may be analyzed for concentrations of metabolites of Compound 9. An additional sample for analysis of Compound 9 concentrations may be collected at any time if clinically indicated and at the discretion of the investigator (e.g. for unusual or severe AEs). Samples for CYP induction drugs will be processed and transported as directed by the Sponsor. Timing for sample draw times may be adjusted for each cohort based on earlier PK results.
  • Each sample will be marked with unique identifiers as determined by the CRO and agreed by the Sponsor.
  • Blood samples for plasma concentrations of Compound 9 should be taken just prior to any scheduled relaxation epoch when the sample time coincides with an EEG time point.
  • DEQ-5 (see Appendix 8) will be administered as follows:
  • Psychomotor testing will be undertaken to assess cognitive function in a variety of domains such as attention, working memory, episodic secondary memory, executive function, and motor skills. Examples of psychomotor testing include the Detection Task, Identification Task, One Card Learning Task, and Groton Maze Learning Test. The actual tests performed may vary depending on the vendor chosen. Psychomotor testing will be conducted during the MAD cohorts only.
  • daytime dosing days Day 1 and Day 7: pre-dose and 3 hours post-dose (post the morning dose if twice daily dosing).
  • Psychomotor testing will not be performed for Cohort 3 Part 2.
  • Measures of brain electrical activity will indicate any direct impact on the nervous system and are used as a critical adjunct to behavioral assessment. Findings can be used to investigate subclinical behavioral effects of Compound 9 and can be easily quantified and compared to changes in pharmacokinetic measures.
  • the samples will be cleaned for EMG, eye motion, head movement or other non-cerebral artifacts; cleaned data will then be submitted to power spectral analysis to quantitatively assess impact on the brain over time.
  • Previous studies with the benzodiazepine midazolam have shown significant dose-dependent slowing of peak velocity, peak acceleration, peak deceleration, reduced saccade acceleration/deceleration ratio and saccade accuracy, as well as increased sedation self-rating.
  • the current study will use measures of saccadic velocity to assess sedative effects of Compound 9.
  • An EEG with at least 24 channels set for continuous recording will be applied approximately 1 hour prior to dosing and kept in place for approximately 9 hours after dosing for subjects participating in MAD cohorts 1, 2 and 3 (Part 1 only) on Days 1 and 7.
  • EEG relaxation epochs and eye tracking will completed at approximately 30 minutes pre-dose and at approximately 2 and 8 hours post-dose.
  • the post-dose assessment timing may be adjusted depending on earlier PK results from the SAD study Example 2 or previous MAD cohorts.
  • subjects are asked to close their eyes, relax and empty their minds of thoughts. Eye tracking will be assessed at the same time as the EEG is being recorded.
  • a 6-item subject-rated sleep quality questionnaire created for internal use will be administered to subjects in Cohort 3 Part 2 (nighttime dosing) upon awakening in the morning the mornings of Days 16 to 22.
  • a “Window Allowance Document” document will be prepared which will outline acceptable windows for intervals between nominal times and actual times for study procedures, e.g. ⁇ 5 minutes for PK sampling times. This will allow flexibility when multiple procedures are scheduled for the same time point, e.g., PK sampling and vital signs both taken at “1 h after dosing”.
  • An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered casually related to the product.
  • an AE can include an undesirable medical condition occurring at any time, including baseline or washout periods, even if no study treatment has been administered.
  • a serious adverse event is an AE occurring during any study phase (i.e., baseline, treatment, washout, or follow-up), and at any dose of the investigational product, comparator or placebo, that fulfils one or more of the following:
  • Sedation will be assessed using specific rating scales in this study.
  • Investigators need not record sedation as an adverse event unless there is a score of ⁇ 5 on the SSS and/or a score of ⁇ 2 on the MOAA/S. Consideration should be given to the most appropriate term to describe the sedation characteristics.
  • An Investigator who is qualified in medicine must make the determination of relationship to the investigational product for each AE (Unrelated, Possibly Related or Probably Related). The Investigator should decide whether, in his or her medical judgment, there is a reasonable possibility that the event may have been caused by the investigational product. If no valid reason exists for suggesting a relationship, then the AE should be classified as “unrelated.” If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship between the investigational product and the occurrence of the AE, then the AE should be considered “related.”
  • the relationship between the AE/SAE and the investigational product is determined to be “possible” or “probable” the event will be considered to be related to the investigational product for the purposes of expedited regulatory reporting.
  • the AE term should be reported in standard medical terminology when possible.
  • the Investigator will evaluate and report the onset (date and time), resolution or clinical plateau (date and time), intensity, causality, action taken, outcome, and whether or not it caused the subject to discontinue the study.
  • AEs will be coded using MedDRATM with the version used specified in the clinical study report.
  • SOC System Organ Class
  • preferred term preferred term
  • dose group preferred term
  • dose group preferred term
  • dose group preferred term
  • Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum and maximum.
  • change from baseline values will be calculated at each time point and will be summarized using descriptive statistics.
  • Out-of-range safety endpoints may be categorized as low or high, where applicable. For all categorical endpoints, summaries will include counts and percentages.
  • Derived PK parameters will include area under the plasma concentration curve (AUCO-inf), the distribution half-life and terminal half-life (t1 ⁇ 2), the maximum concentration (Cmax), the time to reach maximum concentration (Tmax), and the clearance (CL) and urine excretion.
  • PK parameters will be summarized using appropriate descriptive statistics. Time to reach maximum concentration (Tmax) will be summarized using n, median, minimum, and maximum. All other PK parameters will be summarized using n, geometric mean, coefficient of variation, median, minimum, and maximum.
  • Dose proportionality of Compound 9 will be analyzed using a linear regression model with the logarithm of PK parameter (AUC and Cmax) as the dependent variable and the logarithm of the dose as the independent variable. Point estimates of the slope coefficient and the corresponding CIs will be provided for both AUC and Cmax.
  • PK parameters for AUC and Cmax for simvastatin and bupropion will be natural log-transformed and evaluated using a linear mixed effects model with fixed effects terms for treatment.
  • An unstructured covariance matrix will be used to allow for unequal treatment variances and to model the correlation between the treatment measurements within each subject via the REPEATED statement in SAS PEOC MIXED.
  • a ninety percent (90%) confidence interval (CI) will be constructed for the difference in least squares means on the log scale for each of AUC and Cmax. Exponentiating the log-scale 90% CI will provide a 90% CI for the geometric mean ratios (simvastatin+Compound 9/simvastatin alone or bupropion+Compound 9/bupropion alone).
  • the secondary endpoints of SSS, MOAA/S, BL-VAS, HADS, and DEQ-5 values and the exploratory sleep quality data will be summarized using the same descriptive statistics described above for the safety variables.
  • the pharmacodynamics analysis of EEG endpoints and their relationship to psychomotor testing and eye tracking measures will be described in a separate analysis plan.
  • PK/PD exploratory analyses will be performed utilizing sedation, mood, anxiety, depression, EEG and psychomotor data. Sleep quality will be assessed by a selfadministered sleep questionnaire.
  • PK/PD analysis will consist of descriptive figures plotting PK concentrations versus numeric ratings or scores associated with SSS, MOAA/S, BL-VAS, HADS and DEQ-5 outcomes.
  • NCT02614547 This multicenter, randomized, double-blind, parallel-group, placebo-controlled trial (NCT02614547) was conducted at 11 sites in the United States with IRB approval from each study site.
  • Sage Therapeutics, Inc. collaborated with the principal investigator (SMB) in the design of the trial and all investigators in the execution of the trial and collection of data. All authors vouch for the accuracy and completeness of the data, data analyses, and the fidelity of this report to the study protocol. Additional study conduct details are provided in the Supplementary Appendix.
  • Enrollment required written informed consent. Eligible subjects were required to have had a major depressive episode that began no earlier than the third trimester and no later than the first four weeks following delivery and to be within six months postpartum at the time of enrollment. PPD diagnoses were confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Enrollment required a 17-item Hamilton Rating Scale for Depression (HAM-D) total score of ⁇ 26. Subjects remained as in-patients during the 60-hour study infusion period.
  • Exclusion criteria included: active psychosis; attempted suicide associated with index case of PPD; history of seizures, bipolar disorder, schizophrenia and/or schizoaffective disorder, and/or alcoholism or drug addiction (including benzodiazepines) in the 12 months prior to screening. Additional inclusion/exclusion details are available in the Supplementary Appendix.
  • Each subject was provided the next randomization number in sequence by a blinded study monitor. Subjects were then randomized, according to a computer-generated randomization schedule, 1:1 to brexanolone or placebo.
  • the randomization schedule was produced by an independent statistician at Applied Statistics and consulting (Spruce Pine, N.C.). Subjects, clinicians, and study teams were blinded to treatment allocation. Subjects in the placebo group received equivalent infusion rates, and both treatments were identical in appearance.
  • Brexanolone is a sterile solution of 5 mg/mL allopregnanolone in 250 mg/mL sulfobutylether--cyclodextrin (SBECD) buffered with citrate, which is diluted with sterile water for injection to render it isotonic for IV infusion.
  • SBECD sulfobutylether--cyclodextrin
  • Each subject received a single continuous IV infusion of blinded study drug for 60 hours during inpatient care under the following schedule: 30 ⁇ g/kg/hour (0-4 hours); 60 ⁇ g/kg/hour (4-24 hours); 90 ⁇ g/kg/hour (24-52 hours); 60 ⁇ g/kg/hour (52-56 hours); 30 ⁇ g/kg/hour (56-60 hours).
  • Infusion rate adjustments were allowed based on tolerability, side effects, and pre-determined protocol rules. Dosing was based on both a prior open-label exploratory trial in PPD (Kanes et al., 2016 ; Human Psychopharmacology , in press) and on pharmacokinetic (PK) modelling. After dosing was complete, subjects were followed through Day 30, with clinical and safety assessments obtained at 7 and 30 days.
  • the primary outcome measure was the change from baseline in the HAM-D total score (brexanolone vs. placebo) at the end of the treatment period (60 hours). Secondary analyses included changes in the HAM-D from baseline at 2 hours through 30 days. Secondary HAM-D endpoints included remission rates (total score ⁇ 7), response rates ( ⁇ 50% reduction in total score), change from baseline in the Bech-6 subscore, which assesses the core symptoms of major depression, and changes in the HAM-D Depressed Mood Item Score.
  • MDRS Montgomery Asberg Depression Rating Scale
  • CGI-I Clinical Global Impression-Global Improvement
  • GAD-7 Generalized Anxiety Disorder Questionnaire
  • EPDS Edinburgh Postnatal Depression Scale
  • PHQ-9 Patient Health Questionnaire-9
  • BIMF Barkin Index of Maternal Function
  • brexanolone The safety and tolerability of brexanolone were evaluated by collecting and summarizing adverse events (AEs), clinical laboratory measures, vital signs, and ECGs (including changes from baseline); concomitant medication usage was also assessed. Emergent suicidal ideation and behaviors were assessed using the Columbia-Suicide Severity Rating scale (C-SSRS); subject-reported sedation/sleepiness was assessed using the Stanford Sleepiness Scale (SSS). Plasma was collected to assay for allopregnanolone, allopregnanolone metabolites, and SBECD.
  • C-SSRS Columbia-Suicide Severity Rating scale
  • SSS Stanford Sleepiness Scale
  • the Safety Population included all randomized subjects who started infusion of study drug or placebo.
  • the Efficacy (EFF) Population included the subset of the Safety Population who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment.
  • the change from baseline in HAM-D and MADRS total score was analyzed using a mixed effects model for repeated measures (MMRM).
  • MMRM mixed effects model for repeated measures
  • the model included center, treatment, baseline HAM-D total score, assessment time point, and time point-by-treatment as explanatory variables. Center was treated as a random effect, while all other explanatory variables were treated as fixed effects.
  • Model based point estimates i.e., LS means, 95% confidence intervals, and p-values
  • a sample size of 10 evaluable subjects per group provided 80% power to detect an effect size of 1.2 between the brexanolone and placebo groups with regard to the primary outcome variable of change from baseline in HAM-D total score.
  • An effect size of 1.2 corresponds to a placebo-adjusted difference of 12 points in the change from baseline in HAM-D total score at 60 hours with an assumed standard deviation of ten points.
  • the effect size for the clinical efficacy of brexanolone at 60 hours was 1.2, and the effect was statistically significant by 24 hours.
  • Assessment using the MADRS total score and change from baseline showed similar results to those obtained using HAM-D ( FIGS. 11A, 11B and Table 16).
  • HAM-D Hamilton Rating Scale for Depression.
  • MADRS Montgomery- ⁇ sberg Depression Rating Scale.
  • CGI-I Clinical Global Impression-Improvement.
  • GAD-7 Generalized Anxiety Disorder 7-item Scale.
  • EPDS Edinburgh Postnatal Depression Scale.
  • PHQ-9 Patient Health Questionnaire.
  • BIMF Barkin's Index of Maternal Functioning. All baseline calculations based on a mixed effects model for repeated measures (MMRM).
  • HAM-D mean total score was assessed for the HAM-D at each time point and in Day 7 and Day 30 follow-ups, as indicated.
  • the HAM-D is a 17-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders. It is comprised of individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight. Higher HAMD-D scores indicate more severe depression.
  • panel B mean total score was assessed for the MADRS at each time point and in Day 7 and Day 30 follow-ups, as indicated.
  • Example 6 HAM-D Remission Rates Over Time in the Study Described in Example 4 (FIG. 12 )
  • Remission was defined as having a HAM-D total score of ⁇ 7.
  • the remission rates at each time point were calculated.
  • a larger percentage of subjects in the brexanolone group than the placebo group achieved HAM-D remission at each time point after +2 hours.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11945836B2 (en) 2014-11-27 2024-04-02 Sage Therapeutics, Inc. Compositions and methods for treating CNS disorders

Families Citing this family (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3572417A3 (fr) 2011-10-14 2020-03-25 Sage Therapeutics, Inc. Composés de 19-nor prégnane disubstitués 3,3, compositions et leurs utilisations
CN104736158A (zh) 2012-01-23 2015-06-24 萨奇治疗股份有限公司 神经活性类固醇制剂和治疗中枢神经系统障碍的方法
WO2014085668A1 (fr) 2012-11-30 2014-06-05 The Regents Of The University Of California Activité anticonvulsivante des stéroïdes
PL2986624T3 (pl) 2013-04-17 2020-11-16 Sage Therapeutics, Inc. Neuroaktywne steroidy 19-NOR do stosowania w sposobach leczenia
WO2014169836A1 (fr) 2013-04-17 2014-10-23 Sage Therapeutics, Inc. 19-nor-stéroïdes neuroactifs et procédés d'utilisation de ceux-ci
US9512165B2 (en) 2013-04-17 2016-12-06 Sage Therapeutics, Inc. 19-nor C3, 3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof
US9725481B2 (en) 2013-04-17 2017-08-08 Sage Therapeutics, Inc. 19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof
CA2918735C (fr) 2013-07-19 2023-08-01 Sage Therapeutics, Inc. Steroides neuroactifs, compositions, et leurs utilisations
EP3035940B1 (fr) 2013-08-23 2018-10-17 Sage Therapeutics, Inc. Stéroïdes neuroactifs, compositions et utilisations
WO2015195962A1 (fr) 2014-06-18 2015-12-23 Sage Therapeutics, Inc. Stéroïdes neuroactifs, leurs compositions et utilisations
CN117024501A (zh) 2014-10-16 2023-11-10 萨奇治疗股份有限公司 靶向cns障碍的组合物和方法
NZ769042A (en) 2014-10-16 2023-12-22 Sage Therapeutics Inc Compositions and methods for treating cns disorders
SI3250210T1 (sl) 2015-01-26 2021-07-30 Sage Therapeutics, Inc. Sestavki in metode za zdravljenje CNS motenj
WO2016134301A2 (fr) 2015-02-20 2016-08-25 Sage Therapeutics, Inc. Stéroïdes neuroactifs, compositions, et leurs utilisations
JOP20170059B1 (ar) 2016-03-08 2021-08-17 Sage Therapeutics Inc ستيرويدات وتركيبات نشطة عصبيًا واستخداماتها
CN109689673B (zh) 2016-07-11 2023-03-14 萨奇治疗股份有限公司 C17、c20和c21取代的神经活性类固醇及其使用方法
AU2017296295B2 (en) 2016-07-11 2022-02-24 Sage Therapeutics, Inc. C7, C12, and C16 substituted neuroactive steroids and their methods of use
JOP20190022B1 (ar) 2016-08-23 2023-03-28 Sage Therapeutics Inc ستيرويد 19- نور c3، 3- به استبدال ثنائي لـ c21-n بيرازوليل بلوري
WO2018147791A1 (fr) * 2017-02-10 2018-08-16 Asarina Pharma Ab 3-bêta-hydroxy-5-alpha-prégnan-20-one destinée à être utilisée dans le traitement des tremblements essentiels
TW202342058A (zh) * 2017-09-07 2023-11-01 美商賽吉醫療公司 神經活性類固醇及其使用方法
WO2019075362A1 (fr) * 2017-10-12 2019-04-18 Sage Therapeutics, Inc. Méthode de traitement de troubles du système nerveux central avec des neurostéroïdes et des composés gabaergiques
WO2019094724A1 (fr) * 2017-11-10 2019-05-16 Marinus Pharmaceuticals, Inc. Ganaxolone destinée à être utilisée dans le traitement de troubles épileptiques génétiques
KR20200096596A (ko) 2017-12-08 2020-08-12 세이지 테라퓨틱스, 인크. Cns 장애의 치료를 위한 중수소화 21 -[4-시아노-피라졸-1 -일]-19-노르-프레간-3. 알파-올-20-온 유도체
WO2019154247A1 (fr) * 2018-02-11 2019-08-15 江苏豪森药业集团有限公司 Régulateur de dérivé de stéroïde, son procédé de préparation et son utilisation
CN112533611A (zh) * 2018-06-12 2021-03-19 萨奇治疗股份有限公司 19-去甲基c3,3-二取代的c21-n-吡唑基类固醇及其使用方法
MX2021005291A (es) * 2018-11-05 2021-06-18 Ovid Therapeutics Inc Uso de gaboxadol, ganaxolona y alopregnanolona para tratar trastornos del movimiento.
CN109503694A (zh) * 2018-11-21 2019-03-22 苏州闻天医药科技有限公司 一种新型gabaa受体调节剂及其用途
WO2020118142A1 (fr) * 2018-12-07 2020-06-11 Marinus Pharmaceuticals, Inc. Ganaxolone destiné à être utilisé dans la prophylaxie et le traitement de la dépression post-partum
TW202043204A (zh) * 2019-01-14 2020-12-01 中國大陸商北京軒義醫藥科技有限公司 四唑啉酮取代的類固醇化合物及其用途
US11497754B2 (en) 2019-02-05 2022-11-15 Washington University Neurosteroids and enantiomers thereof for the prevention and treatment of neurodegenerative conditions
BR112021024033A2 (pt) 2019-05-31 2022-02-08 Sage Therapeutics Inc Esteroides neuroativos e suas composições
CA3145923A1 (fr) 2019-08-05 2021-02-11 David Czekai Ganaxolone destinee a etre utilisee dans le traitement de l'etat de mal epileptique
US10857163B1 (en) 2019-09-30 2020-12-08 Athenen Therapeutics, Inc. Compositions that preferentially potentiate subtypes of GABAA receptors and methods of use thereof
CN114828889A (zh) * 2019-12-06 2022-07-29 马瑞纳斯制药公司 用于治疗结节性硬化症的加奈索酮
CA3167331A1 (fr) * 2020-01-12 2021-07-15 Brii Biosciences, Inc. Steroides neuroactifs et composition pharmaceutique les contenant
US20230346801A1 (en) 2020-03-25 2023-11-02 Sage Therapeutics, Inc. Use of agents for treatment of respiratory conditions
WO2022125408A1 (fr) * 2020-12-07 2022-06-16 Marinus Pharmaceuticals, Inc Utilisation de la ganaxolone dans le traitement d'un trouble épileptique
CN112516086B (zh) * 2020-12-08 2022-05-20 武汉久安药物研究院有限公司 注射用布瑞诺龙脂肪乳及其制备方法
AU2022214187A1 (en) * 2021-01-28 2023-07-13 Sage Therapeutics, Inc. Use of neuroactive steroids for treatment of sexual dysfunction
CN117897160A (zh) * 2021-04-12 2024-04-16 萨奇治疗股份有限公司 特发性震颤的治疗
US11337987B1 (en) * 2021-05-07 2022-05-24 Lipocine Inc. Compositions and methods for treating central nervous system disorders
WO2023009584A1 (fr) 2021-07-28 2023-02-02 Sage Therapeutics, Inc. Formes cristallines d'un stéroïde neuroactif
WO2023146579A1 (fr) * 2022-01-27 2023-08-03 Belnap Pharmaceuticals, Llc Méthodes de traitement mettant en oeuvre l'oxytocine
WO2023164385A1 (fr) * 2022-02-28 2023-08-31 Sage Therapeutics, Inc. Stéroïdes neuroactifs pour le traitement de maladies ou d'états gastro-intestinaux
WO2023211856A1 (fr) * 2022-04-26 2023-11-02 Praxis Precision Medicines, Inc. Méthodes de traitement de troubles neurologiques
US11969434B1 (en) 2022-08-29 2024-04-30 Lipocine Inc. Oral allopregnanolone compositions and methods of use
WO2024059608A1 (fr) * 2022-09-15 2024-03-21 Sage Therapeutics, Inc. Stéroïdes neuroactifs deutérés
CN115957332B (zh) * 2022-11-01 2023-10-10 北京华睿鼎信科技有限公司 透明质酸酶稳定的布瑞诺龙纳米晶及其制备方法与应用

Family Cites Families (137)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3117142A (en) 1961-03-01 1964-01-07 Roussel Uclaf Novel preparation of estradiol and estrone
US3169134A (en) 1963-03-21 1965-02-09 Searle & Co 2, 3-oxygenated-17alpha-methyl-5alpha-androstan-17beta-ols
BE754111A (fr) 1969-07-29 1971-01-29 Upjohn Co Nouveaux 7alpha- et 7beta-methyl-3alpha,5alpha- cycloandrostanes et composes analogues 19-nor et leur procede de preparation
US3943124A (en) 1970-12-17 1976-03-09 Gordon Hanley Phillipps Chemical compounds
GB1430942A (en) 1972-05-05 1976-04-07 Glaxo Lab Ltd 21-substituted 3alpha-hydroxy pregnanes
US3983111A (en) 1972-05-05 1976-09-28 Glaxo Laboratories Limited Steroidal anaesthetics of the pregnane and 19-norpregnane series
US3865939A (en) 1973-02-23 1975-02-11 Procter & Gamble Edible oils having hypocholesterolemic properties
US4071625A (en) 1974-05-13 1978-01-31 Richardson-Merrell Inc. 19-Oxygenated-5α-androstanes for the enhancement of libido
US4192871A (en) 1976-01-06 1980-03-11 Glaxo Laboratories Limited Chemical compounds
GB1570394A (en) 1976-01-06 1980-07-02 Glaxo Lab Ltd 11-acyloxy-3-hydroxy steroids
GB1581234A (en) 1976-04-05 1980-12-10 Glaxo Operations Ltd 11a - amino - 3a - hydroxysteroids
SE8600632D0 (sv) 1986-02-13 1986-02-13 Kabivitrum Ab Novel pharmaceutical composition
US5232917A (en) 1987-08-25 1993-08-03 University Of Southern California Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series
US5319115A (en) 1987-08-25 1994-06-07 Cocensys Inc. Method for making 3α-hydroxy, 3β-substituted-pregnanes
US5120723A (en) * 1987-08-25 1992-06-09 University Of Southern California Method, compositions, and compounds for modulating brain excitability
US5719197A (en) 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
KR0166088B1 (ko) 1990-01-23 1999-01-15 . 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도
EP0603312A4 (fr) 1991-09-13 1995-06-07 Cocensys Inc Nouveau recepteur a gaba a? presentant des sites de liaison de steroides.
JP4008024B2 (ja) 1993-05-24 2007-11-14 パーデュー、ファーマ、リミテッド、パートナーシップ Ｇａｂａａレセプター複合体と相互作用させるための化合物
EP0656365B1 (fr) 1993-12-02 1997-04-09 Akzo Nobel N.V. Dérivés 2-bêta-morpholino de androstane
PT1038880E (pt) 1994-02-14 2008-01-29 Euro Celtique Sa Androstanos e pregnanos para modulação alostérica do receptor de gaba
US5939545A (en) 1994-02-14 1999-08-17 Cocensys, Inc. Method, compositions, and compounds for allosteric modulation of the gaba receptor by members of the androstane and pregnane series
EP0751926B1 (fr) 1994-03-25 2007-09-12 Isotechnika,Inc. Potentialisation de medicaments par deuteration---------------
WO1996003421A1 (fr) 1994-07-21 1996-02-08 Pharmacia & Upjohn Company Aminosteroides actifs au niveau neurologique
KR100394548B1 (ko) 1994-11-23 2004-02-05 퍼듀 파머 리미티드 Gaba수용체의알로스테릭조절을위한안드로스탄및프레그난계열화합물
ATE284895T1 (de) 1995-06-06 2005-01-15 Euro Celtique Sa Neuroaktive steroide der androstan- und pregnanreihe
US6780853B1 (en) 1995-06-06 2004-08-24 Euro-Celtique S.A. Neuroactive steroids of the androstane and pregnane series
EP0840612A1 (fr) 1995-07-24 1998-05-13 Trustees Of Boston University Inhibition de l'activite des recepteurs du n-methyl-d-aspartate au moyen de derives de sulfate de pregnenolone
WO1998005337A1 (fr) 1996-08-01 1998-02-12 Cocensys, Inc. Utilisation de ligands de recepteurs gaba et nmda pour le traitement des cephalees de la migraine
US7630757B2 (en) 1997-01-06 2009-12-08 Flint Hills Scientific Llc System for the prediction, rapid detection, warning, prevention, or control of changes in activity states in the brain of a subject
US6245757B1 (en) 1997-10-03 2001-06-12 Research Corporation Technologies, Inc. Use of progestins to treat ischemic event
ATE307592T1 (de) 1998-03-11 2005-11-15 Torbjoern Backstroem Epiallopregnanolon zur behandlung von krankheiten des cns
US20020198174A1 (en) 2001-05-07 2002-12-26 Allergan Sales, Inc. Disinfecting and solubilizing steroid compositions
US6376531B1 (en) 1998-11-13 2002-04-23 Rupert Charles Bell Method of treatment using deuterium compounds
US20030236236A1 (en) 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
EP1104760B1 (fr) 1999-12-03 2003-03-12 Pfizer Products Inc. Composés de sulfamoylhétéroaryl-pyrazole comme analgésiques et agents anti-inflammatoires
US6613308B2 (en) 2000-09-19 2003-09-02 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US20020072509A1 (en) 2000-10-11 2002-06-13 Stein Donald Gerald Methods for the treatment of a traumatic central nervous system injury
GR1003861B (el) 2000-12-29 2002-04-11 Νεα νευροστεροειδη που αλληλεπιδρουν με τον υποδοχεα gabaa.
US7129343B2 (en) 2001-02-13 2006-10-31 University Of Florida Bi-directional dual promoter complex with enhanced promoter activity for transgene expression in eukaryotes
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US20030032638A1 (en) 2001-05-24 2003-02-13 Kim John J. Delivery of benzodiazepines through an inhalation route
US7090830B2 (en) 2001-05-24 2006-08-15 Alexza Pharmaceuticals, Inc. Drug condensation aerosols and kits
EP1392258B1 (fr) 2001-05-24 2008-11-26 Alexza Pharmaceuticals, Inc. Administration par voie pulmonaire d'alprazolam, d'estazolam, de midazolam ou de triazolam
JP2003063965A (ja) 2001-06-13 2003-03-05 Otsuka Pharmaceut Factory Inc 注射用シロスタゾール水性製剤
AU2003278744B2 (en) 2002-08-28 2010-07-29 Harbor Biosciences, Inc. Therapeutic treatment methods
US9339508B2 (en) 2003-01-17 2016-05-17 Mapreg Use of 3-methoxy-pregnenolone for the preparation of a drug for treating a traumatic brain injury
US7781421B2 (en) 2003-05-29 2010-08-24 Washington University Neuroactive 13, 24-cyclo-18, 21-dinorcholanes and structurally related pentacyclic steriods
US7816074B2 (en) 2003-07-31 2010-10-19 The Research Foundation Of State University Of New York α4 β2 δGABA-A receptors as a strategy for PMS and alcoholism
GB0321607D0 (en) 2003-09-15 2003-10-15 Vectura Ltd Manufacture of pharmaceutical compositions
US20070020299A1 (en) 2003-12-31 2007-01-25 Pipkin James D Inhalant formulation containing sulfoalkyl ether cyclodextrin and corticosteroid
US7892483B2 (en) 2004-03-12 2011-02-22 Cipla Limited Sterilization process
WO2005105822A2 (fr) 2004-04-23 2005-11-10 Euro-Celtique S.A. Procede de fabrication de steroides 3-alpha-hydroxy sustitues, nouveaux derives de steroides et leurs applications
US20060063707A1 (en) 2004-09-17 2006-03-23 Lifelike Biomatic, Inc. Compositions for enhancing memory and methods therefor
US8604011B2 (en) 2004-09-27 2013-12-10 The Regents Of The University Of California Therapy for treatment of chronic degenerative brain diseases and nervous system injury
EP2471536A1 (fr) 2004-09-29 2012-07-04 Harbor BioSciences, Inc. Analogues de steroides, procedes de caracterisation et traitements
MX2007009915A (es) 2005-02-15 2007-11-06 Elan Pharma Int Ltd Formulaciones en aerosol e inyectables de benzodiazepina nanoparticulada.
ES2428313T3 (es) 2005-03-24 2013-11-07 Emory University Métodos para el tratamiento de lesiones del sistema nervioso central mediante un protocolo de administración decreciente
US20080207601A1 (en) 2005-04-07 2008-08-28 Hythiam , Inc. Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence
US20110319386A1 (en) 2005-08-26 2011-12-29 Braincells Inc. Neurogenesis by muscarinic receptor modulation
MX2008006888A (es) 2005-11-28 2008-09-30 Marinus Pharmaceuticals Formulas y metodos para la manufactura y uso de la ganaxolona.
US20070287931A1 (en) 2006-02-14 2007-12-13 Dilorenzo Daniel J Methods and systems for administering an appropriate pharmacological treatment to a patient for managing epilepsy and other neurological disorders
WO2007137247A2 (fr) * 2006-05-22 2007-11-29 Vanda Pharmaceuticals, Inc. Traitement de troubles dépressifs
MX2009002496A (es) 2006-09-08 2009-07-10 Braincells Inc Combinaciones que contienen un derivado de 4-acilaminopiridina.
US20090239942A1 (en) 2006-09-15 2009-09-24 Cloyd James C Topiramate Compositions and Methods of Making and Using the Same
US20090203658A1 (en) 2007-01-08 2009-08-13 Duke University Neuroactive steroid compositions and methods of use therefor
US20090074677A1 (en) * 2007-01-08 2009-03-19 Duke University Neuroactive steroid compositions and methods of use therefor
US7813811B2 (en) 2007-02-08 2010-10-12 Neuropace, Inc. Refillable reservoir lead systems
KR20100016445A (ko) 2007-04-11 2010-02-12 바이오마린 파머수티컬 인크. 테트라하이드로바이오프테린 투여 방법, 관련 조성물 및 측정 방법
US8530463B2 (en) 2007-05-07 2013-09-10 Hale Biopharma Ventures Llc Multimodal particulate formulations
WO2008154579A1 (fr) 2007-06-11 2008-12-18 University Of Southern California Alloprégnanolone dans un procédé destiné à stimuler la fonction neurologique(maladie d'alzheimer)
US8575375B2 (en) 2007-06-15 2013-11-05 Research Triangle Institute Androstane and pregnane steroids with potent allosteric GABA receptor chloride ionophore modulating properties
GB0711948D0 (en) 2007-06-20 2007-08-01 Bionature E A Ltd Neurosteriod compounds
US20100316678A1 (en) 2007-06-28 2010-12-16 Cnsbio Pty Ltd. Combination methods and compositions for treatment of neuropathic pain
US20100297181A1 (en) 2007-12-26 2010-11-25 Eisai R&D Management Co., Ltd. AMPA Receptor Antagonists for Epilepsy, Mental Disorders or Deficits in Sensory Organ
WO2009088530A1 (fr) 2008-01-03 2009-07-16 Biomarin Pharmaceutical Inc. Analogues de la ptérine
US20090198145A1 (en) 2008-02-06 2009-08-06 Chow Harrison Compositions, methods, and systems for rapid induction and maintenance of continuous rem sleep
US8729070B2 (en) 2008-02-20 2014-05-20 Targia Pharmaceuticals CNS pharmaceutical compositions and methods of use
CZ2008434A3 (cs) 2008-07-10 2009-12-09 Ústav organické chemie a biochemie Akademie ved CR, v. v. i. Pregnanové anionické slouceniny, zpusob jejich výroby a jejich použití
SI3135672T1 (sl) 2008-10-10 2020-07-31 Vm Discovery, Inc. Sestavki in postopki za zdravljenje motenj, bolečin in drugih bolezni povezanih z uporabo alkohola
CN102300566A (zh) 2008-11-30 2011-12-28 O·扎查尔 血管收缩剂的皮肤应用
WO2010075863A1 (fr) * 2008-12-29 2010-07-08 University Of Tartu (Tartu Ülikool) Composés qui présentent une activité inhibitrice d'arginase pour utilisation en tant qu'agents thérapeutiquement actifs, utilisation desdits composés pour la fabrication d'une composition pharmaceutique, composition pharmaceutique et procédé pour identifier un composé adapté pour le traitement et/ou la prévention de la dépression et/ou d'une affection associée à la dépression, et procédé pour le traitement et/ou la prévention de la dépression et/ou d'affections associées à la dépression et kit
WO2010088409A2 (fr) 2009-01-30 2010-08-05 Emory University Procédés de neuroprotection utilisant des stéroïdes neuroprotecteurs et une vitamine d
US20120142645A1 (en) 2009-03-17 2012-06-07 Marx Christine E Neuroactive steroid compositions and methods of use for lowering cholesterol
WO2011079047A1 (fr) * 2009-12-23 2011-06-30 Drugtech Corporation Procédés pour réduire l'occurrence d'accouchements prématurés et d'autres conditions associées à une grossesse
WO2011088503A1 (fr) 2010-01-21 2011-07-28 Goodchild Investments Pty Ltd Formulation anesthésique
CN103313744B (zh) 2010-11-03 2015-06-10 赛诺菲-安万特德国有限公司 容纳药物的针插管
US20130309306A1 (en) 2010-12-01 2013-11-21 The Regents Of The University Of California Intrapulmonary benzodiazepine for the treatment and prevention of seizures
CZ303443B6 (cs) 2011-02-15 2012-09-12 Ústav organické chemie a biochemie Akademie ved CR, v.v.i. Deriváty pregnanolonu substituované v poloze 3alfa kationickou skupinou, zpusob jejich výroby, jejich použití a prostredek je obsahující
WO2012116290A2 (fr) 2011-02-25 2012-08-30 Washington University Stéroïdes neuroactifs substitués par 17(20)-z-vinylcyano, promédicaments de ceux-ci et procédés de traitement les utilisant
FR2973031B1 (fr) 2011-03-23 2013-11-29 Univ Strasbourg Derives de l'allopregnanolone et de l'epiallopregnanolone et leurs utilisations pour traiter un etat neuropathologique
US9084797B2 (en) 2011-05-23 2015-07-21 Besins Healthcare Luxembourg Sarl Progesterone treatment for improving sleep quality
US9526718B2 (en) 2011-06-28 2016-12-27 Vivozon, Inc. Combination of effective substances causing synergistic effects of multiple targeting and use thereof
EP2736919A4 (fr) * 2011-07-29 2015-01-14 Univ California Nouveaux stéroïdes substitués en 17b par un hétéroaryle, capables de moduler les récepteurs gabaa
EP4245369A3 (fr) 2011-09-08 2023-11-22 Sage Therapeutics, Inc. Stéroïdes neuroactifs, compositions et leurs utilisations
WO2013043985A1 (fr) 2011-09-23 2013-03-28 The Regents Of The University Of California Huiles comestibles favorisant l'administration de stéroïdes administrés par voie orale
EP3572417A3 (fr) 2011-10-14 2020-03-25 Sage Therapeutics, Inc. Composés de 19-nor prégnane disubstitués 3,3, compositions et leurs utilisations
CA2856599C (fr) 2011-11-29 2017-05-30 Amino Up Chemical Co., Ltd. Composition comprenant de la vicenine-2 ayant un effet benefique sur la fonction neurologique et/ou cognitive
CN104736158A (zh) 2012-01-23 2015-06-24 萨奇治疗股份有限公司 神经活性类固醇制剂和治疗中枢神经系统障碍的方法
WO2013188792A2 (fr) 2012-06-15 2013-12-19 Sage Therapeutics, Inc. Stéroïdes neuroactifs, compositions, et leurs utilisations
WO2014028398A2 (fr) 2012-08-13 2014-02-20 The Regents Of The University Of California Mitigation de crises épileptiques par une polythérapie à l'aide de benzodiazépines et de neurostéroïdes
RU2018132041A (ru) * 2012-08-21 2018-11-13 Сейдж Терапьютикс, Инк. Способы лечения эпилепсии или эпилептического статуса
US9765110B2 (en) 2012-10-08 2017-09-19 Washington University Neuroactive 19-alkoxy-17(20)-Z-vinylcyano-substituted steroids, prodrugs thereof, and methods of treatment using same
US9757391B2 (en) 2012-11-09 2017-09-12 Goodchild Investments Pty Ltd Neuroactive steroids and their use to facilitate neuroprotection
WO2014085668A1 (fr) 2012-11-30 2014-06-05 The Regents Of The University Of California Activité anticonvulsivante des stéroïdes
TR201808616T4 (tr) 2012-12-18 2018-07-23 Sage Therapeutics Inc Nöroaktif 19-alkoksi-17-ikameli steroidler, bunların ön ilaçları ve bunları kullanan tedavi yöntemleri.
WO2014108808A2 (fr) 2013-01-09 2014-07-17 Henry James Lorne Formulations pharmaceutiques pour le traitement et la prévention de la neuropathologie et de la neurodégénérescence induites par un traumatisme
US9725481B2 (en) 2013-04-17 2017-08-08 Sage Therapeutics, Inc. 19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof
WO2014169836A1 (fr) 2013-04-17 2014-10-23 Sage Therapeutics, Inc. 19-nor-stéroïdes neuroactifs et procédés d'utilisation de ceux-ci
PL2986624T3 (pl) 2013-04-17 2020-11-16 Sage Therapeutics, Inc. Neuroaktywne steroidy 19-NOR do stosowania w sposobach leczenia
US9512165B2 (en) 2013-04-17 2016-12-06 Sage Therapeutics, Inc. 19-nor C3, 3-disubstituted C21-N-pyrazolyl steroids and methods of use thereof
CA2918735C (fr) 2013-07-19 2023-08-01 Sage Therapeutics, Inc. Steroides neuroactifs, compositions, et leurs utilisations
EP3035940B1 (fr) 2013-08-23 2018-10-17 Sage Therapeutics, Inc. Stéroïdes neuroactifs, compositions et utilisations
HUE059829T2 (hu) * 2014-05-29 2022-12-28 Sage Therapeutics Inc Neuroaktív szteroidok, készítményeik és alkalmazásuk
WO2015195962A1 (fr) * 2014-06-18 2015-12-23 Sage Therapeutics, Inc. Stéroïdes neuroactifs, leurs compositions et utilisations
JOP20200195A1 (ar) * 2014-09-08 2017-06-16 Sage Therapeutics Inc سترويدات وتركيبات نشطة عصبياً، واستخداماتها
CN107427458A (zh) 2015-02-06 2017-12-01 马瑞纳斯制药公司 静脉内加奈索酮制剂及其在治疗癫痫持续状态和其他癫痫发作病症中的用途
GB2541015A (en) 2015-08-06 2017-02-08 Ge Oil & Gas Uk Ltd Subsea flying lead
CN108697712A (zh) 2015-10-14 2018-10-23 加利福尼亚大学董事会 增强β细胞复制和/或存活
JOP20170059B1 (ar) 2016-03-08 2021-08-17 Sage Therapeutics Inc ستيرويدات وتركيبات نشطة عصبيًا واستخداماتها
KR102518846B1 (ko) 2016-08-11 2023-04-05 오비드 테라퓨틱스 인크. 간질 장애의 치료를 위한 방법 및 조성물
US20180050107A1 (en) 2016-08-16 2018-02-22 Janssen Pharmaceutica Nv Neurosteroid compositions and methods of use thereof
US20180050005A1 (en) 2016-08-16 2018-02-22 Janssen Pharmaceutica Nv Concentrated Solution of 17-Hydroxydocosahexaenoic Acid
IL265225B (en) 2016-09-07 2022-08-01 Glia Llc Treatment of symptoms related to neurodegenerative disorders through pharmacological dermal activation of cranial nerves
US10391105B2 (en) 2016-09-09 2019-08-27 Marinus Pharmaceuticals Inc. Methods of treating certain depressive disorders and delirium tremens
WO2018169798A1 (fr) 2017-03-11 2018-09-20 The Regents Of The University Of California Atténuation de troubles du snc par polythérapie faisant intervenir des neurostéroïdes, et des bloqueurs ampa
KR20190137839A (ko) 2017-04-18 2019-12-11 마리누스 파마슈티컬스 인코포레이티드 지속 방출 주사용 뉴로스테로이드 제제
US20180338959A1 (en) 2017-05-24 2018-11-29 Ovid Therapeutics Inc. Treatment of depressive disorders
US11752115B2 (en) 2017-06-21 2023-09-12 The Board Of Trustees Of The University Of Illinois PPAR-alpha agonist treatment of neuropsychiatric disorders
EP3642206A4 (fr) 2017-06-23 2021-04-07 The Regents of The University of California Amélioration de la capacité de gaba pour moduler des réponses immunitaires
US11266663B2 (en) 2017-06-23 2022-03-08 The Board Of Trustees Of The University Of Illinois Treatment of neuropsychiatric disorders with neurosteroids and analogues thereof
WO2019094724A1 (fr) 2017-11-10 2019-05-16 Marinus Pharmaceuticals, Inc. Ganaxolone destinée à être utilisée dans le traitement de troubles épileptiques génétiques
UY38213A (es) 2018-05-04 2019-10-31 Acerus Pharmaceuticals Corp Derivados de neuroesteroides y usos de estos
US11311529B2 (en) 2018-11-08 2022-04-26 Varsona Therapeutics, Inc. Topical formulations of 5-α-reductase inhibitors and uses thereof
BR112021009944A2 (pt) 2018-11-21 2021-08-17 Certego Therapeutics Inc. gaboxadol para reduzir risco de suicídio e alívio rápido de depressão
WO2020118142A1 (fr) 2018-12-07 2020-06-11 Marinus Pharmaceuticals, Inc. Ganaxolone destiné à être utilisé dans la prophylaxie et le traitement de la dépression post-partum
MX2021007032A (es) 2018-12-14 2021-10-22 Acerus Biopharma Inc Derivados activos de éster de testosterona, composiciones y usos de los mismos.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11945836B2 (en) 2014-11-27 2024-04-02 Sage Therapeutics, Inc. Compositions and methods for treating CNS disorders

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