WO2020094591A1 - Inhibiteurs de pde10a pour le traitement de symptômes négatifs et de troubles cognitifs chez un patient souffrant de schizophrénie - Google Patents

Inhibiteurs de pde10a pour le traitement de symptômes négatifs et de troubles cognitifs chez un patient souffrant de schizophrénie Download PDF

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WO2020094591A1
WO2020094591A1 PCT/EP2019/080151 EP2019080151W WO2020094591A1 WO 2020094591 A1 WO2020094591 A1 WO 2020094591A1 EP 2019080151 W EP2019080151 W EP 2019080151W WO 2020094591 A1 WO2020094591 A1 WO 2020094591A1
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pde10a inhibitor
negative symptoms
symptoms
pde10a
patient
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PCT/EP2019/080151
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English (en)
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Jacob Nielsen
Raimund Buller
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H. Lundbeck A/S
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Priority to BR112020013820-7A priority Critical patent/BR112020013820A2/pt
Publication of WO2020094591A1 publication Critical patent/WO2020094591A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • the present invention relates to PDE10A inhibitors and compositions comprising PDE10A inhibitors for treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions, particularly in schizophrenia.
  • Schizophrenia is a psychiatric disorder characterized by three main symptom domains; positive symptoms (delusions, hallucinations, or disorganized/catatonic behavior etc.), negative symptoms (affective flattening, social withdrawal, asociality, anhedonia, avolition, blunted affect, alogia, psychomotor poverty, or poverty of thought and content of speech etc.), and symptoms of cognitive dysfunctions (impaired executive functioning, working memory, attention deficits, social cognitive impairment, jumping to conclusions, Theory of Mind (TOM) impairments, deficits in emotion recognition or affect discrimination etc.). Further information regarding schizophrenia and related diagnosis as well as the various symptom domains described above are available in e.g. the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), American Psychiatric Publishing, 2013.
  • Negative symptoms and cognitive impairments are also a predominant part of the prodromal phase of schizophrenia, sometimes referred to as psychosis prodrome.
  • the prodromal phase of schizophrenia is characterized by a heterogeneous group of behaviors temporally related to the onset of psychosis. Accordingly, the prodromal phase of schizophrenia can be defined as the time interval from the onset of unusual behavioral symptoms to the onset of psychotic symptoms.
  • An individual who is in the prodromal phase of schizophrenia is at clinical high risk of developing psychosis, which can be assessed by suitable diagnostic tools, such as the Structured Interview for Prodromal Syndromes (SIPS) (Miller TJ, et. al, 2003, Schizophr Bull., 29(4): 703-15).
  • SIPS Structured Interview for Prodromal Syndromes
  • Alzheimer's disease and other dementias such as frontotemporal dementia (FTD), Huntington's disease, autism spectrum disorder (ASD), bipolar disorder (BPD), stress disorders, anxiety disorders, major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI) (Boone et al., 2003, J Int Neuropsychol Soc., 9, 698- 709; Bastiaansen, J. et al., 2011, J. Autism Dev.
  • FDD frontotemporal dementia
  • ASD autism spectrum disorder
  • BPD bipolar disorder
  • stress disorders anxiety disorders
  • MDD major depressive disorder
  • Parkinson's disease temporal lobe epilepsy
  • stroke and traumatic brain injury (TBI) (Boone et al., 2003, J Int Neuropsychol Soc., 9, 698- 709; Bastiaansen, J. et al., 2011, J. Autism Dev.
  • apathy In some patient groups, these negative symptoms are generally referred to as apathy. This is true for both Parkinson's and Alzheimer's patients, as well as patients with associated dementias, frontotemporal dementias and stroke (Robert P. et al., 2009, European Psychiatry, 24, 98-104). In these patients, the apathy is characterized by the loss of initiation and motivation to participate in activities, social withdrawal, and emotional indifference. Patients with apathy are at increased risk to progressively suffer from decreased daily function and specific cognitive deficits such as executive cognitive dysfunction. In Alzheimer's disease and Parkinson's disease the apathy symptoms exist alongside the neurodegenerative symptoms classically associated with such diseases. The level of apathy related symptoms in a patient can be assessed by e.g.
  • NPI Neuropsychiatric Inventory
  • SCIA Structured Clinical Interview for Apathy
  • AES Apathy Evaluation Scale
  • AS Apathy Scale
  • AL Apathy Inventory
  • L Geb Apathy Rating Scale
  • PDE10A phosphodiesterase 10A
  • MSNs medium spiny neurons
  • This hydrolyzation transforms cAMP and cGMP into their inactive forms; 5'AMP and 5'GMP, respectively (Fujishige K. et al., 1999, J Biol Chem., 274(26): 18438-18445).
  • PDE10A inhibitors are expected to positively modulate (activate) signalling from dopamine D1 receptors via the direct pathway and negatively modulate (inhibit) signalling from dopamine D2 receptors via the indirect pathway (Polito M. et al., 2015, eNeuro, 31, 2(4)).
  • PDE10A inhibitors could embody a new class of antipsychotics, which could provide efficacy on all three symptom domains of schizophrenia (positive, negative and cognitive symptoms), concurrently (Kehler and Nielsen, 2011, Current Pharmaceutical Design, 17: 137-150; Kehler et al., 2007, Expert Opinion on Therapeutic Patents, 17:2,147-158; Dunlop et al., 2015, Journal of Psychopharmacology, 29(2), 230-238; Arnt J. et al., 2008, Drugs of the Future, 33(9): 777-791; Siuciak J., 2008, CNS Drugs; 22(12): 983-993).
  • PDE10A inhibitors have recently been moved into clinical development as monotherapy of schizophrenia. Two major clinical trials have been conducted by Pfizer and Takeda, exploring the efficacy of PDE10A inhibitor monotherapy, in cohorts of patients with acutely exacerbated schizophrenia. Pfizer tested their PDE10A inhibitor, MP-10, in clinical trial NCT01175135, and Takeda, tested their PDE10A inhibitor, TAK- 063, in clinical trial NCT02477020. Both trials failed to meet their endpoints (Macek et al, 2019, Schizophrenia Research 204, 289-294; DeMartinis N.
  • PDE10A inhibitors can be useful in treating specific subpopulations of schizophrenic patients, who are phenotypical distinct from acutely exacerbated schizophrenic patients and comprise relevant clinical populations, because a significantly unmet treatment need exist in these subpopulations.
  • the present invention relates to PDE10A inhibitors, for use in treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive impairments in a patient suffering from CNS disorders, in particular a schizophrenic patient with clinically stable positive symptoms, wherein said PDE10A inhibitor is administered as monotherapy.
  • the present invention also relates to methods of treating persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from CNS disorders, in particular a schizophrenic patient with clinically stable positive symptoms, provided that said PDE10A inhibitor is administered as monotherapy, said method of treatment comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.
  • the present invention relates to use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from CNS disorders, in particular a schizophrenic patient with clinically stable positive symptoms, wherein said PDE10A inhibitor is administered as monotherapy.
  • the patient to be treated may be a schizophrenic patient or a patient who displays psychosis risk syndrome and/or prodrome of schizophrenia.
  • the patient to be treated may be suffering from Alzheimer's disease or Parkinson's disease with comorbid apathy.
  • the PDE10A inhibitor is selected from the group consisting of compound (I), compound (II), MP-10, or a pharmaceutically acceptable salt of any of said compounds.
  • the PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof.
  • negative symptoms as used herein is meant to describe one or more symptom(s) associated with a CNS disorders, in particular schizophrenia. Specific examples of such symptoms are: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, poverty of speech, dysphoric mood, lack of insight and demoralisation.
  • the term "persistent negative symptoms” is meant to describe a clinical state of a patient where the negative symptoms have been persistent for at least about 6 months.
  • prominent negative symptoms is meant to describe a clinical state of a patient where the negative symptoms are a prominent part of the patient's clinical presentation.
  • prominent negative symptoms are meant to describe a subpopulation of patients with "prominent negative symptoms” who display negative symptoms that are at least moderate in severity, as evaluated on an accepted and validated rating scale (e.g. the PANSS negative symptom score, PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS)) and display no or only little positive symptoms (e.g. assessed by the PANSS positive symptom score).
  • PANSS negative symptom score PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS)
  • BNSS Brief Negative Symptom Scale
  • the term “persistent predominant negative symptoms” are meant to describe “predominant negative symptoms”, as defined above, that have been persistent for at least about 6 months.
  • the terms “cognitive dysfunction” and “cognitive impairment” are used interchangeably and is meant to describe symptoms affecting cognition such as impaired executive functioning, impaired working memory, attention deficits, social cognitive impairment, jumping to conclusions, Theory of Mind (TOM) impairments, deficits in emotion recognition or affect discrimination.
  • TOM Theory of Mind
  • clinically stable positive symptoms or “clinically stable phase” as used herein is meant to describe a clinical state of a patient suffering from schizophrenia, who has had no exacerbation of their positive symptoms, for a period of about 6 months. Any positive symptoms, which may be present during the clinically stable phase, should not exceed moderate severity, as evaluated on an accepted and valid rating scale, such as the PANSS.
  • the term "monotherapy” in the present context is meant to describe the treatment regimen related directly to the schizophrenic diagnosis.
  • PDE10A inhibitors when the present invention describes the use of PDE10A inhibitors as monotherapy, it means that they should not be administered as adjunctive/add-on treatment to any background antipsychotic treatment regimens, which may be comprised of either typical or atypical antipsychotics (examples of such drugs are given below). Consequently, a patient being administered a PDE10A inhibitor as monotherapy for treatment of persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptom, persistent predominant negative symptoms and/or cognitive impairments may in parallel with such treatment receive other drugs to treat potential additional pathological conditions, which are unrelated to the schizophrenic diagnosis.
  • antipsychotic drugs are meant to describe a specific class of drugs, which is primarily used to manage psychosis.
  • antipsychotic drugs may for example be selected from the group comprising haloperidol, pimozide, chlorpromazine, fluphenazine, perazine, perphenazine, trifluoperazine, clopenthixol, thiothixene, loxapine, sultopride, iloperidone, lurasidone, paliperidone, risperidone, ziprasidone, aripiprazole, brexpiprazole, cariprazine, asenapine, clozapine, olanzapine, quetiapine, zotepine, blonanserin, pimavanserin and sertindole.
  • Fig. 1 Effect of PDE10A inhibitors in the Conditioned Avoidance Response (CAR) assay in Rats.
  • CAR Conditioned Avoidance Response
  • Fig. 2 Effect of PDE10A inhibition on synaptic transmission in brain slices from rat prefrontal cortex.
  • Fig. 3 PDE10A inhibition modulates cAMP in both dopamine D1 and D2 receptor expressing neurons of the striatum.
  • Fig. 5 The chronic mild stress (CMS) model used to assess stress-induced hedonic deficits.
  • CMS chronic mild stress
  • Fig. 6 The novel object recognition (NOR) task in rats.
  • the inventors of the present invention have surprisingly found that when animals are administered a low dose of amphetamine to mimicking patients with exacerbated positive symptoms and tested in the conditioned avoidance response (CAR) assay, the antipsychotic effect of PDE10A inhibitors, which is seen in control animals, is abolished (figure 1). This finding strongly indicates that schizophrenic patients with exacerbated positive symptoms are not a well-suited patient group to treat with PDE10A inhibitors. This finding is unexpected in view of the general anticipation that PDE10A inhibitors could be useful as antipsychotic treatment as described in prior art.
  • CAR conditioned avoidance response
  • PDE10A inhibitor's mechanism of action indicates that the patient groups that are suitable to receive treatment with PDE10A inhibitors should unexpectedly be selected from the group comprising the following subpopulations of schizophrenic patients: patients with negative symptoms, patients with persistent negative symptoms, patients with prominent negative symptoms, patients with persistent prominent negative symptoms, patients with predominant negative symptoms, patients with persistent predominant negative symptoms, patients with cognitive dysfunctions, patients with cognitive impairments and patients displaying a combination of characteristics associated with such subpopulations, wherein said patients are further characterized by being in a clinically stable phase in regards to their positive symptoms, such as patients who do not display strong positive symptoms as a part of their clinical presentation or patients who have pharmacologically well-managed positive symptoms.
  • the patient groups described above who have pharmacologically well- managed positive symptoms is switched from their current antipsychotic treatment regimen onto a PDE10A inhibitor monotherapy regimen.
  • the negative and/or cognitive symptoms observed in any of the subpopulations of schizophrenic patients described above is treated by administering a therapeutically effective amount of a PDE10A inhibitor, such as Compound (I), Compound (II) or MP-10 as monotherapy.
  • the phenotypical distinction of the above-mentioned subpopulations from acutely exacerbated schizophrenic patients originates from a specific clinical presentation of the schizophrenic symptoms, wherein the negative and/or cognitive symptoms constitute the majority of the patient's symptoms associated with schizophrenia, meaning that these patients have a specific disease presentation with none or only little positive symptoms.
  • the phenotypical distinction of the above-mentioned subpopulations from acutely exacerbated schizophrenic patients originates from a clinical efficacious management of the positive symptoms with antipsychotics, while the negative and/or cognitive symptoms are not well-treated, meaning that the patient has well-treated and clinically stable positive symptoms, but that the negative and/or cognitive symptoms remains and currently constitute the majority of the displayed symptoms associated with schizophrenia.
  • the monotherapeutic treatment with a PDE10A inhibitor maintains stability of the positive symptoms and prevents exacerbations, while providing beneficial effect on the poorly-managed negative and/or cognitive symptoms.
  • the patient who currently has clinical efficacious management of their positive symptoms with antipsychotics, while the negative and/or cognitive symptoms are not well-treated is switched from the current antipsychotic treatment onto treatment with a PDE10A inhibitor administered as monotherapy.
  • Such switch in treatment will maintain of the clinical stability of the positive symptoms, while providing reduction in the severity and/or amount of negative and/or cognitive symptoms.
  • the PDE10A inhibitors have no target overlap with classic antipsychotics, which will likely reduce common peripheral side effects normally observed with such drugs, e.g. weight gain. It is an object of the present invention to provide new methods of treatment of negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions, particularly in schizophrenic patients with no exacerbated positive symptoms.
  • PDE10A inhibitors are believed to be useful in treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms and/or persistent predominant negative symptoms in patients which, despite on-going standard of care with e.g. antipsychotic therapy, continue to be socially withdrawn or amotivated/emotionless and limited in their interaction with their surroundings, which may significantly diminishes their quality of life.
  • the present invention discloses that PDE10A inhibitors exhibit their primary efficacy on negative symptoms and/or cognitive dysfunctions, but that this effect is abolished when the striatal level of dopamine is elevated, such as in states of acutely exacerbated schizophrenia.
  • the invention provides new methods for the treatment of individuals who are in the prodromal phase of schizophrenia.
  • individuals can for example be identified with suitable valid questionnaires, such as the Structured Interview for Prodromal Syndromes (SIPS).
  • SIPS Structured Interview for Prodromal Syndromes
  • the treatment with a PDE10A inhibitor may represent a prophylactic treatment strategy, which can ameliorate present symptoms as well as potentially delay or prevent future psychotic incidents.
  • the invention also relates to PDE10A inhibitors for use in a method for treating a patient suffering from cognitive dysfunction/impairment, provided that the PDE10A inhibitor is administered as monotherapy - these patients may or may not be schizophrenic.
  • the invention relates to PDE10A inhibitors for use as monotherapy in a method for treating schizophrenic patients with prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms and/or persistent predominant negative symptoms, wherein the patients are in a clinically stable phase with respect to the patient's positive symptoms.
  • PDE10A inhibitors is useful in the treatment of non-schizophrenic patients suffering from negative symptoms and/or cognitive dysfunctions.
  • this include patients who suffers from Alzheimer's disease or Parkinson's disease.
  • these patients have comorbid apathy associated with Alzheimer's disease or Parkinson's disease.
  • Compounds that are potent PDE10A inhibitors may be identified by testing their inhibitory potency in a PDE10A inhibition assay.
  • Such assay may for example be performed by mixing a fixed amount of the PDE10A enzyme and varying amounts of the compound to be tested. The assay is initiated when a fixed amount of labelled cyclic nucleotide substrate is added to the enzyme-inhibitor mix. Following this step, the a mount of converted substrate can be measured for various concentrations of the inhibitor compound and compared to the amount found in an uninhibited control (100 %). The concentration of the compound to be tested, which result in a 50% reduction of the substrate conversion is known as the IC50, and this value is used to define the potency of a specific compound.
  • the PDE10A Inhibitors of the present invention is considered potent when the IC50 ⁇ 1000 nM, more preferably IC50 ⁇ 100 nM, IC50 ⁇ 50 nM, IC50 ⁇ 10 nM and even more preferably IC50 ⁇ 5 nM.
  • the PDE10A inhibitor of the invention is a small molecule, which is a potent PDE10A inhibitor.
  • small molecules may originate from various chemical scaffolds selected from the group comprising: phenylimidazole, imidazole, isoquinoline, quinoline, cinnoline, quinoxaline, quinazoline, naphthyridine, tetrahydropyridopyrimidine, pyrazolopyrimidine and 2-oxindole.
  • potent PDE10A inhibitors are illustrated hereinbelow in table 1 and methods for preparation of said PDE10A inhibitors are described in W02009/152825 (see example 12 for preparation of Compound (I)); W02012/065612 (see example 2 for preparation of Compound (II)); and W02006/072828 (see example 3 for preparation of MP-10)).
  • the PDE10A inhibitor of the present invention is selected from the group consisting of Compound (I) and pharmaceutically acceptable salts thereof, Compound (II) and pharmaceutically acceptable salts thereof and MP-10 and pharmaceutically acceptable salts thereof.
  • the negative symptoms to be treated are primary negative symptoms.
  • Primary negative symptoms are etiological ly related to the core pathophysiology of schizophrenia, whereas secondary negative symptoms are derivatives of other symptoms of schizophrenia (e.g. positive symptoms), other disease processes, medications and/or environment.
  • the invention is not limited to any specific PDE10A inhibitor(s), since an abundant number of PDE10A inhibitors will be able to provide the technical effect claimed.
  • This statement is further supported in the experimental section (example 1, 4A and 5) where both MP-10, Compound (I) and Compound (II) are shown to be effective in various in vivo assays, even though the chemical structure of these compounds are distinct.
  • the efficacy appears to be occupancy driven and all PDE10A inhibitors are expected to display equivalent pharmacological effect if the suitable occupancy level at the PDE10A receptor is reached.
  • the desired occupancy level can be reached by adjusting the dose and/or the dosing regimen of the PDE10A inhibitor in question to obtain the suitable pharmacokinetic profile.
  • the occupancy can be determined by using a PET ligand capable of binding to the PDE10A receptor in the CNS, an example of such PET ligand is described in W02012/062319.
  • PDE10A inhibitors are used as monotherapy to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who displays no or only little positive symptoms and who are treatment-naive to antipsychotic drugs, i.e. said patient has not previously been treated with any type of antipsychotic.
  • PDE10A inhibitors are used as monotherapy to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who was previously treated with an antipsychotic drug but discontinued such treatment, e.g.
  • PDE10A inhibitors are used as monotherapy to treat negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a schizophrenic patient who, up until now, has been treated with an antipsychotic drug but such treatment has not provided adequate improvement in regards to the negative symptoms.
  • the invention relates to PDE10A inhibitors for use as monotherapy in the treatment of negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia, who are clinically stable in regards to the positive symptoms, or an individual who is in the prodromal phase of schizophrenia.
  • the patient to be treated with the PDE10A inhibitor suffers from deficit schizophrenia or residual schizophrenia.
  • the patient to be treated with the PDE10A inhibitor suffers from simple type schizophrenia or simple schizophrenia.
  • the invention relates specifically to the exemplified PDE10A inhibitors; i.e. MP-10, Compound (I) or Compound (II) or a pharmaceutically acceptable salt thereof as monotherapy for the treatment of negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia or are in the prodromal phase of schizophrenia.
  • MP-10 the exemplified PDE10A inhibitors
  • Compound (I) or Compound (II) or a pharmaceutically acceptable salt thereof as monotherapy for the treatment of negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia or are in the prodromal phase of schizophrenia.
  • the invention relates to Compound (I) or a pharmaceutically acceptable salt thereof, for use as monotherapy in the treatment of persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia in a patient suffering from schizophrenia, who are clinically stable in regards to the positive symptoms, or an individual who is in the prodromal phase of schizophrenia.
  • the Compound (I) hemiadipate is used as monotherapy to treat persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in a patient suffering from schizophrenia, who are clinically stable with reference to the positive symptoms.
  • the Compound (I) hemiadipate is used as monotherapy to treat negative symptoms and/or cognitive impairments in an individual who is in the prodromal phase of schizophrenia.
  • the patient suitable for treatment with a PDE10A inhibitor has schizophrenia diagnosed according to DSM-V and has suffered from persistent prominent or predominant negative symptoms for at least about 6 months.
  • the patient may have been treated with stable doses of an oral antipsychotic and with no dose increase during the last 6 months.
  • the patient has had no psychiatric admissions/hospitalization due to a clinical deterioration during the last 6 months.
  • the patient with clinically stable positive symptoms is characterized by having positive symptoms, which are not more than moderate in severity, that is a score of ⁇ 4 (moderate) out of a score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behavior (P3), Suspiciousness / opposition (P6), Uncooperativeness (G8), Unusual thought content (G9) and a score ⁇ 5 on Conceptual disorganization (P2).
  • the schizophrenic patient suitable for treatment as disclosed in the present invention has prominent or predominant negative symptoms as demonstrated by a PANSS Marder Negative Symptom Factor Score (NSFS) >20.
  • NSFS PANSS Marder Negative Symptom Factor Score
  • NSFS is the sum of scores of the following PANSS items: Blunted affect (Nl), Emotional withdrawal (N2), Poor rapport (N3), Passive/apathetic social withdrawal (N4), Lack of spontaneity & flow of conversation (N6), Motor retardation (G7) and Active social avoidance (G16).
  • the schizophrenic patient suitable for treatment as disclosed in the present invention has a Clinical Global Impression-Schizophrenia Severity of Illness (CGI-SCH-S) overall severity score ⁇ 4.
  • CGI-SCH-S Clinical Global Impression-Schizophrenia Severity of Illness
  • the treatment effect on the negative symptoms by administration of a PDE10A inhibitor as described in the present invention can be assessed by e.g. a statistically significant change in Negative Symptom Scale (BNSS) total score after 12 weeks of treatment compared to placebo.
  • the BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit).
  • the BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale.
  • the BNSS total scores ranges from 0 to 78.
  • the PDE10A inhibitors of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • such salts may be prepared by treating a solution or suspension of the free base of the PDE10A inhibitor with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described below.
  • Pharmaceutically acceptable salts in the present context is intended to indicate non-toxic, i.e. physiologically acceptable salts.
  • the term pharmaceutically acceptable salts includes salts formed with inorganic and/or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, adipic acid, nitrous acid, sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid.
  • di- or tri-acids i.e. acids containing two or three acidic hydrogens, such as phosphoric acid, sulphuric acid, fumaric acid and maleic acid.
  • Di- and tri-acids may form 1:1, 1:2 or 1:3 (tri-acids) salts, i.e. a salt formed between two or three molecules of the compound of the present invention and one molecule of the acid.
  • the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, arrest, partially arrest, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of a PDE10A inhibitor.
  • An amount adequate to accomplish this is defined as “therapeutically effective amount”. Effective amounts for each purpose will depend on the severity of the symptoms as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, which is all within the ordinary skills of a trained physician.
  • treatment or “treating” is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the negative symptoms and/or cognitive dysfunctions.
  • the treatment period is at least one week, at least two weeks, at least four weeks, at least six weeks, at least eight weeks, at least 10 weeks or at least twelve weeks.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (e.g. subcutaneous, intramuscular, and intravenous) route; the oral route being preferred.
  • suitable route such as the oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (e.g. subcutaneous, intramuscular, and intravenous) route; the oral route being preferred.
  • compositions and excipients The present invention also provides new use of pharmaceutical composition comprising one or more PDE10A inhibitors.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable excipients in accordance with conventional techniques such as those disclosed in Remington, The Science and Practice of Pharmacy, 22 th edition (2012), Edited by Allen, Loyd V., Jr.
  • excipient or “pharmaceutically acceptable excipient” refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.
  • compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups as well as powders and granules to be dissolved or suspended in an appropriate liquid.
  • Solid oral dosage forms may be presented as discrete units (e.g. tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably one or more suitable excipients.
  • the solid dosage forms may be prepared with coatings such as enteric coatings or they may be formulated so as to provide modified release of the active ingredient such as delayed or extended release according to methods well known in the art.
  • the solid dosage form may be a dosage form disintegrating in the saliva, such as for example an orodispersible tablet.
  • excipients suitable for solid oral formulation include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatine, pectin, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • the solid formulation may include excipients for delayed or extended release formulations known in the art, such as glyceryl monostearate or hypromellose.
  • the formulation may for example be prepared by mixing the active ingredient with solid excipients and subsequently compressing the mixture in a conventional tableting machine; or the formulation may for example be placed in a hard capsule e.g. in powder, pellet or mini tablet form.
  • the amount of solid excipient will vary widely but will typically range from about 25 mg to about 1 g per dosage unit.
  • Liquid oral dosage forms may be presented as for example elixirs, syrups, oral drops or a liquid filled capsule. Liquid oral dosage forms may also be presented as powders for a solution or suspension in an aqueous or non-aqueous liquid.
  • excipients suitable for liquid oral formulation include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol, poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palm oil, and water.
  • Liquid oral dosage forms may for example be prepared by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.
  • excipients may be used in solid and liquid oral formulations, such as colourings, flavourings and preservatives etc.
  • compositions for parenteral administration include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion as well as sterile powders to be reconstituted in sterile solutions or dispersions for injection or infusion prior to use.
  • excipients suitable for parenteral formulation include, but are not limited to water, coconut oil, palm oil and solutions of cyclodextrins.
  • Aqueous formulations should be suitably buffered if necessary and rendered isotonic with sufficient saline or glucose.
  • compositions include suppositories, inhalants, creams, gels, dermal patches, implants and formulations for buccal or sublingual administration.
  • the PDE10A inhibitors of the present invention are administered in an amount from about 0.001 mg/kg body weight to about 100 mg/kg body weight per day.
  • daily dosages may be in the range of 0.01 mg/kg body weight to about 50 mg/kg body weight per day. The exact dosages will depend upon the frequency and mode of administration, the sex, the age the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art.
  • a typical oral dosage for adults will be in the range of 0.1-1000 mg/day of a compound of the present invention, such as 1-500 mg/day, 1-100 mg/day, 1-50 mg/day, 1-10 mg/day, 2 mg/day, 3 mg/day, 4 mg/day, 5, mg/day or 6 mg/day.
  • the PDE10A inhibitors of the invention are administered in a unit dosage form containing said compounds in an amount of about 0.1 to 500 mg, such as, 2 mg, 3 mg, 4 mg, 5, mg, 6 mg, 10 mg, 50 mg 100 mg, 150 mg, 200 mg, 250 mg or 500 mg.
  • the first embodiment is denoted El
  • the second embodiment is denoted E2 and so forth.
  • a PDE10A inhibitor for use in treating a patient suffering from negative symptoms provided that said PDE10A inhibitor is administered as monotherapy.
  • a PDE10A inhibitor for use in treating a patient suffering from persistent negative symptoms provided that said PDE10A inhibitor is administered as monotherapy.
  • a PDE10A inhibitor for use in treating a patient suffering from prominent negative symptoms provided that said PDE10A inhibitor is administered as monotherapy.
  • a PDE10A inhibitor for use in treating a patient suffering from persistent prominent negative symptoms provided that said PDE10A inhibitor is administered as monotherapy.
  • a PDE10A inhibitor for use in treating a patient suffering from predominant negative symptoms provided that said PDE10A inhibitor is administered as monotherapy.
  • a PDE10A inhibitor for use in treating a patient suffering from persistent predominant negative symptoms provided that said PDE10A inhibitor is administered as monotherapy.
  • any of the preceding embodiments, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.
  • a PDE10A inhibitor for use in treating a patient suffering from cognitive impairments provided that said PDE10A inhibitor is administered as monotherapy.
  • E12. A PDE10A inhibitor for use according to any of the preceding embodiments, wherein the patient suffers from schizophrenia.
  • E15 A PDE10A inhibitor for use according to embodiment 14, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.
  • E16 A PDE10A inhibitor for use according to any of the preceding embodiments, wherein the patient suffers from deficit schizophrenia.
  • a PDE10A inhibitor for use according to any of the preceding embodiments wherein the patient suffers from schizotypal personality disorder or schizoaffective disorder.
  • E19. A PDE10A inhibitor for use according to any of embodiments 1-10, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.
  • E20 A PDE10A inhibitor for use according to any of embodiments 1-10, wherein the patient is not diagnosed with schizophrenia.
  • a method of treating a patient suffering from negative symptoms comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.
  • a method of treating a patient suffering from persistent negative symptoms comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.
  • a method of treating a patient suffering from prominent negative symptoms comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.
  • a method of treating a patient suffering from persistent prominent negative symptoms comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.
  • a method of treating a patient suffering from predominant negative symptoms comprising the administration of a therapeutically effective amount of a PDE10A to a patient in need thereof as monotherapy.
  • a method of treating a patient suffering from persistent predominant negative symptoms comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.
  • E27 A method of treating a patient according to any of embodiments 21-26, wherein the negative symptoms are primary negative symptoms.
  • E28. A method of treating a patient according to any of embodiments 21-27, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • E29 A method of treating a patient according to any of embodiments 21-28, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.
  • a method of treating a patient suffering from cognitive impairments comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof as monotherapy.
  • E35 A method of treating a patient according to embodiment 34, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.
  • E36 A method of treating a patient any of embodiments 21-35, wherein the patient suffers from deficit schizophrenia or residual schizophrenia.
  • E37 A method of treating a patient according to any of embodiments 21-35, wherein the patient suffers from simple schizophrenia or simple type schizophrenia.
  • E39 A method of treating a patient according to any of embodiments 21-31, wherein the patient displays psychosis risk syndrome and/or prodrome of schizophrenia.
  • E40 A method of treating a patient according to any of embodiments 21-31, wherein the patient is not diagnosed with schizophrenia.
  • E46 Use of a PDE10A inhibitor in the manufacture of a medicament for the treatment of persistent predominant negative symptoms, provided that said compound is administered as monotherapy.
  • E47 Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-46, wherein the negative symptoms are primary negative symptoms.
  • E48 Use of a PDE10A inhibitor in the manufacture of a medicament according to any of embodiments 41-47, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • a PDE10A inhibitor in the manufacture of a medicament according to embodiment 50, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.
  • E54 Use of a PDE10A inhibitor in the manufacture of a medicament according to embodiment 53, wherein the schizophrenic patient is in a clinical stable phase with respect to the patient's positive symptoms.
  • E55 Use of a PDE10A inhibitor in the manufacture of a medicament according to embodiment 54, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.
  • E63 Any of embodiments 1-60 and 62, wherein the PDE10A inhibitor is administered by the oral route in a therapeutically effective amount.
  • E64 Any of the preceding embodiments, wherein the PDE10A inhibitor is administered in a dose between 0.1 - 15 mg/day.
  • E73 Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Clinical Global Impression - Schizophrenia (CGI-SCH-DC) negative symptom score.
  • CGI-SCH-DC Clinical Global Impression - Schizophrenia
  • E74 Any of the preceding embodiments, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in Calgary Depression Scale for Schizophrenia (CDSS) total score.
  • CDSS Calgary Depression Scale for Schizophrenia
  • E76 A PDE10A inhibitor for use in the treatment of 22qll.2 deletion syndrome.
  • a PDE10A inhibitor for use in the treatment of a neurological disorder such as Alzheimer's disease and other dementias, such as frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI).
  • a neurological disorder such as Alzheimer's disease and other dementias, such as frontotemporal dementia (FTD), Huntington's disease, Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI).
  • E78 A PDE10A inhibitor for use in the treatment of apathy and/or cognitive impairments associated with Alzheimer's disease or Parkinson's disease.
  • PDE10A inhibitor has an IC50 ⁇ 5 nM.
  • PDE10A inhibitor is selected from the group consisting of compound (I), compound (II), MP-10, or a pharmaceutically acceptable salt of any of said compounds:
  • PDE10A inhibitor is a pharmaceutically acceptable salt of Compound (I), which is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo-glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of Compound (I):
  • a PDE10A inhibitor for use in the treatment of persistent negative symptoms in a patient suffering from schizophrenia wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • E91. A PDE10A inhibitor for use in treatment of prominent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • a PDE10A inhibitor for use in treating cognitive impairments in a patient suffering from schizophrenia wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • a PDE10A inhibitor for use according to embodiment 97 wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.
  • E99. A PDE10A inhibitor for use according to any of embodiments 90-98, wherein the clinical stable positive symptoms are defined by the positive symptoms not surpassing moderate severity.
  • E101 A PDE10A inhibitor for use according to either of embodiments 99-100, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring hospitalization within the last 6 months.
  • E102 A PDE10A inhibitor for use according to any of embodiments 99-101, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring change in antipsychotic medication within the last 6 months.
  • E103 A PDE10A inhibitor for use according to any of embodiments 90-102, wherein the negative symptoms are primary negative symptoms.
  • E104 A PDE10A inhibitor for use according to any of embodiments 90-103, wherein the patient suffers from deficit schizophrenia or residual schizophrenia.
  • E105 A PDE10A inhibitor for use according to any of embodiments 90-103, wherein the patient suffers from simple schizophrenia or simple type schizophrenia.
  • E108. A PDE10A inhibitor for use according to embodiment 104, wherein the patient with negative symptoms are further characterized by having a PANSS Marder Negative Symptom Factor Score >20.
  • E109 A PDE10A inhibitor for use according to any of embodiments 90-108, wherein the patient to be treated has not previously been treated with an antipsychotic drug.
  • E114 A PDE10A inhibitor for use according to embodiment 113, wherein said PDE10A inhibitor is effective in treating the negative symptoms as quantified by a clinically relevant change in BNSS score.
  • E115 A PDE10A inhibitor for use according to embodiment 113, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by a clinically relevant change in PANSS score.
  • E116. A PDE10A inhibitor for use according to any of embodiments 90-115, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within 24 weeks of regularly administration of said PDE10A inhibitor.
  • PDE10A inhibitor for use according to embodiment 117, wherein said PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof:
  • E122 A method of treating persistent negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.
  • E123 A method of treating prominent negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.
  • E124 A method of treating persistent prominent negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.
  • E125 A method of treating predominant negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.
  • E126 A method of treating persistent predominant negative symptoms in a patient suffering from schizophrenia, comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.
  • E127 A method of treatment according to any of embodiments 122-126, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • E128 A method of treatment according to embodiments 127, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.
  • a method of treating cognitive impairments in a patient suffering from schizophrenia comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.
  • E130 A method of treatment according to embodiment 129, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.
  • E132 A method of treatment according to embodiment 131, wherein the clinical stable positive symptoms are defined by a score of ⁇ 4 out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness/persecution (P6),
  • E134 A method of treatment according to any of embodiments 131-133, wherein said patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring change in antipsychotic medication within the last 6 months.
  • E135. A method of treatment according to any of embodiments 122-134, wherein the negative symptoms are primary negative symptoms.
  • E136 A method of treatment according to any of embodiments 122-135, wherein said patient suffers from deficit schizophrenia or residual schizophrenia.
  • E137 A method of treatment according to any of embodiments 122-135, wherein said patient suffers from simple schizophrenia or simple type schizophrenia.
  • E138 A method of treatment according to any of embodiments 122-135, wherein said patient suffers from schizotypal personality disorder or schizoaffective disorder.
  • E139 A method of treatment according to any of embodiments 122-138, wherein said patient's negative symptoms are at least moderate in severity.
  • E140 A method of treatment according to embodiment 139, wherein said patient with negative symptoms are further characterized by having a PANSS Marder Negative Symptom Factor Score >20.
  • E141 A method of treatment according to any of embodiments 122-140, wherein said patient to be treated has not previously been treated with an antipsychotic drug.
  • E142 A method of treatment according to any of embodiments 122-140, wherein said patient to be treated is currently treated with an antipsychotic drug, and wherein the patient is switched to treatment with a PDE10A inhibitor administered as monotherapy.
  • E144 A method of ameliorating negative symptoms and/or delaying the onset of psychosis in a patient displaying prodrome of schizophrenia comprising the administration of a therapeutically effective amount of a PDE10A inhibitor to said patient as monotherapy and wherein said patient has clinically stable positive symptoms.
  • E145 A method of treatment according to any of embodiments 122-144, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in the relevant score on any clinically valid scale to assess such symptoms.
  • E146 A method of treatment according to embodiment 145, wherein said PDE10A inhibitor is effective in treating the negative symptoms as quantified by a clinically relevant change in BNSS score.
  • E147 A method of treatment according to embodiment 145, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by a clinically relevant change in PANSS score.
  • E148 A method of treatment according to any of embodiments 122-147, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within 24 weeks of regularly administration of said PDE10A inhibitor.
  • said PDE10A inhibitor is selected from the group consisting of compound (I), compound (II) and MP-10, or a pharmaceutically acceptable salt of any of said compounds:
  • E151 A method of treatment according to embodiment 150, wherein said pharmaceutically acceptable salt is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate,
  • E152 A method of treatment according to any of embodiments 122-151, wherein said PDE10A inhibitor is administered in a pharmaceutical composition.
  • PDE10A inhibitor in the manufacture of a medicament for treatment of persistent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • PDE10A inhibitor in the manufacture of a medicament for treatment of prominent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • PDE10A inhibitor in the manufacture of a medicament for treatment of persistent prominent negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • PDE10A inhibitor in the manufacture of a medicament for treatment of predominant negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • E158 Use of a PDE10A inhibitor in the manufacture of a medicament for treatment of persistent predominant negative symptoms in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • E159 Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-159, wherein the negative symptoms are selected from the group consisting of: alogia, amotivation, anhedonia, asociality, emotional withdrawal, social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking, affective flattening, avolition, dysphoric mood, lack of insight, and demoralisation.
  • E160 Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 159, wherein the negative symptoms are selected from the group consisting of: social withdrawal, anhedonia and avolition.
  • PDE10A inhibitor in the manufacture of a medicament for treatment of cognitive impairments in a patient suffering from schizophrenia, wherein said PDE10A inhibitor is administered as monotherapy and wherein the patient has clinically stable positive symptoms.
  • a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 161, wherein the cognitive impairment is selected from the group consisting of: impaired executive functioning, impaired working memory and attention deficits.
  • PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 163, wherein the clinical stable positive symptoms are defined by a score of ⁇ 4 out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness/persecution (P6), Uncooperativeness (G8), and Unusual thought content (G9).
  • PANSS items Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness/persecution (P6), Uncooperativeness (G8), and Unusual thought content (G9).
  • E165 Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to either of embodiments 163-164, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring hospitalization within the last 6 months.
  • E166 Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 163-165, wherein the patient with clinical stable positive symptoms are defined by having had no acute exacerbation requiring change in antipsychotic medication within the last 6 months.
  • E168 Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-167, wherein the patient suffers from deficit schizophrenia or residual schizophrenia.
  • E170 Use of a PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-167, wherein the patient suffers from schizotypal personality disorder or schizoaffective disorder.
  • E176 Use of a PDE10A inhibitor in the manufacture of a medicament for ameliorating negative symptoms and/or for prophylactic treatment delaying the onset of psychosis in a patient displaying prodrome of schizophrenia.
  • PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-176, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by the change in the relevant score on any clinically valid scale to assess such symptoms.
  • PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 177, wherein said PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions as quantified by a clinically relevant change in PANSS score.
  • PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-179, wherein the PDE10A inhibitor is effective in treating the negative symptoms and/or the cognitive dysfunctions and the treatment effect has commenced within 24 weeks of regularly administration of said PDE10A inhibitor.
  • PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiments 154-180, wherein said PDE10A inhibitor is selected from the group consisting of compound (I), compound (II) and MP-10, or a pharmaceutically acceptable salt of any of said compounds:
  • PDE10A inhibitor in the manufacture of a medicament for treatment according to any of embodiment 181, wherein said PDE10A inhibitor is compound (I) or a pharmaceutically acceptable salt thereof:
  • a PDE10A inhibitor in the manufacture of a medicament for treatment according to embodiment 182, wherein said pharmaceutically acceptable salt is selected from the group comprising: the hemiadipate, hydrogen bromide, hydrogen chloride, dihydrogen phosphate, hydrogen sulphate, citrate, fumarate, hemifumarate, D-glucoronate, glutarate, 2-oxo-glutarate, L(-)-malate, maleate, malonate, mesylate, oxalate, hemi-succinate, L(+)-tartrate, and tosylate salt of Compound (I):
  • PDE10A inhibitors are known to reduce this conditioned avoidance response and hence, expected to have effective antipsychotic activity Patients with exacerbated positive symptoms can be expected to have increased striatal dopamine levels and since the dopamine receptors regulate the dopamine signal by controlling cAMP synthesis and PDE10A regulates the gain of this signal by controlling cAMP degradation, the effect of PDE10A inhibition might be altered in conditions with increased striatal dopamine tonus, such as found in patients with strong positive symptoms.
  • Figure 1 shows the effect of PDE10A inhibitors in the Conditioned Avoidance Response (CAR) assay in Rats as further described in example 1.
  • CAR Conditioned Avoidance Response
  • the compounds were tested alone and in combination with a low dose d-amphetamine to induce a h igh dopamine state.
  • the efficacy was measured as the mean number of avoidances and results are depicted as mean +/- SEM.
  • PDE10A inhibitors dosed alone reduced CAR as expected, but when combined with d-amphetamine, this effect was abolished. This suggests that the antipsychotic efficacy of PDE10A inhibitors is likely reduced in a high dopamine state.
  • A: Effect of Compound (I) alone and in combination with low dose d-amphetamine. Bars represent the following dose groups (left to right): 1) Vehicle; 2) d-amphetamine (0.2 mg/kg); 3) Compound (I) (0.6 mg/kg); 4) Compound (I) (0.3 mg/kg) + d-amphetamine (0.2 mg/kg); 5) Compound (I) (0.6 mg/kg) + d- amphetamine (0.2 mg/kg); and 6) Compound (I) (3.0 mg/kg) + d-amphetamine (0.2 mg/kg). ** p ⁇ 0.01 compared to vehicle. ns non-significant.
  • Figure 2 shows the effect of PDE10A inhibition on synaptic transmission in brain slices from rat prefrontal cortex as further described in example 2. Negative symptoms and cognitive dysfunctions are believed to be associated with low dopamine activity in the prefrontal cortex, caused by reduced cortical dopamine D1 receptor signalling. This data show that PDE10A inhibition increase synaptic transmission in brain slices from rat prefrontal cortex, and hence, has potential to treat the associated negative and cognitive symptoms.
  • fEPSP normalized field excitatory postsynaptic potential
  • Example 3 - PDE10A inhibition Modulates cAMP in both Dopamine D1 and D2 Expressing Neurons of the Striatum:
  • c-Fos is known to be regulated by cAMP and thus this peptide functions as an indirect marker for cAMP levels and thereby also PDE10A activity. It was seen that c-Fos was strongly upregulated in the striatum of Compound (l)-treated animals compared to vehicle-treated animals, and this was true for both Dl- and D2-expressing MSNs of the striatum.
  • Figure 3 shows that PDE10A inhibition modulates cAMP in both dopamine Dl and D2 receptor expressing neurons of the striatum, which are both relevant to schizophrenia; Dopamine Dl receptors in the striatum are relevant for reward processing, which is perturbed in patients with negative symptoms, whereas Dopamine D2 receptor antagonism underlies the effect of current antipsychotics on positive symptoms of schizophrenia.
  • PDE10A inhibition increase c-Fos expression in both Dl (Fig 3 A, black bars) and D2 (Fig 3 B, black bars) receptor expressing neurons compared to vehicle (white bars), **** p ⁇ 0.0001 vs vehicle.
  • C-Fos is an indirect marker of neuronal activity, known to be upregulated by cAMP, hence the data show that PDE10A inhibition increase cAMP levels in Dl expressing neurons, similar to a Dl agonist, and in D2 receptor expressing neurons similar to D2 antagonists.
  • Figure 4 shows the effect of PDE10A inhibitors on social interaction deficit elicited by sub-chronic treatment with PCP as further described in example 4.
  • Social withdrawal or asociality is a core domain of negative symptomatology in schizophrenia and in animal models PCP (administered once daily for 14 days at a dose of 13 mg/kg) can induce significant deficit in social interaction as measured by mean interaction time(s) and results are depicted as mean +/- SEM.
  • These deficits in social interaction were counteracted by PDE10A inhibition and indicate that PDE10A inhibitors may be useful in the treatment of core domains of negative symptoms, such as social withdrawal.
  • Dosing groups (left to right): 1) Vehicle treated control animals (no PCP treatment); 2) sub chronic treatment with PCP + vehicle; 3) sub-chronic treatment with PCP + Compound (I) 0.02 mg/kg; 4) sub-chronic treatment with PCP + Compound (I) 0.08 mg/kg. *p ⁇ 0.05 compared to sub-chronic treatment with PCP + vehicle.
  • CMS chronic mild stress
  • FIG. 5 The chronic mild stress (CMS) model is used to assess stress-induced hedonic deficits, measured as intake of a 1% sucrose solution in rats subjected to CMS for 7 weeks. Chronic mild stress led to the expected reduction in sucrose and subsequent administration of a PDE10A inhibitor rapidly normalized the sucrose intake in a dose dependent manner. This data suggests that PDE10A inhibitors may be useful in the treatment of anhedonia. This assay is further described in example 4.
  • A This graph shows the sucrose consumption in control animals (non -stressed animals) and the effect of Compound (I) (0-10 mg/kg, p.o) or vehicle (10% cremophor, 1 mL/kg) on this parameter.
  • Dosing groups Vehicle/cremophor (open circles); Compound (1) 0.1 mg/kg (open squares); Compound (I) 0.3 mg/kg (open triangles); Compound (I) 1.0 mg/kg (closed circles); Compound (I) 10 mg/kg (closed squares).
  • Novel object recognition (NOR) in rodents is analogous in some ways to human declarative (episodic) memory, one of the cognitive domains which are abnormal in schizophrenia.
  • the NOR task is a test paradigm reflecting visual learning and recognition processing that has been compared to human cognitive tests, such as the visual paired comparison task (Rajagopal L. et al., 2014, Current Pharmaceutical Design, 20, 5104-5114).
  • Sub-chronic administration of phencyclidine (subPCP) has been shown to induce a behavioural and neurobiological syndrome in rodents upon cessation of treatment that is similar to symptoms related to schizophrenia, including cognitive dysfunctions.
  • the vehicle-treated rats spent significantly more time exploring a novel object during the 3-minute test period compared to subPCP rats (figure 6). Animals that had received PCP for 7 days prior to testing spent approximately an equal amount of time exploring both a familiar and a novel object.
  • the novel object recognition (NOR) task in rats is an in vivo assay used to mimic cognitive impairments as further described in example 5.
  • Sub-chronic administration of PCP induces a behavioural and neurobiological syndrome in rodents upon cessation of treatment that bears a remarkable similarity to some of the core symptoms in schizophrenic patients, including cognitive disruption.
  • As expected vehicle-treated rats spent significantly more time exploring a novel object compared to a familiar object, which is the natural behavior of rodents.
  • animals that has received PCP for 7 days prior to testing spent approximately an equal amount of time exploring a familiar and a novel object, which indicate a state of cognitive impairment.
  • Administration of PDE10A inhibitors significantly attenuated the PCP- induced deficits in novel object exploration time, which demonstrate that PDE10A inhibitors might be useful in the treatment of cognitive dysfunction.
  • V+V Vehicle+Vehicle
  • PCP+V PCP+Vehicle
  • PCP+0.1 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (I) 0.1 mg/kg prior to performing the NOR task
  • PCP+0.3 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (I) 0.3 mg/kg prior to performing the NOR task
  • V+V Vehicle+Vehicle
  • PCP+V PCP+Vehicle
  • PCP+0.03 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (II) 0.03 mg/kg prior to performing the NOR task
  • PCP+0.1 mg/kg represent animals that have been administered PCP for 7 days prior to testing and on the day of testing they were treated with Compound (II) 0.1 mg/kg prior
  • the clinical efficacy of the compound of the invention for treating negative symptoms, persistent negative symptoms, prominent negative symptoms, persistent prominent negative symptoms, predominant negative symptoms, persistent predominant negative symptoms and/or cognitive dysfunctions in patients can be tested by conducting a randomized double blinded placebo-controlled study. Such study may include the evaluation of the efficacy of two fixed-flexible doses (1-2 mg and 3-4 mg per day) of the PDE10A inhibitor.
  • the primary outcome measures could be the change in negative symptoms from baseline to week 12 of the study when assessment of said negative symptoms are done on a valid rating scale, such as the PANSS Marder Negative Symptom Factor score or the Brief Negative Symptom Scale (BNSS).
  • the secondary outcome measures could be the change in Personal and Social Performance (PSP) score, Positive and Negative Syndrome Scale (PANSS) total score, PANSS Marder Negative Symptom Factor score, PANSS Negative subscale score, Clinical Global Impression - Schizophrenia (CGI-SCH-S) negative symptoms score and/or Global Impression - Schizophrenia (CGI-SCH-DC) negative symptoms score between baseline and 12 weeks of treatment.
  • Patients to be included should correlate with the subpopulations of schizophrenia suitable to be treated with compounds of the invention as described herein above.
  • Such patient may be diagnosed with schizophrenia and suffers from persistent prominent or persistent predominant negative symptoms. Further, the patient is in a clinically stable phase of schizophrenia and has not more than moderate severity on relevant positive symptoms, which may be selected from delusions, hallucinatory behavior, suspiciousness/persecution, uncooperativeness, unusual thought content and conceptual disorganization.
  • a positive response in treatment could e.g. be defined as at least 10, 20, 30 or 40% decrease in negative symptoms and/or cognitive impairments, when measured on a validated scale (such as BNSS total score or any of the other suitable scales, such as those mentioned herein above and in the description of the present invention), between baseline and 12 or 24 weeks of treatment or between treatment and placebo at 12 or 24 weeks.
  • a validated scale such as BNSS total score or any of the other suitable scales, such as those mentioned herein above and in the description of the present invention
  • PDE10A inhibitor low dose (1-2 mg/day), tablet, once daily, 12 or 24 weeks
  • PDE10A inhibitor low dose (3-4 mg/day), tablet, once daily, 12 or 24 weeks 3. Placebo, tablet, once daily, 12 or 24 weeks Inclusion Criteria
  • the patient has schizophrenia, diagnosed according to DSM-5 ® as confirmed by the Mini- International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders Studies (MINI- Schz).
  • the patient is in a clinically stable phase of schizophrenia and has not more than moderate severity on relevant positive symptoms, that is a score of ⁇ 4 (moderate) out of score of 7 on each of the following PANSS items: Delusions (PI), Hallucinatory behaviour (P3), Suspiciousness / opposition (P6), Uncooperativeness (G8), Unusual thought content (G9) at Screening Visit 1, Washout Visit(s), Screening Visit 2, and Baseline Visit and a score ⁇ 5 on Conceptual disorganization (P2).
  • PI Delusions
  • P3 Hallucinatory behaviour
  • P6 Suspiciousness / opposition
  • Uncooperativeness G8
  • Unusual thought content G9
  • NSFS Marder Negative Symptom Factor Score
  • Nl Blunted affect
  • N2 Emotional withdrawal
  • N3 Poor rapport
  • N4 Passive/apathetic social withdrawal
  • N6 Lack of spontaneity & flow of conversation
  • G7 Motor retardation
  • G16 Active social avoidance
  • CGI-SCH-S Clinical Global Impression-Schizophrenia Severity of Illness
  • the patient does not currently have a diagnosis of Major Depressive Disorder or have depressive symptoms rated with a total score >5 on the Calgary Depression Scale for Schizophrenia (CDSS). « The patient has no history of violent behaviour for the last 12 months prior to Screening Visit 1.
  • the patient has a caregiver or an identified responsible person (for example, partner, family member, social worker, case worker, or nurse) considered reliable by the investigator in providing support to the patient to ensure compliance with study treatment, outpatient visits, and protocol procedures.
  • a caregiver or an identified responsible person for example, partner, family member, social worker, case worker, or nurse
  • the patient has had an acute exacerbation requiring change in antipsychotic medication (with reference to drug or dose) within the last 6 months prior to Screening Visit 1.
  • the patient has a current diagnosis or a history of substance use disorder according to DSM-5 ® criteria within 6 months prior to Screening Visit 1 with the exception of tobacco, or mild cannabis or mild alcohol use disorder (occasional - but not weekly recreational cannabis use is acceptable).
  • Patients with a positive drug screen test for opiates, methadone, cocaine, amphetamines [including ecstasy], barbiturates, verified by repeated testing, are excluded from the study. •
  • the patient is at significant risk of harming himself/herself or others in the investigator's opinion.
  • the patient has tested positive for hepatitis A virus antibody (anti-FIAV IgM), hepatitis B surface antigen (H BsAg), or hepatitis C virus antibody (anti-HCV). If the anti-FICV test result is positive, but acute/chronic infection is excluded with a negative FICV RNA test patient can be included in the study.
  • anti-FIAV IgM hepatitis A virus antibody
  • H BsAg hepatitis B surface antigen
  • anti-HCV hepatitis C virus antibody
  • HIV human immunodeficiency virus
  • the patient has a present condition that might compromise liver function (for example, alcohol abuse, hepatitis, hepatic insufficiency, cholestasis, haemachromatosis, deficit in alpha 1 antitrypsine, Wilson's Disease, autoimmune diseases, cirrhosis).
  • liver function for example, alcohol abuse, hepatitis, hepatic insufficiency, cholestasis, haemachromatosis, deficit in alpha 1 antitrypsine, Wilson's Disease, autoimmune diseases, cirrhosis).
  • the patient has any other disorder for which the treatment takes priority over treatment of schizophrenia or is likely to interfere with the study treatment or impair treatment compliance.
  • BNSS Negative Symptom Scale
  • the BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit).
  • the BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders. The BNSS total scores ranges from 0 to 78.
  • the PSP is a clinician-rated scale designed and validated to measure a patient's current level of social functioning.
  • the PSP consists of 4 items: socially useful activities (including work and study), personal and social relationships, self-care, and disturbing and aggressive behaviours.
  • the 4 items are assessed on a 6- point scale, from absent to very severe. Based on these assessments and their combination, individual scores are converted into a global score ranging from 1 to 100.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items. 7 items make up the positive scale (for example: delusions, conceptual disorganization and hallucinatory behaviour), 7 items make up the negative scale (for example: blunted affect, emotional withdrawal and poor rapport) and 16 items make up the general psychopathology scale (for example: somatic concern, anxiety and guilt feelings). Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe).
  • the PANSS total score is the sum of all items, and ranges from 30 to 210. Subscale scores are the sum of items within each subscale.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items.
  • CGI-SCH-S Clinical Global Impression - Schizophrenia
  • the CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • the CGI-SCH-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill).
  • the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered.
  • CGI-SCFI-DC Clinical Global Impression - Schizophrenia
  • the CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse).
  • Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.
  • the CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse).
  • Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.
  • Response defined as CGI-SCFI-DC negative symptoms 1 or 2
  • the BNSS is a brief clinician rating scale, intended to measure negative symptoms. It consists of 13 items organized into 6 subscales: anhedonia, distress, asociality, avolition, blunted affect and alogia. The items score the impairment. Items 1 to 4 are rated from 0 (Normal) to 6 (Extremely severe) and items 5 to 13 are rated from 0 (No impairment) to 6 (Severe deficit).
  • the BNSS total score is calculated by summing the 13 individual items; subscale scores are calculated by summing the individual items within each subscale. Users of the BNSS should have training in psychiatric interview techniques and have clinical experience working with patients with schizophrenia and related psychotic disorders.
  • the BNSS total scores ranges from 0 to 78. Response criteria defined as 20, 30 or 40% decrease in BNSS total score.
  • the PANSS is a clinician rated scale designed to measure severity of psychopathology in adult patients with schizophrenia, schizoaffective disorders and other psychotic disorders. It emphasizes positive and negative symptoms.
  • the PANSS includes 3 sub-scales and 30 items
  • CGI-SCH-S Clinical Global Impression - Schizophrenia
  • the CG l-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CG l-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • the CGI-SCH-S severity of illness category symptoms and overall severity are rated on a 7-point scale ranging from 1 (normal - not ill) to 7 (Among the most severely ill). For the first four ratings (positive, negative, depressive, and cognitive symptoms), the assessment should focus on the severity of symptoms only. Additionally, for 'overall severity' rating, both severity of symptoms and interference with functioning should be considered.
  • CGI-SCH-DC Clinical Global Impression - Schizophrenia
  • the CGI-SCH is a clinician-rated scale to assess global illness severity and degree of change in patients with schizophrenia.
  • the CGI-SCH consists of four different groups of symptoms (positive, negative, cognitive and depressive) and the overall severity of the disorder.
  • category symptoms and overall severity are rated on a 7- point scale ranging from 1 (very much improved) to 7 (very much worse). Each single rating (conditions of severity and degree of improvement) and overall ratings of severity and improvement are scored independently and no total score is derived.
  • CDSS Calgary Depression Scale for Schizophrenia
  • the CDSS is a 9-item clinician rated scale specifically developed for the assessment of depression in patients with schizophrenia.
  • the items on the CDSS are all typical depressive symptoms and do not appear to overlap with the negative symptoms of schizophrenia. All items are rated on a 4-point scale from 0 (absent) to 3 (severe).

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Abstract

La présente invention concerne des inhibiteurs de PDE10A et des compositions comprenant des inhibiteurs de PDE10A pour traiter des symptômes négatifs, des symptômes négatifs persistants, des symptômes négatifs proéminents, des symptômes négatifs proéminents persistants, des symptômes négatifs prédominants, des symptômes négatifs prédominants persistants et/ou des dysfonctionnements cognitifs dans la schizophrénie.
PCT/EP2019/080151 2018-11-06 2019-11-05 Inhibiteurs de pde10a pour le traitement de symptômes négatifs et de troubles cognitifs chez un patient souffrant de schizophrénie WO2020094591A1 (fr)

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WO2022060978A1 (fr) * 2020-09-16 2022-03-24 Matador Therapeutics, Inc. Méthodes de traitement de la maladie de parkinson et de troubles apparentés avec des inhibiteurs de pde10a

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WO2022060978A1 (fr) * 2020-09-16 2022-03-24 Matador Therapeutics, Inc. Méthodes de traitement de la maladie de parkinson et de troubles apparentés avec des inhibiteurs de pde10a

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