WO2017029353A1 - Traitement de comportements chez des patients atteints de démence - Google Patents

Traitement de comportements chez des patients atteints de démence Download PDF

Info

Publication number
WO2017029353A1
WO2017029353A1 PCT/EP2016/069594 EP2016069594W WO2017029353A1 WO 2017029353 A1 WO2017029353 A1 WO 2017029353A1 EP 2016069594 W EP2016069594 W EP 2016069594W WO 2017029353 A1 WO2017029353 A1 WO 2017029353A1
Authority
WO
WIPO (PCT)
Prior art keywords
scyllo
inositol
aggression
agitation
npi
Prior art date
Application number
PCT/EP2016/069594
Other languages
English (en)
Inventor
Antonio Cruz
Original Assignee
Transition Therapeutics Ireland Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Transition Therapeutics Ireland Limited filed Critical Transition Therapeutics Ireland Limited
Publication of WO2017029353A1 publication Critical patent/WO2017029353A1/fr

Links

Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention relates to treatment of agitation, aggression, apathy and/or anxiety in dementia patients.
  • Agitation is one of the most troublesome dementia symptoms, characterized by inappropriate verbal, vocal, or motor activity that can be independent of perceptible needs or confusion (Cohen-Mansfield and Billig , J Am Geriatr Soc. 1986;34(10):711-21; Voyer et al BMC Geriatr. 2005;5: 13).
  • These verbal and physical behaviors can deviate from social norms and include irrelevant vocalizations, screaming, cursing, restlessness, wandering, strange movements, and handling things inappropriately (Cohen-Mansfield et al Int Psychogeriatr. 1995;7(3):447-58.).
  • Such disruptive behaviors are a major source of stress for caregivers and loved ones and take a significant toll over time (Voyer et al 2005).
  • AD Alzheimer's Disease
  • Approved drugs for symptomatic treatment of AD have limited benefit. Cholinesterase inhibitors appear to have a small but measurable effect on depression, dysphoria, apathy/indifference, and anxiety but are probably not an effective short-term treatment for agitation or aggression (Gauthier et al, Int. Psychogeriatr. 2002;14(4):389-404). Memantine has shown some benefits in the treatment of irritability, agitation/aggression, and psychosis in AD patients (Gauthier et al Int J Geriatr Psychiatry. 2008;23(5):537-45; McShane et al Cochrane Database Syst Rev.
  • the present invention provides methods and compositions that can be used to treat, prevent or attenuate aggression, agitation, apathy and/or anxiety in dementia patients.
  • methods and compositions are provided that can be used to treat, prevent or attenuate aggression and/or agitation in dementia patients with moderate to severe disease.
  • methods and compositions are provided that can be used to treat, prevent or attenuate agitation and/or aggression in Alzheimer's disease (AD) patients with moderate to severe agitation and/or aggression.
  • AD Alzheimer's disease
  • methods and compositions are provided that can be used to treat, prevent or attenuate apathy in dementia patients.
  • methods and compositions are provided that can be used to treat, prevent or attenuate anxiety in dementia patients.
  • the methods are carried out by administering to the patient a scyllo-inositol compound, in particular scyllo-inositol, or pharmaceutically acceptable salt thereof, in a manner that is effective for treating, preventing or attenuating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly severe agitation and/or aggression.
  • a scyllo-inositol compound in particular scyllo-inositol, or pharmaceutically acceptable salt thereof
  • a manner effective for treating, preventing or attenuating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression may comprise administering a predetermined amount of a scyllo-inositol compound or pharmaceutically acceptable salt thereof, and/or utilizing a particular dosage regimen, formulation, mode of administration, combination with other treatments, and the like.
  • the invention relates to a method of treatment comprising administering a therapeutically effective amount of one or more scyllo-inositol compound, in particular scyllo-inositol, or pharmaceutically acceptable salt thereof or a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, to a dementia patient to treat, prevent or attenuate agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression.
  • the efficacy of methods of the invention may be assessed using one or more methods that evaluate agitation, aggression, apathy and/or anxiety behaviors of the patient as described below (see, for example, the Neuropsychiatric Inventory-Clinician (NPI-C) rating scale and Neuropsychiatric Inventory-Clinician Agitation and Aggression rating scale (NPI-C A+A).
  • the efficacy of the methods may be assessed using one or more methods that evaluate caregiver distress (for example, NPI-C caregiver distress), a clinician's global assessment of agitation, (for example, the Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change or mADCS-CGIC), neuropsychiatric inventory questionnaire (NPI-Q) and/or cognitive status (MMSE).
  • the NPI-C A+A mean score change is about 3 to 5 fold.
  • the present invention relates to methods and compositions that can be used to treat, prevent or attenuate agitation and/or aggression in a selected subpopulation of dementia patients.
  • the methods are carried out by administering to a selected dementia subpopulation patient; a scyllo-inositol compound or pharmaceutically acceptable salt thereof, in a manner that is effective for treating, preventing or attenuating agitation and/or aggression.
  • the selected dementia subpopulation patient has a Neuropsychiatric Inventory- Clinician Agitation and Aggression (NPI-C A+A) rating scale score equal to or greater than 20, 22, 24 or 26, in particular 22.
  • NPI-C A+A Neuropsychiatric Inventory- Clinician Agitation and Aggression
  • the present invention relates to methods and compositions that can be used to treat, prevent or attenuate apathy in a selected subpopulation of dementia patients.
  • the methods are carried out by administering to a selected dementia subpopulation patient; a scyllo-inositol compound or pharmaceutically acceptable salt thereof, in a manner that is effective for treating, preventing or attenuating apathy.
  • the selected dementia subpopulation patient has a NPI-C apathy score equal to or greater than 19.
  • the present invention relates to methods and compositions that can be used to treat, prevent or attenuate anxiety in a selected subpopulation of dementia patients.
  • the methods are carried out by administering to a selected dementia subpopulation patient; a scyllo-inositol compound or pharmaceutically acceptable salt thereof, in a manner that is effective for treating, preventing or attenuating anxiety.
  • the selected dementia subpopulation patient has a NPI-C anxiety score equal to or greater than 15.
  • the invention relates to a method for treating or delaying the progression of apathy in a dementia patient with moderate to severe symptoms of apathy comprising administering to the patient a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, in a therapeutically effective amount for treating or delaying the progression of apathy.
  • the invention relates to a method for treating or delaying the progression of anxiety in a dementia patient with moderate to severe symptoms of anxiety comprising administering to the patient a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, in a therapeutically effective amount for treating or delaying the progression of anxiety.
  • the invention also relates to a method for treating or delaying the progression of agitation and/or aggression in a dementia patient with moderate to severe symptoms of agitation and/or aggression comprising administering to the patient a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising a scyllo- inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, in a therapeutically effective amount for treating or delaying the progression of aggression and/or agitation.
  • the invention relates to a method for treating or delaying the progression of agitation in a dementia patient with moderate to severe symptoms of agitation comprising administering to the patient a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, in a therapeutically effective amount for treating or delaying the progression of the agitation.
  • the invention also relates to a method for treating or delaying the progression of aggression in a dementia patient with moderate to severe symptoms of aggression comprising administering to the patient a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, in a therapeutically effective amount for treating or delaying the progression of the aggression.
  • the invention provides a method for treating or delaying the progression of apathy and/or anxiety behaviors in a dementia patient, wherein the behaviors consist of the NPI-C apathy and/or anxiety behaviors, such method comprising administering to the patient a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, in a therapeutically effective amount for treating or delaying the progression of the apathy and/or anxiety behaviors.
  • the invention provides a method for treating or delaying the progression of agitation and/or aggression behaviors in a dementia patient, wherein the behaviors consist of the NPI-C aggression behavior domains and/or the NPI-C agitation behavior domains, such method comprising administering to the patient a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or vehicle, in a therapeutically effective amount for treating or delaying the progression of the aggression and/or agitation behaviors.
  • the agitation behaviors are chosen, selected from the group consisting of, or consist of NPI-C agitation domains, in particular upset, stubborn, resistive, ask, restless, fidget, complain, refuse, pace, leave, phone, hoard and hide.
  • the aggression behaviors are chosen, selected from the group consisting of, or consist of NPI-C aggression domains, in particular shout, slam, hurt, push, argue, intrusive, conflict and danger.
  • the invention provides medicaments for use in the treatment of agitation, aggression, apathy and/or anxiety in dementia patients.
  • the invention provides a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof, in particular a therapeutically effective amount of a scyllo-inositol compound or pharmaceutically acceptable salt thereof, for treating agitation, aggression, apathy and/or anxiety in dementia patients.
  • the medicament can be in a pharmaceutically acceptable carrier, excipient, or vehicle.
  • the invention provides medicaments for use in the treatment of agitation and/or aggression behaviors in dementia patients with moderate to severe agitation and/or aggregation.
  • the invention provides a medicament comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof, in particular a therapeutically effective amount of a scyllo-inositol compound or pharmaceutically acceptable salt thereof, for treating agitation and/or aggression behaviors in dementia patients.
  • the invention relates to a composition for treating or attenuating agitation, aggression, apathy and/or anxiety in a selected dementia subpopulation patient comprising scyllo-inositol characterized in that said composition is administered at a dose disclosed herein.
  • the scyllo-inositol is administered at an oral dose of 1000 mg twice daily.
  • the scyllo-inositol is administered at an oral dose of 250 mg twice daily.
  • a composition for treating or attenuating agitation and/or aggression in a dementia patient who has a Neuropsychiatric Inventory-Clinician Agitation and Aggression (NPI-C A+A) score of at least or greater than 22, 24 or 26 comprising scyllo-inositol, characterized in that the scyllo-inositol is administered at an oral dose of 2000 mg daily in single or multiple dosage units.
  • NPI-C A+A Neuropsychiatric Inventory-Clinician Agitation and Aggression
  • NPI-C Neuropsychiatric Inventory-Clinician rating scale
  • subpopulations of patients or patients with moderate to severe apathy have a NPI-C apathy score of at least or greater than 19.
  • subpopulations of patients or patients with moderate to severe anxiety have a NPI-C anxiety score of at least or greater than 15.
  • patients with moderate to severe agitation and/or aggression may be identified using the NPI-C A+A rating scale and/or the Neuropsychiatric Inventory Agitation/Aggregation (NPI-A/A) rating scale.
  • the patient has a NPI-C A+A score of at least or greater than 20.
  • the patient has a NPI-C A+A score of at least or greater than 22.
  • the patient has a NPI-C A+A score of at least or greater than 24.
  • the patient has a NPI-C A+A score of at least or greater than 26.
  • the patient has a score for NPI-C agitation domains of at least or greater than 16. In aspects of the invention, the patient has a score for NPI-C agitation domains of at least or greater than 17. In aspects of the invention, the patient has a score for NPI-C agitation domains of at least or greater than 18.
  • the patient has a score for NPI-C aggression domains of at least or greater than 7. In aspects of the invention, the patient has a score for NPI-C aggression domains of at least or greater than 8. In aspects of the invention, the patient has a score for NPI-C aggression domains of at least or greater than 9. In aspects of the invention, the patient has a score for NPI-C aggression domains of at least or greater than 10.
  • the invention provides a method of treating or attenuating apathy in selected dementia patients exhibiting a NPI-C apathy score at least or greater than 19, comprising administering a scyllo-inositol compound to said patients.
  • the invention also provides the use of scyllo-inositol for the manufacture of a medicament for treating or attenuating apathy in selected dementia patients exhibiting a NPI-C apathy score at least or greater than 19.
  • the invention provides a method of treating or attenuating anxiety in selected dementia patients exhibiting a NPI-C anxiety score at least or greater than 15, comprising administering a scyllo-inositol compound to said patients.
  • the invention also provides the use of scyllo-inositol for the manufacture of a medicament for treating or attenuating anxiety in selected dementia patients exhibiting a NPI-C anxiety score at least or greater than 15.
  • the invention provides a method of treating or attenuating agitation and/or aggression behaviors in selected dementia patients exhibiting a NPI-C A+A score at least or greater than 22, comprising administering a scyllo-inositol compound to said patients.
  • the invention also provides the use of scyllo-inositol for the manufacture of a medicament for treating or attenuating agitation and/or aggression behaviors in selected dementia patients exhibiting a NPI-C A+A score at least or greater than 22.
  • the invention provides a method of treating or attenuating agitation and/or aggression behaviors in selected dementia patients exhibiting a NPI-C A+A score at least or greater than 24, comprising administering a scyllo-inositol compound to said patients.
  • the invention also provides the use of scyllo-inositol for the manufacture of a medicament for treating or attenuating agitation and/or aggression behaviors in selected dementia patients exhibiting a NPI-C A+A score at least or greater than 24.
  • the invention provides a method of treating or attenuating agitation and/or aggression behaviors in selected dementia patients exhibiting a NPI-C A+A score at least or greater than 26, comprising administering a scyllo-inositol compound to said patients.
  • the invention also provides the use of scyllo-inositol for the manufacture of a medicament for treating or attenuating agitation and/or aggression behaviors in selected dementia patients exhibiting a NPI-C A+A score at least or greater than 26.
  • the invention provides a method of treating or attenuating agitation behaviors in selected dementia patients exhibiting a NPI-C agitation domain score at least or greater than 16, 17 or 18, in particular 16, comprising administering a scyllo-inositol compound to said patients.
  • the invention also provides the use of scyllo-inositol for the manufacture of a medicament for treating or attenuating agitation behaviors in selected dementia patients exhibiting a NPI-C agitation domains score at least or greater than 16, 17 or 18, in particular 16.
  • the invention provides a method of treating or attenuating aggression behaviors in selected dementia patients exhibiting a NPI-C aggression domain score at least or greater than 7, 8, 9, or 10, in particular 8, comprising administering a scyllo-inositol compound to said patients.
  • the invention also provides the use of scyllo-inositol for the manufacture of a medicament for treating or attenuating aggression behaviors in selected dementia patients exhibiting a NPI-C aggression domains score at least or greater than 7, 8, 9, or 10, in particular 8.
  • the invention provides a method for treating agitation and/or aggression in a selected dementia subpopulation patient, in particular a dementia patient with moderate to severe agitation and/or aggression or behaviors associated therewith, comprising administering to the patient a therapeutically effective amount of scyllo-inositol or pharmaceutically acceptable salt thereof wherein the selected behaviors correspond to domains or sub-items of NPI-C A+A chosen, selected from the group consisting of, or consisting of:
  • efficacy of the treatment of the selected behaviors is defined by a statistically significant difference compared to a control for the agitation and aggression domains of NPI-C.
  • efficacy of the treatment of the selected behaviors is defined by a statistically significant difference compared to a control for the agitation domains of NPI-C chosen, selected from the group consisting of, or consisting of upset, stubborn, resistive, ask, restless, fidget, complain, refuse, pace, leave, phone, hoard and hide.
  • efficacy of the treatment of the selected behaviors is defined by a statistically significant difference compared to a control for the aggression domains of NPI-C chosen, selected from the group consisting of, or consisting of shout, slam, hurt, push, argue, intrusive, conflict and danger.
  • the NPI-C A+A baseline score for the domains or sub-items selected from the group consisting of, or consisting of stubborn, restless, fidget, phone, hoard, hide, shout, slam, push, argue, conflict, intrusive, ask, and hurt is at least 8, 9, or 10, preferably 9.
  • efficacy of the treatment of the selected behaviors is defined by a statistically significant difference compared to a control for the domains or sub- items of NPI-C A+A chosen, selected from the group consisting of, or consisting of stubborn, restless, fidget, phone, hoard, hide, shout, slam, push, argue, conflict, refuse, pace and leave.
  • the NPI-C A+A baseline score for the domains or sub-items selected from the group consisting of, or consisting of stubborn, restless, fidget, phone, hoard, hide, shout, slam, push, argue, conflict, refuse, pace and leave is at least 8, 9, or 10, preferably 9.
  • the invention provides methods for treating or attenuating one or more behaviors of agitation, aggression, apathy and/or anxiety in a dementia patient which are carried out by administering to a selected patient a therapeutically effective amount of a scyllo-inositol compound or a pharmaceutical composition of the invention.
  • methods are provided for treating or attenuating one or more behaviors of agitation and/or aggression in a dementia patient with moderate to severe agitation and/or aggression, which are carried out by administering to a selected patient a therapeutically effective amount of a scyllo-inositol compound or a pharmaceutical composition of the invention.
  • the invention provides a method for treating or attenuating apathy in a dementia patient, the method comprising: (a) selecting a dementia patient who has a NPI-C apathy score of at least or greater than 19; (b) administering to said patient in need thereof a therapeutically effective amount of a scyllo-inositol compound; and (c) treating or reducing apathy in said patient.
  • the invention provides a method for treating or attenuating anxiety in a dementia patient, the method comprising: (a) selecting a dementia patient who has a NPI-C anxiety score of at least or greater than 15; (b) administering to said patient in need thereof a therapeutically effective amount of a scyllo-inositol compound; and (c) treating or reducing anxiety in said patient.
  • a method for treating or attenuating agitation and/or aggression in a dementia patient comprising: (a) selecting a dementia patient who has a NPI-C A+A score of at least or greater than 22, 24 or 26; (b) administering to said patient in need thereof a therapeutically effective amount of a scyllo-inositol compound, in particular scyllo-inositol; and (c) treating or reducing agitation and/or aggression in said patient.
  • the invention also provides a method for treating or attenuating agitation and/or aggression behaviors in a dementia patient with moderate to severe agitation and/or aggression, the method comprising: (a) selecting a dementia patient who has a NPI-C A+A score of at least or greater than 22; (b) administering to said patient in need thereof a therapeutically effective amount of a scyllo-inositol compound; and (c) treating or reducing the agitation and/or aggression behaviors in said patient.
  • the invention also provides a method for treating or attenuating agitation in a dementia patient with moderate to severe agitation, the method comprising: (a) selecting a dementia patient who has a NPI-C A+A agitation score of at least or greater than 16, 17 or 18; (b) administering to said patient in need thereof a therapeutically effective amount of a scyllo- inositol compound; and (c) treating or reducing agitation in said patient.
  • the invention also provides a method for treating or attenuating aggression in a dementia patient with moderate to severe aggression, the method comprising: (a) selecting a dementia patient who has a NPI-C A+A aggression score of at least or greater than 7, 8, 9 or 10; (b) administering to said patient in need thereof a therapeutically effective amount of a scyllo-inositol compound; and (c) reducing aggression in said patient.
  • the invention provides a method for treating or attenuating apathy in a dementia patient, the method comprising:
  • the invention provides a method for treating or attenuating anxiety in a dementia patient, the method comprising:
  • the invention provides a method for treating or attenuating agitation and/or aggression in a dementia patient, in particular a patient with moderate to severe agitation and/or aggression, the method comprising:
  • the invention provides a method for treating or attenuating agitation in a dementia patient with moderate to severe agitation, the method comprising:
  • the invention provides a method for treating or attenuating aggression in a dementia patient with moderate to severe aggression, the method comprising:
  • the invention also contemplates the use of a scyllo-inositol compound or pharmaceutically acceptable salt thereof for treating agitation, aggression, apathy and/or anxiety in dementia patients or for the preparation or manufacture of a medicament or pharmaceutical composition for treating agitation, aggression, apathy and/or anxiety in dementia patients.
  • the invention relates to use of a scyllo-inositol compound or pharmaceutically acceptable salt thereof or medicament for treating or reducing agitation and/or aggression, or for the preparation or manufacture of a medicament or pharmaceutical composition for treating agitation and/or aggression in dementia patients with moderate to severe disease or in a selected subpopulation of dementia patients.
  • the invention relates to use of a scyllo-inositol compound or pharmaceutically acceptable salt thereof for treating selected agitation and/or aggression behaviors, or for the preparation or manufacture of a medicament or pharmaceutical composition for treating selected agitation and/or aggression behaviors in dementia patients with moderate to severe agitation and/or aggression.
  • a pharmaceutical composition or medicament may be in a pharmaceutically acceptable carrier, excipient, or vehicle, and it may be in a form for consumption by a subject such as a pill, tablet, caplet, soft and hard gelatin capsule, lozenge, sachet, cachet, vegicap, liquid drop, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium) suppository, sterile injectable solution, and/or sterile packaged powder.
  • a pharmaceutically acceptable carrier such as a pill, tablet, caplet, soft and hard gelatin capsule, lozenge, sachet, cachet, vegicap, liquid drop, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium) suppository, sterile injectable solution, and/or sterile packaged powder.
  • the invention further provides a dietary supplement composition comprising one or more scyllo-inositol compound or pharmaceutically acceptable salt thereof or nutraceutically acceptable derivatives thereof, for treatment of agitation, aggression, apathy and/or anxiety in dementia patients.
  • the invention provides a dietary supplement composition comprising one or more scyllo-inositol compound or pharmaceutically acceptable salt thereof or nutraceutically acceptable derivatives thereof, for treatment of agitation and/or aggression behaviors in patients with moderate and severe agitation and/or aggression or in a selected subpopulation of dementia patients.
  • a dietary supplement of the invention is preferably pleasant tasting, effectively absorbed into the body and provides substantial therapeutic effects.
  • a dietary supplement of the present invention is formulated as a beverage, but may be formulated in granule, capsule or suppository form.
  • the invention also provides a kit comprising one or more scyllo-inositol compound or pharmaceutically acceptable salt thereof, or a medicament comprising same for treating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression in patients.
  • the invention provides a kit for treating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, containing a medicament comprising one or more scyllo-inositol compound or pharmaceutically acceptable salt thereof) a container, and instructions for use.
  • the composition of the kit can further comprise a pharmaceutically acceptable carrier, excipient, or vehicle.
  • the invention provides a method of promoting sales of a medicament or kit of the invention comprising the public distribution of information that administration of the medicament or kit is associated with treatment or prophylaxis of agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, in dementia patients.
  • aspects of the invention provide screening tools and methods for using the screening tools for identifying patients suitable for treatment with a scyllo-inositol compound.
  • Figure 1 shows graphs of the change from baseline in Neuropsychiatric Inventory-Clinician Agitation and Aggression (NPI-C A+A) in severity in AD patients.
  • Figure 2 shows bar graphs of the results of the NPI-C agitation and aggression items or questions at week 12.
  • Figure 3 shows graphs of the change from baseline in NPI-C anxiety in severity in AD patients.
  • Figure 4 shows graphs of the change from baseline in NPI-C apathy in severity in AD patients.
  • administering and “administration” refer to the process by which a therapeutically effective amount of a scyllo-inositol compound or pharmaceutically acceptable salt thereof or medicament contemplated herein is delivered to a subject for prevention and/or treatment purposes.
  • the compounds and medicaments are administered in accordance with good medical practices taking into account the subject's clinical condition, the site and method of administration, dosage, patient age, sex, body weight, and other factors known to physicians.
  • dementia patient refers to a subject, in general a human, who suffers from dementia, in particular a dementia of the Alzheimer type including, but not limited to Alzheimer's disease, Parkinson's disease dementia, and related maladies in humans involving cognitive and behavioral dysfunction such as Lewy body dementia vascular dementia, Down syndrome and traumatic brain injury.
  • the dementia patient has moderate to severe dementia.
  • a dementia patient suffers from Alzheimer's disease.
  • a dementia patient has moderate to severe dementia.
  • a dementia patient suffers from moderate to severe Alzheimer's disease.
  • a dementia patient has moderate to severe agitation and/or aggression, in particular moderate to severe agitation and/or aggression behaviors as contemplated in the NPI-C A+A.
  • a dementia patient has moderate to severe apathy, in particular moderate to severe apathy behaviors as contemplated in the NPI-C.
  • a dementia patient has moderate to severe anxiety, in particular moderate to severe anxiety behaviors as contemplated in the NPI-C.
  • a dementia patient has a NPI-C score of at least or greater than 20, 22, 24 or 26. In embodiments, a dementia patient has a NPI-C A+A score of at least or greater than 20, 22, 24, or 26. In embodiment for treating agitation, a dementia patient has a score for the NPI-C agitation domains of at least or greater than 16, 17, or 18. In embodiment for treating aggression, a dementia patient has a score for the NPI-C aggression domains of at least or greater than 7, 8, 9 or 10.
  • the dementia patient has a NPI-C A+A score of at least or greater than 20. In an embodiment, the dementia patient has a NPI-C A+A score of at least or greater than 22. In an embodiment, the dementia patient has a NPI-C A+A score of at least or greater than 24. In an embodiment, the dementia patient has a NPI-C A+A score of at least or greater than 26.
  • the dementia patient has a score for NPI-C agitation domains of at least or greater than 16. In aspects of the invention, the dementia patient has a score for NPI-C agitation domains of at least or greater than 17. In aspects of the invention, the dementia patient has a score for NPI-C agitation domains of at least or greater than 18.
  • the dementia patient has a score for NPI-C aggression domains of at least or greater than 7. In aspects of the invention, the dementia patient has a score for NPI-C aggression domains of at least or greater than 8. In aspects of the invention, the dementia patient has a score for NPI-C aggression domains of at least or greater than 9. In aspects of the invention, the dementia patient has a score for NPI-C aggression domains of at least or greater than 10.
  • selected dementia subpopulation patient refers to dementia patients with selected scores on the NPI-C, NPI A/A and/or NPI-C A+A.
  • a selected dementia subpopulation patient exhibits one or both of the following characteristics: a NPI-C A+A score of at least or greater than 18, 19, 22, 24 or 26 and a NPI-A/A score of at least or greater than 9.
  • the selected dementia subpopulation patient has moderate to severe agitation and/or aggression and is identified using the Neuropsychiatric Inventory-Clinician Agitation and Aggression rating scale (NPI-C A+A).
  • NPI-C A+A Neuropsychiatric Inventory-Clinician Agitation and Aggression rating scale
  • the selected dementia subpopulation patient has a NPI-C A+A score of at least or greater than 19.
  • the selected dementia subpopulation patient has a NPI-C A+A score of at least or greater than 20.
  • the selected dementia subpopulation patient has a NPI-C A+A score of at least or greater than 21.
  • the selected dementia subpopulation patient has a NPI-C A+A score of at least or greater than 22.
  • the selected dementia subpopulation patient has a NPI-C A+A score of at least or greater than 24. In another embodiment, the selected dementia subpopulation patient has a NPI-C A+A score of at least or greater than 26. In another embodiment, the selected dementia subpopulation patient has a NPI-C A+A score of at least or greater than 30.
  • the selected dementia subpopulation patient has a score for NPI-C agitation domains of at least or greater than 16. In aspects of the invention, the selected dementia subpopulation patient has a score for NPI-C agitation domains of at least or greater than 17. In aspects of the invention, the selected dementia subpopulation patient has a score for NPI-C agitation domains of at least or greater than 18.
  • the selected dementia subpopulation patient has a score for NPI-C aggression domains of at least or greater than 7. In aspects of the invention, the selected dementia subpopulation patient has a score for NPI-C aggression domains of at least or greater than 8. In aspects of the invention, the selected dementia subpopulation patient has a score for NPI-C aggression domains of at least or greater than 9. In aspects of the invention, the selected dementia subpopulation patient has a score for NPI-C aggression domains of at least or greater than 10. In aspects of the invention, the selected dementia subpopulation patient has moderate to severe agitation and/or aggression and is identified using the NPI-A/A. In an embodiment, the selected dementia subpopulation patient has a NPI-A/A score of 9 or greater.
  • the selected dementia subpopulation patient has moderate to severe apathy and is identified using the NPI-C apathy domains. In an embodiment, the selected dementia subpopulation patient has a NPI-C apathy domains score of at least or greater than 19.
  • the selected dementia subpopulation patient has moderate to severe anxiety and is identified using the NPI-C anxiety domains.
  • the selected dementia subpopulation patient has NPI-C anxiety domains score of at least or greater than 15.
  • the dementia patient does not respond to conventional neuropsychotropic drugs.
  • the dementia patient has severe agitation and/or aggression and does not respond to conventional neuropsychotropic drugs.
  • neuropsychotropic drugs include without limitation, antidepressants, mood stabilizers, antipsychotics (e.g., risperidone), cholinesterase inhibitors, memantine, dextromethorphan compounds (e.g., Nuedexta® a combination of dextromethorphan and quinidine; AVP-786 a combination of deuterium modified dextromethorphan and ultra-low dose quinidine, Avanir Pharmaceuticals, Aliso Viejo, CA) and selective serotonin inverse agonists (SSIA) preferentially targeting 5-HT2A receptors (e.g. Nuplazid®, Acadia Pharmaceuticals, San Diego, CA) (generic name pimavanserin).
  • 5-HT2A receptors e.g. Nuplazid®, Acadia Pharmaceuticals, San Diego,
  • MMSE or “Mini Mental State Examination” is a 30-point questionnaire that is used in clinical and research settings to measure cognitive impairment and to follow the course of cognitive changes in an individual over time (see for example, Folstein, MF et al, J Psychiatr Res. 1975 Nov; 12(3):189-98).
  • Neuropsychiatric Inventory refers to the 12-item NPI (Cummings JL, et al, Neurology. 1994; 44(12):2308-14) which assesses psychopathology in dementia patients and has been widely used in AD clinical trials. It evaluates 12 neuropsychiatric symptoms (NPS) or domains common in dementia. Neuropsychiatric symptoms are rated on the basis of questions administered to the subject's caregiver/study partner. The score for each NPI domain is me frequency score (0-4) multiplied by the severity score (0-3), based on the item/question with the highest score or severity. The maximal domain score is 12 (4 x 3), and the possible values for each domain include 1, 2, 3, 4, 6, 8, 9, and 12.
  • NPI-A/A NPI Agitation and NPI Aggression
  • the maximal score on NPI-A/A is 12 (4 for frequency, 3 for severity).
  • the maximal score on each is 12 (4 for frequency, 3 for severity).
  • the total NPI score represents overall burden of NPS in AD patients. This is calculated by summing the domain scores from all 12 domains.
  • the maximal total score for the 12-item NPI is 144 (12 x 12). Higher scores on the NPI are associated with greater frequency and severity of NPS; therefore, a negative change from baseline score indicates an improvement from baseline.
  • Neuropsychiatric Inventory-Clinician rating scale or "NPI-C” is an expanded form of the widely used Neuropsychiatric Inventory (12-item NPI, Cummings 1997) (See de Medeiros et al Int Psychogeriatr. 2010;22(6):984-94).
  • Neuropsychiatric Inventory-Chnician Agitation and Aggression or "NPI-C A+A” reflects the NPI-C rating of the combined agitation and aggression domains.
  • the NPI-C was developed and validated by a consortium of neuropsychiatric AD experts.
  • the NPI-C scale has the following characteristics that support its use as a primary outcome measure for clinical trials of agitation and aggression in AD.
  • NPI-C Agitation and NPI-C Aggression have separate domains to evaluate agitation and aggression
  • NPI-C A+A has a total of 21 items versus 8 items on the NPI-A/A
  • utilizing an experienced and trained rater to perform the assessments of clinical severity after direct patient observation and interviews of both the patient and caregiver.
  • the NPI-C scoring is based on the clinician's rating of the severity of each NPS or domain (i.e., agitation or aggression) after an interview of both patient and their caregiver/study partner.
  • Each domain score of the NPI-C is calculated by summing the "clinical severity" scores of all items/questions within that domain. For each domain, the overall clinical severity score ranges 0 to 3 for each item/question; therefore, the maximal score for each domain is 3 x number of items within that domain. Therefore, the maximal score for agitation is 39 (13 x 3) and for aggression is 24 (8 x 3).
  • the range on the NPI-C combined Agitation and Aggression (NPI-C A+A) scores is 0-63. Higher scores on the NPI-C domains are associated with a greater clinical severity of symptoms, therefore a negative change from baseline score indicates an improvement from baseline.
  • NPI-Q is a brief questionnaire form of the NPI developed for use in routine clinical practice (NPI-Q) (see, Kaufer, DI, J Neuropsychiatry Clin Neurosci. 2000 Spring; 12(2):233-9).
  • substitutes refers to a derivative or substitute for the stated chemical species that operates in a similar manner to produce the intended effect, and is structurally similar and physiologically compatible.
  • substitutes include without limitation salts, esters, hydrates, or complexes of the stated chemical.
  • the substitute could also be a precursor or prodrug to the stated chemical, which subsequently undergoes a reaction in vivo to yield the stated chemical or a substitute thereof.
  • the terms "patient” and “subject” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • the subject is a human.
  • the patient or subject is a human a subject at least 50 years old, at least 60 years old or at least 70 years old.
  • the patient or subject is a dementia patient.
  • pharmaceutically acceptable carrier, excipient, or vehicle refers to a medium which does not interfere with the effectiveness or activity of an active ingredient and which is not toxic to the hosts to which it is administered.
  • a carrier, excipient, or vehicle includes diluents, binders, adhesives, lubricants, disintegrates, bulking agents, wetting or emulsifying agents, pH buffering agents, and miscellaneous materials such as absorbants that may be needed in order to prepare a particular medicament.
  • carriers etc. include but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The use of such media and agents for an active substance is well known in the art. Acceptable carriers, excipients or vehicles may be selected from any of those commercially used in the art.
  • “Pharmaceutically acceptable salt(s),” refers to a salt that is pharmaceutically acceptable and has the desired pharmacological properties.
  • pharmaceutically acceptable salts are meant those salts which are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are described for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66:1.
  • Suitable salts include salts that may be formed where acidic protons in the compounds are capable of reacting with inorganic or organic bases.
  • Suitable inorganic salts include those formed with alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminum.
  • Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Suitable salts also include acid addition salts formed with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benezenesulfonic acid). When there are two acidic groups present, a pharmaceutically acceptable salt may be a mono-acid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified.
  • organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • Suitable salts also include
  • a “scyllo-inositol compound” is understood to refer to a compound of the formula I or pharmaceutically acceptable salt thereof:
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof includes a functional derivative, a chemical derivative, variant or analog.
  • a "functional derivative” refers to a compound that possesses an activity (either functional or structural) that is substantially similar to the activity of a scyllo-inositol compound or pharmaceutically acceptable salt thereof disclosed herein.
  • the term "chemical derivative” describes a molecule that contains additional chemical moieties which are not normally a part of the base molecule.
  • variant is meant to refer to a molecule substantially similar in structure and function to a scyllo-inositol compound or pharmaceutically acceptable salt thereof or a part thereof.
  • a molecule is "substantially similar” to a scyllo-inositol compound or pharmaceutically acceptable salt thereof if both molecules have substantially similar structures or if both molecules possess similar biological activity.
  • analog includes a molecule substantially similar in function to a scyllo-inositol compound or pharmaceutically acceptable salt thereof.
  • An “analog” can include a chemical compound that is structurally similar to another but differs slightly in composition. Differences include without limitation the replacement of an atom or functional group with an atom or functional group of a different element. Analogs and derivatives may be identified using computational methods with commercially available computer modeling programs.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof includes crystalline forms which may exist as polymorphs. Solvates of the compounds formed with water or common organic solvents are also intended to be encompassed within the term. In addition, hydrate forms of the compounds and their salts are encompassed within this invention. Further prodrugs of compounds of a scyllo-inositol compound or pharmaceutically acceptable salts thereof are encompassed within the term.
  • the scyllo-inositol compound is ELND005 (1,3 ,5/2,4 ,6-hexahydroxycyclohexane; j?cy//o-inositol) an orally bioavailable small molecule with a molecular weight of 180 g/mol (Daltons) (Transition Therapeutics Ireland Limited).
  • Scyllo-inositol compounds or pharmaceutically acceptable salt thereof can be prepared using conventional processes or they may be obtained from commercial sources.
  • scyllo-inositol compounds can be prepared using chemical and/or microbial processes.
  • a scyllo-inositol is produced using process steps described by M. Sarmah and Shashidhar, M., Carbohydrate Research, 2003, 338, 999-1001; Husson, C, et al, Carbohydrate Research 307 (1998) 163-165; Anderson R. and E.S. Wallis, J.
  • a scyllo-inositol is prepared using the chemical process steps described in Husson, C, et al, Carbohydrate Research 307 (1998) 163- 165.
  • a scyllo-inositol is prepared using microbial process steps similar to those described in WO05035774 (EP1674578 and US20060240534) JP2003102492, or JP09140388 (Hokko Chemical Industries).
  • Derivatives may be produced by introducing substituents into a scyllo-inositol compound using methods well known to a person of ordinary skill in the art.
  • “Therapeutically effective amount” relates to the amount or dose of an active scyllo- inositol compound or pharmaceutically acceptable salt thereof or medicament thereof, that will lead to one or more desired therapeutic effects.
  • a therapeutically effective amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the substance to elicit a desired response in the subject.
  • a dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • treating refers to alleviating, inhibiting the progress of, or reducing the severity of agitation, aggression, apathy and/or anxiety in a patient, in particular agitation and/or aggression, more particularly agitation and/or aggression behaviors in a patient. Treating includes the management and care of a subject at diagnosis or later. A treatment may be either performed in an acute or chronic way.
  • An objective of treatment is to administer one or more scyllo-inositol compound to prevent or delay the onset of agitation, aggression, apathy and/or anxiety in a patient, in particular agitation and/or aggression behaviors; alleviate agitation, aggression, apathy and/or anxiety in a patient, in particular agitation and/or aggression behaviors; or, eliminate or partially eliminate agitation, aggression, apathy and/or anxiety in a patient, in particular, agitation and/or aggression behaviors.
  • treating includes "preventing" or "prevention", which include without limitation, the attenuation, elimination, minimization, alleviation, or amelioration of agitation, aggression, apathy and/or anxiety in a patient, in particular agitation or aggression.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof or salts thereof as an active ingredient can be directly administered to a patient, but it is preferably administered as a preparation in the form of a pharmaceutical composition or medicament containing the active ingredient and pharmaceutically acceptable carriers, excipients, and vehicles. Therefore, the invention contemplates a pharmaceutical composition or medicament comprising a therapeutically effective amount of a scyllo-inositol compound or pharmaceutically acceptable salt thereof, for treating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors, in dementia patients.
  • compositions or medicaments of the present invention or fractions thereof comprise suitable pharmaceutically acceptable carriers, excipients, and vehicles selected based on the intended form of administration, and consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical carriers, excipients, and vehicles are described in the standard text, Remington: The Science and Practice of Pharmacy (21st Edition, Popovich, N (eds), Advanced Concepts Institute, University of the Sciences in Philadelphia, Philadelphia, PA. 2005).
  • a medicament of the invention can be in any form suitable for administration to a patient including, without limitation, a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • preparations which are appropriate for oral administration can include capsules, tablets, powders, fine granules, solutions and syrups, where the active components can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, sodium saccharine, magnesium carbonate mannitol, sorbital, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, methyl cellulose, magnesium stearate, glucose, calcium sulfate, dicalcium phosphate, sodium saccharine, magnesium carbonate mannitol, sorbital, and the like.
  • the active components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Suitable binders e.g.
  • gelatin starch, com sweeteners, natural sugars including glucose, natural and synthetic gums, and waxes
  • lubricants e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride
  • disintegrating agents e.g. starch, methyl cellulose, agar, bentonite, and xanthan gum
  • flavoring agents, and coloring agents may also be combined in the medicaments or components thereof.
  • Medicaments as described herein can further comprise wetting or emulsifying agents, or pH buffering agents.
  • Medicaments which are appropriate for parenteral administration may include aqueous solutions, syrups, aqueous or oil suspensions and emulsions with edible oil such as cottonseed oil, coconut oil or peanut oil.
  • medicaments for parenteral administration include sterile aqueous or non-aqueous solvents, such as water, isotonic saline, isotonic glucose solution, buffer solution, or other solvents conveniently used for parenteral administration of therapeutically active agents.
  • Dispersing or suspending agents that can be used for aqueous suspensions include synthetic or natural gums, such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, and polyvinylpyrrolidone.
  • a medicament intended for parenteral administration may also include conventional additives such as stabilizers, buffers, or preservatives, e.g. antioxidants such as methylhydroxybenzoate or similar additives.
  • a medicament can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Various known delivery systems can be used to administer a medicament of the invention, e.g. encapsulation in liposomes, microparticles, microcapsules, and the like.
  • Medicaments can also be formulated as pharmaceutically acceptable salts as described herein.
  • a medicament can be sterilized by, for example, filtration through a bacteria retaining filter, addition of sterilizing agents to the medicament, irradiation of the medicament, or heating the medicament.
  • the medicaments may be provided as sterile solid preparations e.g., lyophilized powder, which are readily dissolved in sterile solvent immediately prior to use.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof may be in a form suitable for administration as a dietary supplement.
  • a supplement may optionally include inactive ingredients such as diluents or fillers, viscosity-modifying agents, preservatives, flavorings, colorants, or other additives conventional in the art.
  • inactive ingredients such as diluents or fillers, viscosity-modifying agents, preservatives, flavorings, colorants, or other additives conventional in the art.
  • conventional ingredients such as beeswax, lecithin, gelatin, glycerin, caramel, and carmine may be included.
  • a dietary supplement composition may optionally comprise a second active ingredient such as pinitol or an active derivative or metabolite thereof.
  • a dietary supplement may be provided as a liquid dietary supplement e.g., a dispensable liquid) or alternatively the compositions may be formulated as granules, capsules or suppositories.
  • the liquid supplement may include a number of suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like.
  • the dietary compositions are formulated in admixture with a pharmaceutically acceptable carrier.
  • a supplement may be presented in the form of a softgel which is prepared using conventional methods.
  • a softgel typically includes a layer of gelatin encapsulating a small quantity of the supplement.
  • a supplement may also be in the form of a liquid-filled and sealed gelatin capsule, which may be made using conventional methods.
  • compositions comprising scyllo-inositol compound or pharmaceutically acceptable salt thereof may be intimately admixed with a pharmaceutically acceptable carrier according to conventional formulation techniques.
  • suitable carriers and additives such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be included.
  • kits comprising a scyllo- inositol compound or pharmaceutically acceptable salt thereof or a pharmaceutical composition or medicament of the invention in kit form.
  • a medicament or formulation in a kit of the invention may comprise any of the formulations or compositions disclosed herein.
  • the kit can be a package which houses a container which contains a scyllo-inositol compound or pharmaceutically acceptable salt thereof or medicament of the invention and also houses instructions for administering the scyllo-inositol compound or pharmaceutically acceptable salt thereof or medicament to a subject.
  • the invention further relates to a commercial package comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof or medicament together with instructions for its use.
  • a label may include amount, frequency, and method of administration.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of a medicament of the invention.
  • containers can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the labeling, manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration.
  • the invention also relates to articles of manufacture and kits containing materials useful for treating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors, in dementia patients.
  • An article of manufacture may comprise a container with a label. Examples of suitable containers include bottles, vials, and test tubes which may be formed from a variety of materials including glass and plastic.
  • a container holds a medicament or formulation of the invention comprising a scyllo-inositol compound or pharmaceutically acceptable salt thereof which is effective for treating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, in particular selected agitation and/or aggression behaviors.
  • a medicament or formulation in a container may comprise any of the medicaments or formulations disclosed herein.
  • kits may additionally include other materials desirable from a commercial and user standpoint, including, without limitation, buffers, diluents, filters, needles, syringes, and package inserts with instructions for performing any methods disclosed herein (e.g., methods for treating agitation and/or aggression).
  • a kit of the invention comprises a container described herein and a second container comprising a buffer.
  • kits may be useful for any of the methods disclosed herein, including, without limitation treating a dementia patient suffering from moderate to severe disease, in particular moderate to severe agitation and/or aggression.
  • Kits of the invention may contain instructions for practicing any of the methods described herein.
  • kits of parts for treating agitation, aggression, apathy and/or anxiety comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • kits of parts for treating apathy comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • a dementia patient should be assessed as suitable for treatment with a scyllo-inositol compound if the dementia patient has a NPI-C apathy domain score of at least or greater than 19; and (ii) 1000 mg of a scyllo-inositol compound should be administered orally twice daily (BID) for 4 to 12 weeks, in particular 4 to 6 weeks, followed by maintenance doses of250 mg BID.
  • BID twice daily
  • kits of parts for treating anxiety comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • a dementia patient should be assessed as suitable for treatment with a scyllo-inositol compound if the dementia patient has a NPI-C anxiety domain score of at least or greater than 15; and (ii) 1000 mg of a scyllo-inositol compound should be administered orally twice daily (BID) for 4 to 12 weeks, in particular 4 to 6 weeks, followed by maintenance doses of250 mg BID.
  • BID twice daily
  • kits of parts for treating agitation and/or aggression comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • a dementia patient should be assessed as suitable for treatment with a scyllo-inositol compound if the dementia patient has a NPI-C A+A score of at least or greater than 20, 22, 24, or 26; and (ii) 1000 mg of a scyllo-inositol compound should be administered orally twice daily (BID) for 4 to 12 weeks, in particular 4 to 6 weeks, followed by maintenance doses of 250 mg BID.
  • BID twice daily
  • kits of parts for treating agitation and/or aggression comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • kits of parts for treating agitation and/or aggression comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • kits of parts for treating agitation comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • a dementia patient should be assessed as suitable for treatment with a scyllo-inositol compound if the dementia patient has a NPI-C agitation domain score of at least or greater than 16, 17 or 18; and (ii) 1000 mg of a scyllo-inositol compound should be administered orally twice daily (BID) for 4 to 12 weeks, in particular 4 to 6 weeks, followed by maintenance doses of 250 mg BID.
  • BID twice daily
  • kits of parts for treating aggression comprising:
  • a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol;
  • a dementia patient should be assessed as suitable for treatment with a scyllo-inositol compound if the dementia patient has a NPI-C aggression domain score of at least or greater than 7, 8, 9 or 10; and (ii) 1000 mg of a scyllo-inositol compound should be administered orally twice daily (BID) for 4 to 12 weeks, in particular 4 to 6 weeks, followed by maintenance doses of 250 mg BID.
  • BID twice daily
  • kits of parts for treating agitation and/or aggression comprising: 1) a medicament comprising a scyllo-inositol compound, in particular scyllo- inositol; and
  • a dementia patient should be assessed as suitable for treatment with a scyllo-inositol compound if the dementia patient has a NPI-A/A score of 9 or greater; and (ii) 1000 mg of a scyllo- inositol compound should be administered orally twice daily (BID) for 4 to 12 weeks, in particular 4 to 6 weeks, followed by maintenance doses of 250 mg BID
  • aspects of the invention provide screening tools and methods of using the screening tools for identifying patients suitable for treatment with a scyllo-inositol compound.
  • the screening tool comprises questions for the agitation domains or sub-items of NPI-C.
  • the screening tool comprises questions for the aggression domains or sub-items of NPI-C.
  • the screening tool comprises questions for the domains or sub-items of NPI-C A+A.
  • the screening tool comprises NPI-C caregiver distress, mADCS-CGIC, a neuropsychiatric inventory questionnaire (NPI-Q), and/or a neuropsychiatric cognitive assessment (MMSE).
  • the screening tool comprises MMSE and patients with a MMSE score between 5 and 24 are suitable for treatment with a scyllo-inositol compound. In an aspect, the screening tool comprises MMSE and patients with a MMSE score greater than 8 are suitable for treatment with a scyllo-inositol compound.
  • the invention contemplates the use of therapeutically effective amounts of a scyllo- inositol compound or pharmaceutically acceptable salt thereof or medicament of the invention for treating agitation, aggression, apathy, and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors, in dementia patients, in particular patients with moderate to severe dementia.
  • the invention also contemplates methods for treating or attenuating agitation, aggression, apathy, and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors, in a dementia patient using the medicaments or treatments of the invention.
  • agitation, aggression, apathy, and/or anxiety in particular agitation and/or aggression, in a dementia patient may be assessed using conventional methods.
  • agitation, aggression, apathy, and/or anxiety, in particular agitation and/or aggression are defined by the Neuropsychiatric Inventory-Clinician (NPI-C) rating scale and/or the Neuropsychiatric Inventory (NPI) rating scale.
  • agitation, aggression, apathy, and/or anxiety are defined by NPI-C caregiver distress, mADCS-CGIC, a neuropsychiatric inventory questionnaire (NPI-Q), and/or a neuropsychiatric cognitive assessment (MMSE).
  • Assessments may be performed at least about 5, 10 or 20 days prior to the start of treatment; such as, for example, at least about 30 days, at least about 40 days or at least about 90 days prior to the start of treatment.
  • a subpopulation of dementia patients experiencing severe agitation and/or aggression may particularly benefit from treatment with scyllo-inositol.
  • the selection criteria for the identified subpopulation may comprise one or more of the following: a NPI-C A+A score greater than 18 and/or aNPI-A/A score of 9 or greater.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof or a medicament of the invention are used to treat a dementia patient having a NPI-C A+A score of at least or greater than 20, 22, 24 or 26.
  • the dementia patient has a NPI-C A+A score greater than 19. In another embodiment, the dementia patient has a NPI-C A+A score greater than 20. In another embodiment, the dementia patient has a NPI-C A+A score greater than 21. In another embodiment, the dementia patient has a NPI-C A+A score greater than 22. In another embodiment, the dementia patient has a NPI-C A+A score greater than 24. In another embodiment, the dementia patient has a NPI-C A+A score greater than 26.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof or a medicament of the invention are used to treat a dementia patient having a NPI-C A+A agitation domains score of at least or greater than 16, 17 or 18, in particular 16.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof or a medicament of the invention are used to treat a dementia patient having a NPI-C A+A aggression domains score of at least or greater than 7, 8, 9 or 10, in particular 8.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof or a medicament of the invention are used to treat a dementia patient having a MMSE score of between 5 and 24. In an embodiment, a scyllo-inositol compound or pharmaceutically acceptable salt thereof or a medicament of the invention are used to treat a dementia patient having a MMSE score of greater than 8.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof or a medicament of the invention are used to treat a dementia patient that does not respond to conventional neuropsychotropic drugs such as antidepressants, anti-psychotics, dextromethorphan compounds (e.g., Nuedexta® and AVP-786, Avanir Pharmaceuticals, Aliso Viejo, CA), selective serotonin inverse agonist (SSIA) preferentially targeting 5-HT2A receptors (e.g. Nuplazid, Acadia Pharmaceuticals, San Diego, CA) (generic name pimavanserin).
  • neuropsychotropic drugs such as antidepressants, anti-psychotics, dextromethorphan compounds (e.g., Nuedexta® and AVP-786, Avanir Pharmaceuticals, Aliso Viejo, CA), selective serotonin inverse agonist (SSIA) preferentially targeting 5-HT2A receptors (e.g. Nuplazid, Acadia Pharmaceuticals
  • compositions/medicaments and methods of the invention can be used in combination with antidepressants, mood stabilizers, antipsychotics (e.g., risperidone), cholinesterase inhibitors, memantine, dextromethorphan compounds (e.g., Nuedexta® a combination of dextromethorphan and quinidine; AVP-786 a combination of deuterium modified dextromethorphan and ultra-low dose quinidine, Avanir Pharmaceuticals, Aliso Viejo, CA) and selective serotonin inverse agonists (SSIA) preferentially targeting 5-HT2A receptors (eg.
  • antidepressants e.g., mood stabilizers, antipsychotics (e.g., risperidone), cholinesterase inhibitors, memantine, dextromethorphan compounds (e.g., Nuedexta® a combination of dextromethorphan and quinidine; AVP-786 a combination of
  • compositions/medicaments and methods of the invention can be used in combination with lorazepam, haloperidol, droperidol, olanzapine, zipradisone, amantadine, methotrimeprazine, methylphenidate, carbamazepine, valproic acid, propranolol and pindolol.
  • compositions/medicaments and methods of the invention can be used in combination with an antipsychotic, in particular quetiapine, risperidone or aripiprazole.
  • the invention also contemplates the use of a medicament comprising at least one scyllo-inositol compound or pharmaceutically acceptable salt thereof for treating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors, or for the preparation of a medicament in treating agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors.
  • the invention provides the use of a scyllo-inositol compound or pharmaceutically acceptable salt thereof for prolonged or sustained treatment of agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors, or for the preparation of a medicament for prolonged or sustained treatment of agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof and medicaments for use in the present invention can be administered by any means that produce contact of the active agent(s) with the agent's sites of action in the body of a subject or patient to produce a therapeutic effect.
  • the active ingredients can be administered simultaneously or sequentially and in any order at different points in time to provide the desired beneficial effects.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof and medicament for use in the invention can be formulated for sustained release, for delivery locally or systemically. It lies within the capability of a skilled physician or veterinarian to select a form and route of administration that optimizes the effects of the medicaments and treatments to provide desired therapeutic effects.
  • the scyllo-inositol compound or pharmaceutically acceptable salt thereof and medicaments may be administered in oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular forms, all utilizing dosage forms well known to those of ordinary skill in the pharmaceutical arts.
  • the scyllo-inositol compound or pharmaceutically acceptable salt thereof and medicaments for use in the invention may be administered by intranasal route via topical use of suitable intranasal vehicles, or via a transdermal route, for example using conventional transdermal skin patches.
  • a dosage protocol for administration using a transdermal delivery system may be continuous rather than intermittent throughout the dosage regimen.
  • a sustained release formulation can also be used for the therapeutic agents.
  • the dosage regimen of the invention will vary depending upon known factors such as the pharmacodynamic characteristics of the selected scyllo-inositol compound or pharmaceutically acceptable salt thereof and their mode and route of administration; the species, age, sex, health, medical condition, and weight of the patient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the desired effect.
  • An amount of a scyllo-inositol compound or pharmaceutically acceptable salt thereof which will be effective in the treatment of agitation, aggression, apathy and/or anxiety, in particular agitation and/or aggression, more particularly selected agitation and/or aggression behaviors, to provide therapeutic effects can be determined by standard clinical techniques.
  • the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the symptoms, and will be decided according to the judgment of the practitioner and each patient's circumstances. Suitable dosage ranges for administration may be particularly selected to provide desired therapeutic effects.
  • a subject may be treated with a scyllo-inositol compound or pharmaceutically acceptable salt thereof or medicament thereof on substantially any desired schedule.
  • a scyllo- inositol compound or pharmaceutically acceptable salt thereof or medicament of the invention may be administered one or more times per day, in particular 1 or 2 times per day, once twice or more frequently per week, once twice or more frequently a month or continuously.
  • a subject may be treated less frequently, such as every other day or once a week, or more frequently.
  • a medicament or scyllo-inositol compound or pharmaceutically acceptable salt thereof may be administered once, twice, three times or more daily, in particular once or twice daily, more particularly twice daily.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof or medicament may be administered to a subject for about or at least about 1 week, 2 weeks to 4 weeks, 2 weeks to 6 weeks, 4 weeks to 6 weeks, 2 weeks to 8 weeks, 2 weeks to 10 weeks, 2 weeks to 12 weeks, 4 weeks to 12 weeks, 2 weeks to 14 weeks, 2 weeks to 16 weeks, 2 weeks to 6 months, 2 weeks to 12 months, 2 weeks to 18 months, 2 weeks to 24 months, or for more than 24 months, periodically or continuously.
  • the dosage ranges of a scyllo-inositol compound or pharmaceutically acceptable salt thereof administered once, twice, three times or more daily, especially once or twice daily are about 0.5 to 25 mg/kg, 1 to 20 mg/kg, 1 to 15 mg/kg, 1 to 10 mg/kg, 2 to 25 mg/kg, 2 to 20 mg/kg, 2 to 15 mg/kg, 2 to 10 mg/kg, 3 to 25 mg/kg, 3 to 20 mg/kg, 3 to 10 mg/kg, 3 to 5 mg/kg or 2 to 5 mg/kg.
  • the required dose of a scyllo-inositol compound or pharmaceutically acceptable salt thereof, administered twice daily is about 0.5 to 25 mg/kg, 1 to 20 mg/kg, 1 to 15 mg/kg, 1 to 10 mg/kg, 2 to 25 mg/kg, 2 to 20 mg/kg, 2 to 15 mg/kg, 2 to 10 mg/kg, 3 to 25 mg/kg, 3 to 20 mg/kg, 3 to 10 mg/kg, 3 to 5 mg/kg or 2 to 5 mg/kg.
  • the dosage ranges for the scyllo-inositol compound or pharmaceutically acceptable salt thereof are about 1 mg to about 50 mg per kg per day, about 1 mg to about 40 mg per kg per day, about 2 mg to about 50 mg per kg per day, about 2 mg to about 40 mg per kg per day, about 3 mg to about 50 mg per kg per day, about 3 mg to about 40 mg per kg per day, about 5 mg to about 50 mg per kg per day, about 5 mg to about 40 mg per kg per day, about 5 mg to 30 mg per kg per day, or about 6 mg to 30 mg per kg per day.
  • the required dose of scyllo-inositol compound or pharmaceutically acceptable salt thereof administered twice daily is about 0.5 to about 25 mg/kg, about 1 to about 20 mg/kg, about 1 to about 15 mg/kg, about 1 to about 10 mg/kg, about 2 to about 25 mg/kg, about 2 to about 20 mg/kg, about 2 to about 15 mg/kg, about 2 to about 10 mg/kg, about 3 to about 25 mg/kg, about 3 to about 20 mg/kg, about 3 to about 15 mg/kg, about 3 to about 10 mg/kg, about 3 to about 5 mg/kg or about 2 to about 5 mg/kg, more particularly 3 mg/kg.
  • the required daily dose of scyllo-inositol compound or pharmaceutically acceptable salt thereof is about 1 mg to about 50 mg per kg per day, about 1 mg to about 40 mg per kg per day, about 2 mg to about 50 mg per kg per day, about 2 mg to about 40 mg per kg per day, about 3 mg to about 50 mg per kg per day, about 3 mg to about 40 mg per kg per day, about 5 mg to about 50 mg per kg per day, about 5 mg to about 40 mg per kg per day, about 5 mg to 30 mg per kg per day, about 6 mg to 30 mg per kg per day, about 5 mg to 35 mg per kg per day, or about 6 mg to 35 mg per kg per day.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof can be provided once daily, twice daily, three times or more daily, in a single dosage unit or multiple dosage units (i.e., tablets or capsules) having about 50 to about 2000 mg, 70 to about 2000 mg, 150 to about 2000 mg, 200 to about 2000, 200 to about 1500 mg, 200 to about 1200 mg, 200 to 1000 mg or 250 to 1000 mg.
  • the scyllo-inositol compound or pharmaceutically acceptable salt thereof is provided once daily, twice daily, three times or more daily, preferably twice daily, in a single dosage unit or multiple dosage units having 2000 mg.
  • the scyllo-inositol compound or pharmaceutically acceptable salt thereof is provided once daily, twice daily, three times or more daily, preferably twice daily, in a single dosage unit or multiple dosage units having 1000 mg. In aspects of the invention the scyllo-inositol compound or pharmaceutically acceptable salt thereof is provided once daily, twice daily, three times or more daily, preferably twice daily, in a single dosage unit or multiple dosage units having 500 mg. In aspects of the invention the scyllo-inositol compound or pharmaceutically acceptable salt thereof is provided once daily, twice daily, three times or more daily preferably twice daily, in a single dosage unit or multiple dosage units having 250 mg.
  • 2000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally daily.
  • 2000 mg a scyllo-inositol compound, in particular the scyllo-inositol compound ELND005, is administered orally daily in a single or multiple dosage units.
  • 2000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally daily in 250 mg dosage units.
  • 500 mg of a scyllo-inositol compound, in particular the scyllo-inositol compound ELND005, is administered orally daily.
  • 500 mg of a scyllo-inositol compound, in particular the scyllo-inositol compound ELND005, is administered orally daily in a single or multiple dosage units.
  • 500 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally daily in 250 mg dosage units.
  • 1000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID).
  • 1000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID) in a single or multiple dosage units.
  • BID twice daily
  • 1000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID) in 250 mg dosage units.
  • BID twice daily
  • 1000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID) in two 250 mg dosage units.
  • BID twice daily
  • 250 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID).
  • 250 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID) in a single or multiple dosage units.
  • BID twice daily
  • 250 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID) in a single dosage unit.
  • BID twice daily
  • 2000 mg of a scyllo-inositol compound, in particular the scyllo-inositol compound ELND005 is administered orally daily in a single or multiple dosage units for four weeks.
  • 500 mg of a scyllo-inositol compound, in particular the scyllo-inositol compound ELND005 is administered orally daily in a single or multiple dosage units for eight weeks.
  • 2000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005
  • 2000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005
  • 2000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005
  • the dosage unit is 250 mg.
  • 1000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005
  • BID twice daily
  • the dosage unit is 250 mg.
  • 250 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally twice daily (BID) for eight weeks.
  • 500 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005, is administered orally once daily (BID) in a single or multiple dosage units for eight weeks.
  • 1000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005
  • BID twice daily
  • 1000 mg of a scyllo-inositol compound in particular the scyllo-inositol compound ELND005
  • BID twice daily
  • the invention provides a regimen for supplementing a human's diet, comprising administering to the human a supplement comprising a scyllo-inositol compound, in particular scyllo-inositol, or pharmaceutically acceptable salt thereof or a nutraceutically acceptable derivative thereof.
  • a subject may be treated with a supplement at least about every day, or less frequently, such as every other day or once a week.
  • a supplement of the invention may be taken daily but consumed at lower frequency, such as several times per week or even isolated doses, may be beneficial.
  • the invention provides a regimen for supplementing a human's diet, comprising administering to the human about 1 to 2000, about 1 to about 1000, about 5 to about 500 or about 25 to about 250 milligrams of a scyllo-inositol compound or pharmaceutically acceptable salt thereof, or nutraceutically acceptable derivative thereof on a daily basis.
  • about 50 to 100 milligrams of a scyllo- inositol compound or pharmaceutically acceptable salt thereof is administered to the human on a daily basis.
  • about 2000 milligrams of a scyllo-inositol compound or pharmaceutically acceptable salt thereof is administered to the human on a daily basis.
  • a scyllo-inositol compound or pharmaceutically acceptable salt thereof is administered to the human on a daily basis. In another aspect, about 250 milligrams of a scyllo-inositol compound or pharmaceutically acceptable salt thereof is administered to the human on a daily basis.
  • a supplement of the present invention may be ingested with or after a meal.
  • a supplement may be taken at the time of a person's morning meal, and/or at the time of a person's noontime meal.
  • a portion may be administered shortly before, during, or shortly after the meal.
  • a portion of the supplement may be consumed shortly before, during, or shortly after the human's morning meal, and a second portion of the supplement may be consumed shortly before, during, or shortly after the human's noontime meal.
  • the morning portion and the noontime portion can each provide approximately the same quantity of a scyllo-inositol compound or pharmaceutically acceptable salt thereof.
  • a supplement and regimens described herein may be most effective when combined with a balanced diet according to generally accepted nutritional guidelines, and a program of modest to moderate exercise several times a week.
  • a regimen for supplementing a human's diet comprising administering to the human a supplement comprising, per gram of supplement: about 5 milligram to about 2000 milligrams, about 5 milligram to about 1000 milligrams, about 5 milligram to about 250 milligrams, or about 5 milligram to about 50 milligrams of one or more scyllo-inositol compound or pharmaceutically acceptable salt thereof or a nutraceutically acceptable derivative thereof.
  • a portion of the supplement is administered at the time of the human's morning meal, and a second portion of the supplement is administered at the time of the human's noontime meal.
  • This example describes a prospective, randomized, double-blind, placebo-controlled, parallel-group, two-arm, multicenter study of the efficacy and safety of ELND005 ((1,3,5/2,4,6-hexahydroxycyclohexane; scy/7o-inositol); an orally bioavailable small molecule with a molecular weight of 180 g/mol (Daltons) administered orally in a fixed dosing regimen for 12 weeks.
  • the primary efficacy objective of the study was to evaluate the effect of ELND005 on agitation and aggression in Mild to Severe AD patients.
  • the study enrolled patients with probable Alzheimer's Disease at the Mild/Moderate, and Severe stages of disease (Mini-Mental State Examination; MMSE score 5-24 inclusive), with enrollment stratified by two MMSE groups: Mild/Moderate >15 and Severe ⁇ 15.
  • the study was designed to enroll patients with clinically significant agitation and aggression defined as a NPI-A/A score >4 at both screening and baseline.
  • Approximately 350 patients were enrolled in a 1:1 ratio into the placebo or ELND005 group.
  • the primary endpoint was the difference in change from Baseline to Week 12 on the NPI-C combined agitation and aggression subscores between the ELND005 and placebo treatment groups.
  • Secondary efficacy outcomes included global assessment of change, cognitive and functional scales, as well as assessments of caregiver burden.
  • the random assignment was stratified according to AD severity (Mild/Moderate defined as screening MMSE scores of 16 to 24, inclusive, and Severe defined as screening MMSE scores of 5 to 15, inclusive), use of antidepressant medications (Y es/No), and regions: North America (United States and Canada) and Western Europe (Spain and UK).
  • the doses of concomitant antidepressants, mood stabilizers (including anticonvulsants), permitted doses of specified antipsychotics, cholinesterase inhibitors, memantine, and permitted medications for the treatment of non- excluded medical conditions were maintained constant.
  • the NPI-A/A scale was selected for screening and eligibility, and the NPI-C scale (summed Agitation and Aggression domains) was selected as a primary outcome measure.
  • the NPI-C scale is an updated version of the 12-item Neuropsychiatric Inventory (NPI) scale and provides enhanced sensitivity to treatment effects (de Medeiros et al 2010).
  • the main updates include 1) expansion of the scale from 12 to 14 items by adding a new domain of "aberrant vocalization” and by separating agitation and aggression in two distinct domains, 2) inclusion of a clinician rating methodology that incorporates patient and caregiver interviews into the clinician's assessment (NPI-C or "clinician rated"), rather than depending primarily on caregiver responses and recall, and 3) enhancing the depth of several domains, including agitation and aggression, by addition of items to those domains.
  • the total numbers of items in the NPI-C agitation and aggression domains were expanded from three each to 13 and 8, respectively. Therefore, the NPI-C retains the original items from the NPI.
  • the maximal possible combined score for the agitation and aggression domains is 63 (21 items with 3 being the maximal possible severity) in contrast to maximal score of 12 for the agitation/aggression domain of the NPI.
  • the total number of NPI-C items across the 14 domains is 142, providing a maximal possible overall NPI-C score of 426, in contrast to the maximal NPI score of 144.
  • the addition of items within the agitation and aggression domains of NPI-C improves the sensitivity of this instrument to potential treatment effects, when compared to the NPI (Trzepacz et a,l Evaluation of mibampator for agitation and aggression in Alzheimer's disease.
  • NPI-C agitation and aggression domains consist of 13 and 8 domains or sub-items, respectively, that are scored independently and then summed up to estimate the severity of the symptoms.
  • ELND005 showed more pronounced drug effects on individual domains or sub- items of the NPIC A+A in AD patients with more severe symptoms ( Figure 2).
  • NPI-C A+A baseline NPI-C agitation and aggression combined score
  • ELND005 treatment resulted in greater than 30% improvement over placebo in 17 domains or sub-items out of 21 total at week 12 (Figure 2B).
  • Figure 2A placebo
  • A+A clinical endpoint revealed subsets of behaviors that showed greater responses to ELND005 than others in AD patients with moderate to severe agitation and aggression.
  • a first behavior set, (mini-NPI-C A+A 1) consisted of STUBBORN, RESTLESS, FIDGET, PHONE, HOARD, HIDE, SHOUT, SLAM, PUSH, ARGUE, CONFLICT, INTRUSIVE, ASK and HURT.
  • the m-NPI-C A+A scale score was calculated by adding up the clinical severity scores of individual behaviors and ranged from 0 to 42.
  • Subjects with moderate and severe agitation and aggression behaviors were defined as having the baseline m-NPI-C A+A score ⁇ 9, which resulted in the total of 211 subjects (107 in the placebo group and 104 in the ELND005 group).
  • a second set included STUBBORN, RESTLESS, FIDGET, PHONE, HOARD, HIDE, SHOUT, SLAM, PUSH, ARGUE, CONFLICT, REFUSE, PACE and LEAVE.
  • 188 subjects had their baseline m-NPI-C A+A score ⁇ 9.
  • ELND005 was shown to have an acceptable safety and tolerability profile in the study.
  • the overall incidence of treatment emergent adverse events ("TEAEs") in the ELND005 group and the placebo group were similar (56.6% vs 54.3%), as was the incidence of study drug-related TEAEs (13.1% vs 14.9%).
  • Most TEAEs were mild or moderate in severity.
  • the most common TEAEs in the ELND005 group that were >5% in incidence were: agitation (8.0% vs. 7.4% in placebo), diarrhea (8.0% vs. 2.9% in placebo), urinary tract infection (6.9% vs. 4.0% in placebo), and fells (6.3% vs. 5.1% in placebo).
  • This example describes a prospective, randomized, double-blind, placebo-controlled, Phase 3 Study of oral ELND005 ((13,5/2,4 ,6-hexahydroxycyclohexane; scy//o-inositol); for the treatment of moderate and severe agitation and aggression in patients with Alzheimer's disease (AD).
  • the primary objective of the Study is to evaluate the efficacy of ELND005 treatment compared with placebo in reducing the severity of agitation and aggression at 12 weeks on the NPI-C combined agitation and aggression domains (NPI-C A+A).
  • a secondary objective is to evaluate the efficacy of ELND005 compared with placebo on NPI-C caregiver distress, the clinician's global assessment of agitation (mADCS-CGIC), neuropsychiatric inventory questionnaire (NPI-Q) and cognitive status (MMSE).
  • the Study will enroll about 250 patients in over 80 sites in multiple countries and patients will be selected with AD who have clinically significant moderate/severe agitation and aggression and are on stable doses of symptomatic AD drugs and/or psychotropic medications. There will be two treatment groups: oral ELND005 or matching placebo tablets for 12 weeks.
  • the fixed dosing regimen will consist of a loading dose of four tablets of 250 mg ELND005 administered orally BID (approximately every 12 hours for 4 weeks) for a total daily dose of 2000 mg for patients in the ELND005 treatment arm.
  • a maintenance dose of 250 mg ELND005 will be administered orally BID (approximately every 12 hours for a subsequent 8 weeks) for a total daily dose of 500 mg for patients in the ELND005 treatment arm.
  • ELND005 is provided as 250 mg immediate release film-coated tablets.
  • ELND005 matching placebo will be administered orally BID (approximately every 12 hours) with the number of tablets matching that of the loading or maintenance treatments.
  • the primary efficacy endpoint is based on the difference in change from Baseline (when a patient meets eligibility criteria) to Week 12 in NPI-C A+A scores between the ELND005 and placebo treatment groups.
  • the key secondary endpoint will be based on the change from Baseline to Week 12 in NPI-C agitation and aggression caregiver distress score.
  • Other secondary endpoints are based on the change from Baseline to Week 12 in mADCS- CGIC agitation domain scores, NIP-Q scores and MMSE scores.

Abstract

La présente invention concerne des procédés pour traiter l'agitation, l'agressivité, l'apathie et/ou l'anxiété chez des patients atteints de démence ayant une maladie modérée et grave, consistant à administrer un composé de type scyllo-inositol, en particulier du scyllo-inositol, ou un sel pharmaceutiquement acceptable de celui-ci. Dans un procédé selon l'invention, des patients atteints de démence ayant un score NPI-C A+A sélectionné, en particulier un score supérieur ou égal à au moins 22, sont traités pour l'agitation et/ou l'agressivité avec un composé de type scyllo-inositol, en particulier du scyllo-inositol, ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/EP2016/069594 2015-08-20 2016-08-18 Traitement de comportements chez des patients atteints de démence WO2017029353A1 (fr)

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US201562207537P 2015-08-20 2015-08-20
US62/207,537 2015-08-20
US201562239537P 2015-10-09 2015-10-09
US62/239,537 2015-10-09
US201562240714P 2015-10-13 2015-10-13
US62/240,714 2015-10-13
US201562258832P 2015-11-23 2015-11-23
US201562258827P 2015-11-23 2015-11-23
US62/258,827 2015-11-23
US62/258,832 2015-11-23

Publications (1)

Publication Number Publication Date
WO2017029353A1 true WO2017029353A1 (fr) 2017-02-23

Family

ID=56738116

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/069594 WO2017029353A1 (fr) 2015-08-20 2016-08-18 Traitement de comportements chez des patients atteints de démence

Country Status (1)

Country Link
WO (1) WO2017029353A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019025934A1 (fr) * 2017-08-02 2019-02-07 Kashiv Pharma Llc Composition pharmaceutique orale stable de pimavansérine
WO2021038035A1 (fr) * 2019-08-30 2021-03-04 Société des Produits Nestlé S.A. Scyllo-inositol et troubles à médiation par des lymphocytes b

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3405663A1 (de) 1984-02-17 1985-08-22 Merck Patent Gmbh, 6100 Darmstadt Verfahren zur herstellung von scyllo-inosit
JPH02184912A (ja) 1989-01-11 1990-07-19 Nec Corp パルス信号発生装置
JPH03102492A (ja) 1989-06-12 1991-04-26 Mitsui Eng & Shipbuild Co Ltd 自動販売機のデータ送信システムおよび複合機能型自動販売機
JPH04126075A (ja) 1990-09-18 1992-04-27 Asahi Chem Ind Co Ltd ミオ・イノシトールデヒドロゲナーゼおよびその製造法
JPH05192163A (ja) 1991-09-30 1993-08-03 Suntory Ltd イノシトールデヒドロゲナーゼ遺伝子
JPH09140388A (ja) 1995-11-17 1997-06-03 Hokko Chem Ind Co Ltd イノシトール立体異性体の製造方法
JP2003102492A (ja) 2001-06-25 2003-04-08 Hokko Chem Ind Co Ltd シロ−イノソースの製造法及びシロ−イノシトールの製造法
WO2005003577A1 (fr) 2003-07-05 2005-01-13 Man B & W Diesel Aktiengesellschaft Palier lisse axial
WO2005035774A1 (fr) 2003-10-14 2005-04-21 Hokko Chemical Industry Co., Ltd. Procede de production de scyllo-inositol
WO2006109479A1 (fr) 2005-03-30 2006-10-19 Niigata Bio-Research Park, Inc. Cassette d’expression de gene et transformant, et procede pour la production de 2-desoxy-scyllo-inosose et procede pour la purification de 2-desoxy-scyllo-inosose en utilisant le transformant
WO2012173808A1 (fr) * 2011-06-03 2012-12-20 Elan Pharmaceuticals, Inc. Scyllo-inositol pour le traitement de troubles du comportement et psychiatriques

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3405663A1 (de) 1984-02-17 1985-08-22 Merck Patent Gmbh, 6100 Darmstadt Verfahren zur herstellung von scyllo-inosit
JPH02184912A (ja) 1989-01-11 1990-07-19 Nec Corp パルス信号発生装置
JPH03102492A (ja) 1989-06-12 1991-04-26 Mitsui Eng & Shipbuild Co Ltd 自動販売機のデータ送信システムおよび複合機能型自動販売機
JPH04126075A (ja) 1990-09-18 1992-04-27 Asahi Chem Ind Co Ltd ミオ・イノシトールデヒドロゲナーゼおよびその製造法
JPH05192163A (ja) 1991-09-30 1993-08-03 Suntory Ltd イノシトールデヒドロゲナーゼ遺伝子
JPH09140388A (ja) 1995-11-17 1997-06-03 Hokko Chem Ind Co Ltd イノシトール立体異性体の製造方法
JP2003102492A (ja) 2001-06-25 2003-04-08 Hokko Chem Ind Co Ltd シロ−イノソースの製造法及びシロ−イノシトールの製造法
WO2005003577A1 (fr) 2003-07-05 2005-01-13 Man B & W Diesel Aktiengesellschaft Palier lisse axial
WO2005035774A1 (fr) 2003-10-14 2005-04-21 Hokko Chemical Industry Co., Ltd. Procede de production de scyllo-inositol
EP1674578A1 (fr) 2003-10-14 2006-06-28 Hokko Chemical Industry Co. Ltd. Procede de production de scyllo-inositol
US20060240534A1 (en) 2003-10-14 2006-10-26 Masanori Yamaguchi Process for producing scyllo-inositol
WO2006109479A1 (fr) 2005-03-30 2006-10-19 Niigata Bio-Research Park, Inc. Cassette d’expression de gene et transformant, et procede pour la production de 2-desoxy-scyllo-inosose et procede pour la purification de 2-desoxy-scyllo-inosose en utilisant le transformant
WO2012173808A1 (fr) * 2011-06-03 2012-12-20 Elan Pharmaceuticals, Inc. Scyllo-inositol pour le traitement de troubles du comportement et psychiatriques

Non-Patent Citations (34)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2005, ADVANCED CONCEPTS INSTITUTE
AMANN ET AL., CLIN PRACT EPIDEMIOL MENT HEALTH, vol. 5, 2009, pages 14
ANDERSON R.; E.S. WALLIS, J. AMERICAN CHEMICAL SOCIETY (US, vol. 70, 1948, pages 2931 - 2935
BENOIT ET AL., REV MED INTERNE, vol. 24, no. 3, 2003, pages 319S - 324S
BUMS ET AL., BR J PSYCHIATRY, vol. 157, 1990, pages 86 - 94
CHUNG, S.K. ET AL., BIOORG MED CHEM., vol. 7, no. 11, 1999, pages 2577 - 2589
COHEN-MANSFIELD ET AL., INT PSYCHOGERIATR., vol. 7, no. 3, 1995, pages 447 - 458
COHEN-MANSFIELD; BILLIG, JAM GERIATR SOC., vol. 34, no. 10, 1986, pages 711 - 721
CUMMINGS JL ET AL., NEUROLOGY, vol. 44, no. 12, 1994, pages 2308 - 2314
DE MEDEIROS ET AL., INT PSYCHOGERIATR., vol. 22, no. 6, 2010, pages 984 - 994
DE MEDEIROS ET AL., INT PSYCHOGERIATR., vol. 22, no. 6, September 2010 (2010-09-01), pages 984 - 994
FINKEL ET AL., J GERIATR PSYCHIATRY, vol. 19, no. 1, 2004, pages 9 - 18
FOLSTEIN, MF ET AL., J PSYCHIATR RES., vol. 12, no. 3, November 1975 (1975-11-01), pages 189 - 198
FOX ET AL., PLOS ONE, vol. 7, no. 5, 2012, pages E35185
GAUTHIER ET AL., INT J GERIATR PSYCHIATRY, vol. 23, no. 5, 2008, pages 537 - 545
GAUTHIER ET AL., INT. PSYCHOGERIATR., vol. 14, no. 4, 2002, pages 389 - 404
HUSSON, C. ET AL., CARBOHYDRATE RESEARCH, vol. 307, 1998, pages 163 - 165
KAUFER, DI: "J Neuropsychiatry Clin Neurosci.", vol. 12, 2000, SPRING, pages: 233 - 239
KIELY D.E.; FLETCHER, H.G., J. AMERICAN CHEMICAL SOCIETY (US, vol. 90, 1968, pages 3289 - 3290
LYKETSOS ET AL., AM J GERIATR PSYCHIATRY, vol. 14, no. 7, 2006, pages 561 - 572
LYKETSOS ET AL., AM J PSYCHIATRY, vol. 157, no. 5, 2000, pages 708 - 714
M. SARMAH; SHASHIDHAR, M., CARBOHYDRATE RESEARCH, vol. 338, 2003, pages 999 - 1001
MCSHANE ET AL., COCHRANE DATABASE SYST REV., vol. 19, no. 2, 2006, pages CS003154
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1
SALZMAN ET AL., J CLIN PSYCHIATRY, vol. 69, no. 6, 2008, pages 889 - 898
STEINBERG ET AL., INT J GERIATR PSYCHIATRY, vol. 23, no. 2, 2008, pages 170 - 177
SUMMARY OF PRODUCT CHARACTERISTICS: "Risperdal® Tablets, Liquid and Quicklet", 29 June 2012 (2012-06-29)
TARIOT ET AL., ARCH GEN PSYCHIATRY, vol. 68, no. 8, 2011, pages 853 - 861
TARIOT PIERRE ET AL: "The Effects of ELND005 (Scyllo-Inositol) on Emergence of Neuropsychiatric Symptoms (NPS) in Mild/Moderate Alzheimer's Disease: Results from a 78-Week Phase 2 Study", NEUROLOGY, vol. 78, no. Suppl. 1, 1 April 2012 (2012-04-01), & 64TH ANNUAL MEETING OF THE AMERICAN-ACADEMY-OF-NEUROLOGY (AAN); NEW ORLEANS, LA, USA; APRIL 21 -28, 2012, pages P04215, XP009192022 *
TERI ET AL., NEUROLOGY, vol. 55, no. 9, 2000, pages 1271 - 1278
TRZEPACZ: "Evaluation of mibampator for agitation and aggression in Alzheimer's disease. In: 50th Annual Meeting of the American College of Neuropsychopharmacology", NEUROPSYCHOPHARMACOLOGY, vol. 36, 4 December 2011 (2011-12-04), pages 227 - 228
VOYER ET AL., BMC GERIATR., vol. 5, 2005, pages 13
WEISSBACH, A., J ORG CHEM (US, vol. 23, 1958, pages 329 - 330
WILCOX ET AL., J CLIN PSYCHIATRY, vol. 69, no. 3, 2008, pages 341 - 348

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019025934A1 (fr) * 2017-08-02 2019-02-07 Kashiv Pharma Llc Composition pharmaceutique orale stable de pimavansérine
WO2021038035A1 (fr) * 2019-08-30 2021-03-04 Société des Produits Nestlé S.A. Scyllo-inositol et troubles à médiation par des lymphocytes b

Similar Documents

Publication Publication Date Title
Smith et al. Over-the-counter cold medications: a critical review of clinical trials between 1950 and 1991
CA2548917C (fr) Combinaison d'un sedatif et d'un modulateur des neurotransmetteurs, et methodes permettant d'ameliorer la qualite du sommeil et de traiter la depression
US20150057306A1 (en) Compositions comprising scopolamine and ketamine in the treatment of depression
AU2005304352A1 (en) Method for treatment of movement disorders
EP2523557B1 (fr) Méthodes permettant de faire perdre du poids à des patients souffrant d'une dépression sévère
TW200803901A (en) Methods of treating anxiety disorders
JP7393943B2 (ja) リソソーム蓄積障害に関する医薬組成物及び使用
AU2015341458B2 (en) Methods for treatment of cognitive decline
JP2021080288A (ja) 吃音を治療するための融合ベンズアゼピン
JP2019031551A (ja) 女性胃不全麻痺に関係する症状の処置
JP2023181398A (ja) 認知症および神経変性状態における興奮、精神病および認知機能低下のためのシクロベンザプリン処置
WO2017029353A1 (fr) Traitement de comportements chez des patients atteints de démence
CA3213576A1 (fr) Combinaison d'un inhibiteur de recaptage de la norepinephrine et d'un cannabinoide pour une utilisation dans le traitement de l'apnee du sommeil
TW200821296A (en) Use of sertindole for the preventive treatment of suicidal behaviour
JP6181754B2 (ja) トゥレット症候群治療のための縮合ベンゾアゼピン
Crain et al. Current treatment options in smoking cessation
KR20230136142A (ko) 치료 방법
CA3066284A1 (fr) Compositions d'ocytocine et methodes d'utilisation
WO2014052394A1 (fr) Procédés et compositions de combinaison comprenant une thérapie du sommeil pour traiter l'humeur
IsHak et al. Overview of approved psychiatric medications 2008-2023: A systematic review
Diener et al. Treatment of migraine attacks und preventive treatment of migraine, S 1 guideline, 2022, DGN and DMKG
JP2018503677A (ja) 神経精神系障害の治療のための組成物および方法
TW201106944A (en) Exo-S-mecamylamine method, use, and compound for treatment
Carvajal et al. Antipsychotic drugs

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16753660

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO R.112(1) EPC

122 Ep: pct application non-entry in european phase

Ref document number: 16753660

Country of ref document: EP

Kind code of ref document: A1