Patent Application
20190216793
The present disclosure in some embodiments relates generally to compositions and methods for treating negative symptoms, and more specifically to treating negative symptoms in patients who do not have a clinical diagnosis of schizophrenia, i.e., non-schizophrenic patients.
Negative symptoms generally refer to a reduction in normal functioning, and include five major sub-domains: blunted affect (affective flattening, blunted expression), alogia (poverty of speech), amotivation (loss of volition), anhedonia (reduced ability to experience or anticipate pleasure) and asociality (social withdrawal). While negative symptoms are a well-documented and intensively studied aspect of schizophrenia, this class of symptoms has been identified in patients with other psychiatric and neurological disorders, including, for example, Alzheimer's disease and other dementias, particularly frontotemporal dementia (FTD), autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, stroke, and traumatic brain injury (TBI) (see, e.g., Boone et al, J. of Internat. Neuropsycol. Soc., 2003, Vol 9, pages 698-709; Bastiaansen, J. et al., J. Autism Dev. Disord. 2011, Vol 41:1256-1266; Getz, K. et al., Am. J. Psychiatry 2002, Vol 159:644-651; Winograd-Gurvich, C. et al., Brain Res. Bulletin, 2006, Vol. 70:312-321; Galynker et al., Neuropsychiatry Neuropsychol Behav Neurol 2000, Vol 13:171-176; Galynker I, et al., J. Nerv. Ment. Dis 1997, Vol 185:616-621; Chaudhury, S., et al., Indian J. of Neurotrauma 2005, Vol 2:13-21; Ameen, S et al., German J. of Psychiatry 2007). Indeed, as early as 2001, it was proposed that negative symptoms are common to mental illnesses generally (Herbener and Harrow, Schizophrenia Bulletin 2001, Vol. 27:527-537). Furthermore, reports of several population studies have concluded that between 20-22% of the general population have one or more negative symptoms, and that the majority of subjects with negative symptoms do not exhibit a clinical diagnosed psychiatric disorder (Werbeloff, N. et al., PLoS ONE 2015, Vol 10:e0119852; Barrantes-Vidal, N., et al., Schizophr. Res. 2010, Vol 122:219-225).
At present, no effective treatments have been approved to treat negative symptoms in schizophrenia or in any other mental disease or neurological condition.
The present disclosure is based, in part, on the results of a prospective Phase IIb, 12-week, randomized, double-blind, placebo-controlled parallel clinical trial, which demonstrated a statistically significant benefit of 32 mg and 64 mg doses of MIN-101 over placebo in improving negative symptoms in a cohort of 244 schizophrenic patients with negative symptoms. During this 12-week trial, positive symptoms remained stable and extrapyramidal symptoms (EPS) were absent, consistent with the notion that MIN-101 has a direct and specific effect on negative symptoms rather than improvements on other symptoms. MIN-101 is under clinical development by Minerva Neurosciences (Waltham, Mass.) for the treatment of negative symptoms in schizophrenia.
The active compound in MIN-101 (previously known as CYR-101 and MT-210) has the chemical name 2-{1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one monohydrochloride dihydrate. The structure of the free base is the compound of formula I (Compound I):
Compound I has specific affinities for sigma2, 5-hydroxytryptamine-2A (5-HT2A) and at lower affinity levels, α1-adrenergic receptors. MIN-101 exhibits very low or no affinity for other receptors including dopaminergic, muscarinic, cholinergic, and histaminergic receptors. In vivo functional studies have established that MIN-101 is an antagonist at both 5-HT2A and sigma2 receptors. Two main metabolites of Compound I have been identified and named BFB-520 and BFB-999. The BFB-520 metabolite has been associated with prolongation of QT intervals at supra-therapeutic levels.
In one aspect, the disclosure provides a composition comprising a compound of formula (I) (Compound I), or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, for use in a method of treating at least one negative symptom in a non-schizophrenic human subject, wherein the method which comprises orally administering a therapeutically effective amount of the composition to the subject. In an embodiment, the composition is formulated for oral delivery and the therapeutically effective amount is a total daily dose of Compound I of between about 1 mg to about 64 mg. In an embodiment, the therapeutically effective amount is a total daily dose of Compound I of between about 10 mg to about 64 mg, 20 mg to about 64 mg, or about 30 mg to about 64 mg. In an embodiment, the therapeutically effective amount is a total daily dose of Compound I of about 8 mg, about 16 mg, about 32 mg or about 64 mg.
In another aspect, the disclosure provides a method of treating at least one negative symptom in a non-schizophrenic human subject, wherein the method comprises administering to the subject a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. In an embodiment, the method comprises orally administering a total daily dose of Compound I of between about 1 mg and about 64 mg. In an embodiment, the total daily dose of Compound I is between about 10 mg to about 64 mg, 20 mg to about 64 mg, or about 30 mg to about 64 mg. In an embodiment, the total daily dose of Compound I is about 8 mg, about 16 mg, about 32 mg or about 64 mg.
In both aspects of the disclosure, the negative symptom to be treated is a primary negative symptom rather than a secondary negative symptom. In an embodiment, the primary negative symptom is selected from the group consisting of: blunted affect, alogia, amotivation, anhedonia and asociality. In an embodiment, the primary negative symptom is selected from the group consisting of: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking.
In some embodiments of any of the above aspects of the disclosure, the non-schizophrenic patient is diagnosed with a mental disorder or a neurological condition. In an embodiment, the mental disorder or neurological condition is selected from the group consisting of: dementia, frontotemporal dementia (FTD), Alzheimer's disease, autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), borderline personality disorder, Parkinson's disease, temporal lobe epilepsy, post-cerebrovascular accident (CVA), traumatic brain injury (TBI), post brain trauma syndrome, mild to moderate mental retardation, viral encephalitis, and drug addiction. In an embodiment, the disorder or condition is FTD or Alzheimer's disease. In an embodiment, the disorder or condition is MDD or BPD. In an embodiment, the disorder or condition is Parkinson's disease.
In some embodiments of any of the above aspects of the disclosure, Compound I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered to the subject for a first treatment period of sufficient length to achieve improvement in at least one negative symptom. In an embodiment, the first treatment period is at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks or at least 12 weeks.
In some embodiments of any of the above aspects of the disclosure, if a subject experiences improvement in at least one negative symptom during the first treatment period, then administration of the therapeutically effective dose of Compound I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is continued for a second treatment period of at least 12 weeks, at least 24 weeks, at least 48 weeks or until the subject is determined to be in remission from the negative symptoms.
In some embodiments of any of the above aspects of the disclosure, Compound I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered in a single dose in the morning or evening. In an embodiment, Compound I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof is administered at least two hours before eating.
In some embodiments of any of the above aspects of the disclosure, a polymorph of Compound I is administered to the subject. In an embodiment, the polymorph is known as Form (A) of Compound (I)·HCl·2H2O (also referred to herein as Form (A)) and has the characteristics described in the international patent application PCT/US2015/062985 (published as WO 2016/089766) and US patent application U.S. Ser. No. 14/954,264 (published as US 2016-0152597 A1), each of which was filed on 30 Nov. 2015, the contents of which are incorporated by reference in their entirety.
In some embodiments of any of the above aspects of the disclosure, Compound I or polymorph Form (A) is administered as part of a pharmaceutical composition which comprises a release modifier that provides a maximum plasma concentration (Cmax) of Compound (I) or polymorph Form (A) below 50 ng/mL when a dose of about 1 mg to about 64 mg of the formulation is administered to a human. In an embodiment, the pharmaceutical composition provides a maximum plasma concentration (Cmax) for the BFB-520 metabolite of below 10.0 ng/mL, below 5.0 ng/mL, below 4.5 ng/mL, below 4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, below 2.5 ng/mL, below 2.0 ng/mL, below 1.5 ng/mL, or below 1.0 ng/mL and an area under the curve (AUC) of BFB-520 below 40 hr*ng/mL, below 35 hr*ng/mL, below 30 hr*ng/mL, below 25 hr*ng/mL, below 20 hr*ng/mL, below 15 hr*ng/mL, or below 10 hr*ng/mL.
In some embodiments of any of the above aspects of the disclosure, the human subject is at least 18 years of age, while in other embodiments of any of the above aspects of the disclosure, the human subject is under 18 years of age.
In some embodiments of any of the above aspects of the disclosure, the human subject has not been previously treated with an anti-psychotic drug. In other embodiments of any of the above aspects of the disclosure, the human subject has discontinued prior treatment with an anti-psychotic drug due to experiencing an inadequate response and/or to intolerable side effects
The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended drawings.
As described in the Examples set forth below, 32 mg and 64 mg daily doses of Compound I have been shown to produce statistically significant improvement in negative symptoms in schizophrenic patients as compared to placebo. Based on these data, and the fact that Compound I antagonizes sigma2 activity, the present disclosure contemplates that similar improvement in negative symptoms will be achieved in non-schizophrenic human subjects. As used herein, a non-schizophrenic subject means the subject exhibits at least one negative symptom but has not been diagnosed with schizophrenia.
Thus, it is an object of the present disclosure to provide a method of treating at least one negative symptom in a human non-schizophrenic subject comprising administering to the subject a therapeutically effective amount of a composition comprising Compound I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof.
It is also an object of the present disclosure to provide a composition comprising Compound I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for use in treating at least one negative symptom in a human subject by a method comprising administering to the subject a therapeutically effective amount of the composition.
It is a further object of the present disclosure to employ the compositions and methods of the disclosure to treat at least one negative symptom in a human non-schizophrenic subject who is diagnosed with a mental disorder or neurological condition.
In an embodiment, the negative symptom is one of the five major sub-domains of negative symptoms: blunted affect, alogia, amotivation, anhedonia and asociality. The core characteristics of each sub-domain are described below.
Blunted affect (affective flattening, blunted expression) is characterized by reduced intensity and range of emotional expression as manifested via vocal and non-verbal modes of communication including intonation (prosody), facial expression, hand-gestures and body movements.
Alogia (poverty of speech) is characterized by decreased quantity of speech, reduced spontaneous speech and loss of conversational fluency.
Amotivation (loss of volition) is characterized by deficits in the initiation and maintenance of goal-directed behaviors like work, study, sport, personal hygiene and daily tasks, especially when requiring and effort (cognitive or physical) and significant organization, as well as deficits in desire to undertake such activities. This sub-domain is related to apathy and lack of energy.
Anhedonia (reduced ability to experience or anticipate pleasure) is characterized by the looking forward to a reward, recreational or other pleasurable experience (“wanting”) being more markedly and consistently impaired (anticipatory anhedonia) than the appreciation (“liking”) of the experience itself (consummatory anhedonia).
Asociality (social withdrawal) is characterized by diminished interest in, motivation for, and appreciation of social interactions with others, like family and friends, loss of interest in intimate (sexual) relationships independent of any somatic problems, and for a child, may include loss of interest in playing with other children.
As used herein, unless otherwise noted, the terms “treat”, “treating”, “treatment” and the like, shall include the management and care of a non-schizophrenic subject for the purpose of improving negative symptoms and include administration of Compound I in an amount and for a treatment period that are sufficient to prevent the onset of one or more negative symptoms, reduce the frequency, intensity or severity of one or more negative symptoms, delay or avoid the development of additional negative symptoms, or any combination of these treatment objectives. In an embodiment, the effect of treatment with Compound I is assessed by comparing the severity of the subject's negative symptoms at baseline (e.g., prior to treatment with Compound I) and after at least one treatment period. In an embodiment, 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.
As used herein, the terms “subject” and “patient” may be used interchangeably, and refer to a human of any age. In an embodiment, the non-schizophrenic subject is six or more years of age. In some embodiments, the subject is at least 18, 19, 20 or 21 years of age. The non-schizophrenic subject exhibits one or more negative symptoms but does not have a diagnosis of schizophrenia. In some embodiments, the non-schizophrenic subject is not diagnosed with a mental disorder or neurological condition. In other embodiments, the non-schizophrenic subject is diagnosed with a mental disorder or neurological condition.
In some embodiments, a composition or method of the disclosure is used to treat a non-schizophrenic subject who is treatment-naïve to an anti-psychotic drug. As used herein, an anti-psychotic drug is any drug that does not contain Compound I and has been approved by a regulatory agency for the treatment of psychosis. Examples of atypical antipsychotics include, but are not limited to fluphenazine, risperidone, olanzapine, clozapine, quetiapine, ziprasidone, aripiprazole, sertindole, zotepine, and perospirone.
In other embodiments, a composition or method of the disclosure is used to treat a non-schizophrenic subject who was previously treated with an antipsychotic drug but discontinued such treatment, e.g., because the drug did not provide adequate improvement in the subject's negative symptoms and/or because the subject could not tolerate the side effects of the drug.
In some embodiments, a composition or method of the disclosure is used to treat a non-schizophrenic subject who is treatment-naïve to an antidepressant drug. As used herein, an antidepressant drug is any drug that does not contain Compound I and has been approved by a regulatory agency for the treatment of major depressive disorder. Examples of antidepressants include, but are not limited to, fluoxetine, citalopram, escitalopram, venlafaxine, duloxetine, and bupropion.
In other embodiments, a composition or method of the disclosure is used to treat a non-schizophrenic subject who was previously treated with an antidepressant drug but discontinued such treatment, e.g., because the drug did not provide adequate improvement in the subject's negative symptoms and/or because the subject could not tolerate the side effects of the drug.
For purposes of the disclosure encompassed herein, the term “negative symptom” or “negative symptoms” is to be understood as including primary negative symptom(s) typically associated with schizophrenia, the negative symptom(s) measured in the PANSS negative subscale score and the negative symptom(s) measured in the BNSS.
The methods of the disclosure employ administering to the subject a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof. As used herein, the term “therapeutically effective amount” means an amount that is effective to reduce the severity of at least one negative symptom by at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% compared to baseline. Improvement in symptoms in the subject may be measured using any measurement tool generally accepted in the art, including but not limited to the PANSS negative subscale score of the pentagonal model or the Brief Negative Symptom Scale (BNSS) as described herein. In an embodiment, the therapeutically effective amount results in a reduction in the PANSS negative subscale from baseline of >20% after 2 weeks, 4 weeks, or 8 weeks of treatment.
In yet another aspect of the disclosure, a composition of the disclosure is formulated and administered to the subject in a manner that provides a dose of Compound I that is substantially equivalent to oral administration of any of the total daily doses specifically described herein. The skilled artisan can readily select formulations and administration routes that would provide such functional equivalence.
The disclosure also provides use of Compound I or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, in the manufacture of a medicament for treating at least one negative symptom in a non-schizophrenic human subject. For example, the medicament is suitable for oral administration. For example, the medicament has a therapeutically effective amount of Compound I, which corresponds to a total daily dose of Compound I of between about 1 mg to about 64 mg.
It will be understood by the skilled artisan that the treating physician may select a dose and dosing regimen within the above guidelines that he or she believes is appropriate based on the health and condition of the subject to be treated, as well as the desired outcome of the treatment. For example, the treating physician may choose to start therapy with a lower than therapeutically effective dose of Compound I and titrate up to a target therapeutically effective dose. For example, the total daily dose of Compound I may be administered in a single dose or in multiple doses.
As used herein, quantitative expressions recited as a range of from about value X to about value Y include any value that is 10% higher or lower than each of X and Y, and also includes any numerical value that falls between X and Y. Thus, for example, a dose of about 32 mg includes a dose of between 30 to 34 mg.
All references to Compound I herein include all pharmaceutically acceptable salts and all solvates and alternative physical forms thereof unless otherwise stated. All doses recited herein are based on the weight of the free base of Compound I, rather than the pharmaceutically acceptable salt, hydrate of solvate thereof or any excipients in the composition, unless otherwise stated. Further, all doses of Compound I recited herein are flat doses (e.g., not dependent on weight of the patient) unless otherwise stated.
For therapeutic administration according to the present disclosure, Compound I may be employed in the form of its free base, but is preferably used in the form of a pharmaceutically acceptable salt. In an embodiment, the form of Compound I used in the compositions and methods of the disclosure is 2-{1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one monohydrochloride dihydrate, which has a molecular formula of C22H23FN2O2, HCl, 2H2O and a molecular weight of 438.92.
Compound (I) may be synthesized using standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations, including the use of protective groups, as can be obtained from the relevant scientific literature or from standard reference textbooks in the field. Although not limited to any one or several sources, recognized reference textbooks of organic synthesis include: Smith, M. B.; March, J. March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed.; John Wiley & Sons: New York, 2001; and Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd; John Wiley & Sons: New York, 1999. A method for preparing Compound (I) is described in U.S. Pat. No. 7,166,617.
The compositions and methods of the disclosure may employ Form (A) of Compound I. Pharmaceutical compositions comprising Form (A) of Compound I may be prepared as described in international patent application PCT/US2015/062985 (published as WO 2016/089766).
In an embodiment, alternative salts of Compound I with pharmaceutically acceptable acids may also be utilized in therapeutic administration, for example salts derived from the functional free base and acids including, but not limited to, palmitic acid, hydrobromic acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, salicylic acid, citric acid, oxalic acid, lactic acid, malic acid, methanesulfonic acid and p-toluene sulfonic acid.
All solvates and all alternative physical forms of Compound I or its pharmaceutically acceptable derivatives as described herein, including but not limited to alternative crystalline forms, amorphous forms and polymorphs, are also within the scope of this disclosure, and all references to a compound of formula I herein (or Compound I) include all pharmaceutically acceptable salts, and all solvates and alternative physical forms thereof.
For therapeutic administration, Compound I or a pharmaceutically acceptable salt thereof, for example, the HCl salt, may be administered in pure form, but will preferably be formulated into any suitable pharmaceutically acceptable and effective composition which provides effective levels of the active ingredient in the body.
The term “pharmaceutically acceptable”, as used herein with respect to a compound or composition, refers to a form of the compound or composition that can increase or enhance the solubility or availability of the compound in a subject, in order to promote or enhance the bioavailability of the compound or composition. In an embodiment, the disclosure herein also encompasses pharmaceutically acceptable, hydrates, solvates, stereoisomers, or amorphous solids of the compounds and compositions embodied herein. For example, the term “pharmaceutically acceptable salt” is to describe a salt form of one or more of the compositions herein which are presented to increase the solubility of the compound, for example, in the gastric juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds and/or compositions. In an embodiment, pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of carboxylic acids and free acid phosphate containing compositions encompassed by the present disclosure. The term “salt” shall mean any salt consistent with the use of the compounds encompassed by the present disclosure. In the case where the compounds are used in pharmaceutical indications, including the treatment of depression, the term “salt” shall mean a pharmaceutically acceptable salt, consistent with the use of the compounds as pharmaceutical agents.
The term “pharmaceutically acceptable derivative” or “derivative”, as used herein, describes any pharmaceutically acceptable prodrug form (such as an ester or ether or other prodrug group) which, upon administration to a patient, provides directly or indirectly the present compound or an active metabolite of the present compound.
As set forth above, the compositions include pharmaceutically acceptable salts of the compounds in the composition. In other embodiments, the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned compounds are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3 naphthoate)] salts, among others.
In an embodiment, compositions comprise base addition salts of the present compounds. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the present compounds that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, among others.
As used herein, the term pharmaceutically acceptable salts or complexes refers to salts or complexes (e.g., solvates, polymorphs) that retain the desired biological activity of the parent compound and exhibit minimal, if any, undesired toxicological effects. Non-limiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acids, naphthalenedisulfonic acids, and polygalacturonic acid; (b) base addition salts formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with an organic cation formed from N,N-dibenzylethylene-diamine, ammonium, or ethylenediamine; or (c) combinations of (a) and (b); e.g., a zinc tannate salt or the like.
Modifications of a compound can affect the solubility, bioavailability and rate of metabolism of the active species, thus providing control over the delivery of the active species. Further, the modifications can affect the anxiolytic activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its activity according to the methods encompassed herein, or other methods known to those skilled in the art.
In an embodiment, the compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and may also be administered in controlled-release formulations. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
Compositions encompassed herein may be administered orally. In other embodiments, compositions may be administered parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, percutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. As will be understood by the skilled artisan, in view of the embodiments encompassed herein, the dosage of active ingredient or ingredients (e.g., a compound of formula I) may be adjusted upward or downward based on the selected route of administration. Furthermore, it will be understood that optimizing the dosage of active ingredient for any selected dosage form may be desired and can be achieved by using the methods described herein or known in the art to evaluate the effectiveness of anxiolytic compounds.
The pharmaceutical compositions embodied herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. In an embodiment, lubricating agents, such as magnesium stearate, are also added. For oral administration in a capsule form, useful diluents include lactose and/or dried corn starch, as two non-limiting examples. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
The pharmaceutical compositions encompassed by the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
In an embodiment, the therapeutically effective amount of Compound I is administered independently of any other medication that is indicated for the treatment of a mental disorder or neurological condition.
In another embodiment, the therapeutically effective amount of Compound I is administered in conjunction with one or more other medications to treat a co-morbid medical condition, including a mental disorder or neurological condition. Such other medications may be administered or co-administered in forms and dosages as known in the art, or in the alternative, as has been described above for administration of compounds of formula I. The other medication(s) may be administered before, after or simultaneously with Compound I during a desired treatment period.
The present disclosure includes, but is not limited to, the following embodiments.
A composition comprising a compound of formula I (Compound I);
or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, for use in a method for treating at least one negative symptom in a non-schizophrenic human subject, wherein the method comprises orally administering to the subject a therapeutically effective amount of the composition, wherein the therapeutically effective amount is a total daily dose of Compound I of between about 1 mg to about 64 mg.
The composition of embodiment 1, wherein the therapeutically effective amount is a total daily dose of Compound I of between about 10 mg to about 64 mg, 20 mg to about 64 mg, or about 30 mg to about 64 mg.
The composition of embodiment 2, wherein the therapeutically effective amount is a total daily dose of Compound I of between 30 mg to 64 mg.
The composition of embodiment 1, wherein the therapeutically effective amount is a total daily dose of Compound I of about 8 mg, about 16 mg, about 32 mg or about 64 mg.
The composition of embodiment 4, wherein the therapeutically effective amount is a total daily dose of Compound I of 32 mg.
The composition of embodiment 4, wherein the therapeutically effective amount is a total daily dose of Compound I of 64 mg.
A method of treating at least one negative symptom in a non-schizophrenic human subject, wherein the method comprises orally administering to the subject a therapeutically effective amount of Compound I, or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, wherein the therapeutically effective amount is a total daily dose of Compound I of between about 1 mg to about 64 mg.
The method of embodiment 7, wherein the total daily dose of Compound I is between about 10 mg to about 64 mg, 20 mg to about 64 mg, or about 30 mg to about 64 mg.
The method of embodiment 8, wherein the therapeutically effective amount is a total daily dose of Compound I of between 30 mg to 64 mg.
The method of embodiment 7, wherein the total daily dose of Compound I is about 8 mg, about 16 mg, about 32 mg or about 64 mg.
The method of embodiment 10, wherein the therapeutically effective amount is a total daily dose of Compound I of 32 mg.
The method of embodiment 10, wherein the therapeutically effective amount is a total daily dose of Compound I of 64 mg.
Use of a compound of formula I (Compound I);
or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, in the manufacture of a medicament for a method for treating at least one negative symptom in a non-schizophrenic human subject, wherein the method comprises orally administering to the subject a therapeutically effective amount of the composition, wherein the therapeutically effective amount is a total daily dose of Compound I of between about 1 mg to about 64 mg.
The use of embodiment 13, wherein the therapeutically effective amount is a total daily dose of Compound I of between about 10 mg to about 64 mg, 20 mg to about 64 mg, or about 30 mg to about 64 mg.
The use of embodiment 13, wherein the therapeutically effective amount is a total daily dose of Compound I of between 30 mg to 64 mg.
The use of embodiment 13, wherein the therapeutically effective amount is a total daily dose of Compound I of about 8 mg, about 16 mg, about 32 mg or about 64 mg.
The use of embodiment 16, wherein the therapeutically effective amount is a total daily dose of Compound I of 32 mg.
The use of embodiment 16, wherein the therapeutically effective amount is a total daily dose of Compound I of 64 mg.
The composition, method, or use of any one of embodiments 1 to 18, wherein the negative symptom is selected from the group consisting of: blunted affect, alogia, amotivation, anhedonia and asociality.
The composition, method, or use of any one of embodiments 1 to 18, wherein the negative symptom is selected from the group consisting of: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking.
The composition, method, or use of any one of embodiments 1 to 20, wherein the non-schizophrenic patient is diagnosed with a mental disorder or a neurological condition.
The composition, method, or use of embodiment 21, wherein the mental disorder or neurological condition is selected from the group consisting of: dementia, frontotemporal dementia (FTD), Alzheimer's disease, autism spectrum disorder (ASD), bipolar disorder (BPD), major depressive disorder (MDD), Parkinson's disease, temporal lobe epilepsy, post-cerebrovascular accident (CVA), traumatic brain injury (TBI), post brain trauma syndrome, mild to moderate mental retardation, viral encephalitis, and drug addiction.
The composition, method, or use of embodiment 22, wherein the mental disorder or neurological condition is FTD or Alzheimer's disease.
The composition, method, or use of embodiment 22, wherein the mental disorder or neurological condition is MDD or BPD.
The composition, method, or use of embodiment 22, wherein the mental disorder or neurological condition is Parkinson's disease.
The composition, method, or use of any one of embodiments 1 to 25, wherein Compound I is administered to the subject for a first treatment period of at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks or at least 12 weeks.
The composition, method, or use of embodiment 26, wherein, if a subject experiences improvement in at least one negative symptom during the first treatment period, then administration of the therapeutically effective amount of Compound I is continued for a second treatment period of at least 12 weeks, at least 24 weeks, at least 48 weeks or until the subject is determined to be in remission from the negative symptoms.
The composition, method, or use of any one of embodiments 1-27, wherein Compound I is administered in a single dose in the morning in fasting condition and at least two hours before eating.
The composition, method, or use of any one of embodiments 1 to 28, wherein the polymorph Form (A) of Compound I is administered to the subject.
The composition, method, or use of any one of embodiments 1 to 29, wherein Compound I or the polymorph Form (A) of Compound I is administered as part of a pharmaceutical composition which comprises a release modifier that provides a maximum plasma concentration (Cmax) of Compound (I) below 50 ng/mL when a dose of about 1 mg to about 64 mg of the formulation is administered to a human.
The composition, method, or use of any one of embodiments 29 to 30, wherein the pharmaceutical composition provides a maximum plasma concentration (Cmax) for the BFB-520 metabolite of below 5.0 ng/mL, below 4.5 ng/mL, below 4.0 ng/mL, below 3.5 ng/mL, below 3.0 ng/mL, below 2.5 ng/mL, below 2.0 ng/mL, below 1.5 ng/mL, or below 1.0 ng/mL and an area under the curve (AUC) of BFB-520 below 40 hr*ng/mL, below 35 hr*ng/mL, below 30 hr*ng/mL, below 25 hr*ng/mL, below 20 hr*ng/mL, below 15 hr*ng/mL, or below 10 hr*ng/mL.
The composition, method, or use of any one of embodiments 1 to 31, wherein the non-schizophrenic subject has not been previously treated with an anti-psychotic drug.
The composition, method, or use of any one of embodiments 1 to 31, wherein the non-schizophrenic subject has discontinued prior treatment with an anti-psychotic drug due to experiencing an inadequate response and/or to intolerable side effects.
The composition, method, or use of any one of embodiments 1 to 33, wherein the non-schizophrenic subject has not been previously treated with an anti-depressant drug.
The composition, method, or use of any one of embodiments 1 to 33, wherein the non-schizophrenic subject has discontinued prior treatment with an anti-depressant drug due to experiencing an inadequate response and/or to intolerable side effects.
The composition, method, or use of any one of embodiments 1 to 35, wherein the form of Compound I administered is 2-{1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-ylmethyl}-2,3-dihydroisoindol-1-one monohydrochloride dihydrate.
Below is a description of the Positive and Negative Syndrome Scale (PANSS) used in the clinical study described in the Examples.
Data gathered from this assessment procedure are applied to the PANSS ratings. Each of the 30 items is accompanied by a specific definition, as well as detailed anchoring criteria for all seven rating points. These seven points represent increasing levels of psychopathology, as follows:
In assigning ratings, one first considers whether an item is at all present, as judging by its definition. If the item is absent, it is scored 1, whereas if it is present, one must determine its severity by reference to the particular criteria from the anchoring points. The highest applicable rating point is always assigned, even if the patient meets criteria for lower points as well. In judging the level of severity, the rater must utilise a holistic perspective in deciding which anchoring point best characterises the patient's functioning and rate accordingly, whether or not all elements of the description are observed.
The rating points of 2 to 7 correspond to incremental levels of symptom severity:
Each item is rated in consultation with the definitions and criteria provided in this manual. The ratings are rendered on the PANSS rating form overleaf by encircling the appropriate number following each dimension.
Of the 30 items included in the PANSS, 7 constitute a Positive Scale, 7 a Negative Scale, and the remaining 16 a General Psychopathology Scale. The scores for these scales are arrived at by summaries of ratings across component items. Therefore, the potential ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale. In addition to these measures, a Composite Scale is scored by subtracting the negative score from the positive score. This yields a bipolar index that ranges from −42 to +42, which is essentially a difference score reflecting the degree of predominance of one syndrome in relation to the other.
Positive Scale (P)
Negative Scale (N)
General Psychopathology Scale (G)
Brief Negative Symptom Scale
Below is a description of the Brief Negative Symptom Scale (BNSS) used in the clinical study described in the Examples.
Brief Negative Symptom Scale: Manual
This rating instrument is designed to measure the current level of severity of negative symptoms in schizophrenia and schizoaffective disorder. Negative symptoms are an absence or decrease in behaviors and subjective experiences that are normally present in a person from the same culture and general age group. Negative symptoms include anhedonia, asociality, avolition, blunted affect, and alogia. Other symptoms may also belong in this group. Negative symptoms are distinct from other features of schizophrenia and related disorders, including psychotic, disorganization, mood, and anxiety symptoms, and from cognitive deficits.
The manual, which is designed for training purposes, includes description of the items, as well as probes and anchors. The Workbook, which is used when making the ratings, includes the probes and anchors only. The score sheet is a separate document.
The scale was designed for use in treatment trials, but may have other applications, including non-research clinical evaluation and tracking of change. There is no attempt to define a negative symptom subtype or syndrome in this scale. Five subscales are included, one for each of the negative symptoms listed above. There is also one other item that is not part of one of these subscales, the Distress item.
All ratings are based on a semi-structured interview with prompts and queries. It is important to include the content of the semi-structured interview as a minimum. However, you should ask any additional questions required to rate the item.
Items are rated on a 7-point (0-6) scale, with anchor points usually ranging from the symptom being absent (0) to severe (6). Ratings should be made based on the anchors, without attempting to adjust the ratings based on any expectations of how people with psychotic disorders usually perform. The time frame for the ratings is one week; ratings based on the entire lifetime of the subject are to be avoided. It may be necessary to remind the subject frequently of this timeframe. While many of the ratings in this section of the scale require self-report, observations of the subject during the interview as well as those provided by outside observers during the rating period should also be given weight, as appropriate, when generating these ratings.
For a particular item, a subject may have normal performance in some areas but clear impairment in others. In this case, a subject's rating should not be the most abnormal or the least abnormal, but an integration of the overall performance for the item; that is, the subject should receive a score that is most representative of his or her overall performance in this area. In addition, whenever there appears to be a tie between two scores on the scale, e.g. a 3 or 4, choose the lower score.
Throughout the scale, the rater should make every effort not to “carry over” ratings from one item to another within a subscale, or from one subscale to another. For instance, reduced vocal expressivity (in the Blunted Affect subscale) should not influence the rating of reduced verbal output (Poverty of Speech).
In general, ratings for Anhedonia, Asociality, and Avolition should be made on the basis of what is reasonably available to the subject. In most cases there should be some form of pleasure, socialization, and opportunities for initiative available.
I. Anhedonia Subscale
This subscale measures two different aspects of pleasure: pleasure during an activity (with intensity and frequency rated separately), and expected or anticipated pleasure from a future activity. For all three items in this subscale, consider all potential sources of pleasure to the subject, including social activities, physical sensations, recreational activities, and work/school. The rating of intensity is based on the most intense pleasure the subject has (or expects) in that area, and is based on the subject's description.
Raters should consider the pleasure associated with social activities in the Anhedonia subscale, while initiation of and persistence in social activities should be considered in the Avolition subscale.
Probe Questions: Items 1 & 2
Item 1: Intensity of Pleasure During Activities
Item 2: Frequency of Pleasure During Activities
Item 3: Intensity of Expected Pleasure from Future Activities
Probe Questions
If the subject did enjoy some activities over the past week: You said you enjoyed (list activities above). Do you expect to do any of those again soon?
If Yes: How do you think you'll feel when you do that? Are you looking forward to it?
If No: Do you want to do that again? Is there something else you would enjoy doing? (If yes: How do you think you'll feel when you do that?)
If the subject did not enjoy any activities in the past week: Are there any activities that you are looking forward to? Is there anything else you'd look forward to doing?
Some subjects may have difficulties understanding the concept of expected pleasure that is the basis of this item. This may be due to cognitive impairment, a global lack of pleasure, or some other reason. If the subjects can't understand the concept, score as a 6, and check yes in the checkbox below this item.
II. Distress
This item rates the subject's experience of unpleasant or distressing emotion of any kind: sadness, depression, anxiety, grief, anger, etc. The source of the distress is not considered; for instance, unpleasant emotions associated with psychotic symptoms are considered here.
Item 4: Distress
Probe Questions
What made you feel bad in the last week? Did anything happen that you didn't like? Did anything make you feel sad or depressed? Worried or anxious? Angry or irritated?
If nothing unpleasant happened: What has happened to you in the past that made you feel bad? How do you feel about that now?
III. Asociality Subscale
Asociality is reduced social activity accompanied by decreased interest in forming close relationships with others. This subscale is intended to capture an apathetic asociality. The item ratings are based on both reports of internal experiences, including the degree to which the subject values and desires close, social bonds, and observable behavior, namely, the extent to which the subject actually engages in interactions with others. The intent of these items is to avoid rating a suspicious withdrawal
As
Asocial behavior can include:
Asocial internal experiences include:
The scores for behavior and internal experience may, however, be quite different; i.e., behavior may not be congruent with internal experience. For instance, a subject may be isolated because of poor social skills or persecutory delusions—resulting in a high (i.e., impaired) score on item 5—but may feel very lonely, think about other people a great deal, and wish for companionship, resulting in a normal score on item 6.
Ratings should be made in the areas of family relationships, intimate relationships, and friendships, and if the subject does not mention anyone from each of these, the interviewer should ask about each. Interactions with the rater should also be considered in scoring this item. If the subject does not have contact with family or other social opportunities because it is not possible to have contact (because they are deceased, or they refuse to have contact with the subject), this lack of contact should not be considered in making Asociality ratings. Some allowance for the unavoidable realities of a patient's life may be necessary. For instance, a patient who is chronically institutionalized or an inpatient may not be able to have contact with family members or friends. In such a case, the rating should be based on what is available to the subject, including other patients and staff. Even in such an environment, it is possible to make connections with others, or choose not to do so, and to feel lonely or not.
Item 5: Asociality: Behavior
Probe Questions
(Refer to the people identified in items 1-3) When you spent time with them, did you contact them or did they contact you? How often do you talk to them about private, personal things? Did you try to contact anyone else?
Item 6: Asociality: Internal Experience
Probe Questions
If involved in social activities: Some people like to be by themselves; others like to be around other people. What do you prefer?
Do you feel close to (the people discussed above)? Do you think about (people discussed above) much? Do you wish you were closer? Do you feel lonely sometimes?
If not involved in social activities: Do you wish you had more contact with people? Do you think about that much? How do you feel about being alone much of the time? Are these relationships important to you?
IV. Avolition Subscale
Avolition is a reduction in the initiation of and persistence in activity. The two items rate over behavior and internal experience, as a failure to initiate and persist in activity may be due to several sources that do not reflect core negative symptoms, e.g., decreased opportunity or paranoid beliefs. A subject may have a decrease in goal-directed behavior but still receive a relatively low rating on avolition if he or she has a desire to engage in such behavior. For instance, a patient who is depressed may have difficulty initiating and sustaining goal-directed behavior, and would receive a high (impaired) score on item 7. The same subject may, however, feel guilty or ashamed about his or her lack of accomplishment, frequently think about his or her obligations, and may receive a lower (more normal) score on item 8. Ratings should be based on an assessment of work, school, hobbies/recreation/pastimes, and self-care. Social activities are rated in the Asociality subscale, not in this subscale. Self-care includes grooming, washing clothes, obtaining a place to live, maintaining a household, and getting to health-related appointments; other activities may also be part of self-care. The subject should not be penalized for a lack of opportunities. For instance, it would not be appropriate to penalize a hospitalized patient for failure to seek housing if discharge from the hospital is not approaching.
In the probes below, work should be defined broadly, to include housework, child care, care of an ailing family member, etc. Similarly, if a patient has little income, or has a physical handicap, it may be difficult to participate in recreational activities, and a lack of initiation and persistence in this area may not be considered of importance.
In assessing behavior and internal experience in this area, very strong motivation and interest in one area may lead to a relatively normal rating, if this is interest accounts for much of the subject's possible time and effort. For instance, someone caring for small children may have little time for other things, and may have normal scores on the avolition subscale items if absorbed in that task.
As in asociality, some allowance for the unavoidable realities of a patient's life may be necessary; the opportunities available to the person should be considered. For instance, a patient who is chronically institutionalized or an inpatient is not able to pursue competitive employment or an education. The rating should be based on what is available to the subject, including, for instance, the activities available in a hospital ward. Even in such an environment, it is possible to find things to do, or choose not to do so, and to feel bored or not.
Item 7: Avolition: Behavior
Probe Questions
General: Tell me how you spend your time. Do you spend much time just sitting, not doing anything in particular?
Work and School:
If currently working or going to school:
How much time did you spend working (or in school or studying) this week? Do you get to there on your own? Do you wait for others to tell you what to do, or do you start the work (or schoolwork) yourself?
(If in a treatment program, and question is appropriate): Did you participate in group activities in your treatment program? If yes: Did someone encourage you to do that, or did you do it on your own?
If not currently working or going to school:
Have you looked for work or looked into taking classes in the past week? Did someone suggest it, or did you do that on your own? What are you goals?
Recreation/hobbies/pastimes: (Consider the information on recreational activities from items 1 - 3.) Do you spend much time watching TV? (If yes to last question: Are you interested in what you watch, or are you just passing the time?)
Self-care: How often have you showered/bathed over the past week? How often did you clean your {apartment, room, house}? Did someone need to remind you do this? Does someone else remind you to do those things? (If applicable): Have you needed to look for a place to live? What have you done about that?
Item 8: Avolition: Internal Experience
Probe Questions
Work and School:
If currently working or going to school: Is your job (or school) is important to you? Do you think about it much? Do you feel motivated about it?
If not working or going to school: Do you think about getting a job or going to school? Do you miss having a job (or going to school)?
Recreation/Hobbies/Pastimes: What do you do in your free time? What hobbies do you have? Were you thinking about these this week?
Self-care: Did you feel motivated to take care of yourself this week? (If an explanation is needed: motivated about bathing, cleaning your home, taking care of your health, etc.)
V. Blunted Affect Subscale
Blunted affect refers to a decrease in the outward expression of emotion, and the interview prompts are designed to elicit emotion. If the subject does not respond to the prompts asking about emotional experiences, this item can be rated based on the responses to other questions during the interview.
Items can be rated based on the responses to other questions during the interview.
Facial Expression
When rating facial expression, consider facial movements across all parts of the face, including in the eyes (e.g., raised brows), mouth (smiling or grimacing), and mid-face (e.g., wrinkled nose when disgusted).
Item 9: Facial Expression
Vocal Expression
One component of blunted affect is modulation of the voice, which includes variation in the speed, volume, and pitch of what is spoken. The content or amount of speech is not rated here.
Item 10: Vocal Expression
Expressive Gestures
Expressive gestures include not only gestures made with the hands, but also those made with the head (e.g., nodding), shoulders (shrugging), and the trunk (e.g. leaning forward). Dyskinetic movements should not to be rated here.
Item 11: Expressive Gestures
VI. Alogia Subscale
There are no specific probes for the Alogia subscale; ratings are based on the responses to all questions during the interview.
Quantity of Speech
This item refers to the quantity of words spoken. Other speech abnormalities, such as disorganization, neologisms, or psychotic content are not rated here. For instance, a disorganized subject may produce a large quantity of speech and have a low (normal) score on this item.
Item 12: Quantity of Speech
Spontaneous Elaboration
This item rates the amount of information given beyond what is strictly necessary in order to respond to the interviewer's questions. Whether or not the subject's responses are appropriate is not considered, so elaboration in this sense can include appropriate background information given to clarify an answer, irrelevant or unnecessary material, delusional or thought-disordered responses.
Item 13: Spontaneous Elaboration
The embodiments encompassed herein are now described with reference to the following Examples. These Examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these Examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein.
A prospective Phase IIb, 12-week, randomized, double-blind, placebo-controlled parallel clinical trial was conducted to evaluate the efficacy, safety and tolerability of MIN-101 in patients with negative symptoms of schizophrenia. The study was designed to evaluate the efficacy of MIN-101 monotherapy on negative symptoms using the pentagonal structure model (PSM) of the Positive and Negative Syndrome Scale (PANSS) as the primary endpoint. A total of 244 patients were randomized in equal groups to receive daily doses of MIN-101 32 mg, MIN-101 64 mg or placebo at 32 clinical sites in Russia and five European countries.
To participate in the trial, patients were required to have stable positive and negative symptoms for three months prior to entry, a PANSS negative sub-score greater than or equal to 20, and scores <4 on the following PANSS items: excitement, hyperactivity, hostility, suspiciousness, uncooperativeness and poor impulse control. The full inclusion and exclusion criteria set forth in the protocol are listed below.
Inclusion Criteria
Each potential patient must satisfy all of the following criteria before study drug administration to be enrolled in the study:
Exclusion Criteria
Any potential patient who meets any of the following criteria before study drug administration will be excluded from participating in the study:
All three cohorts were balanced with respect to demographic and baseline disease characteristics as shown in the Table immediately below.
The mean changes from baseline in the PANSS Negative Subscale score in the placebo and treatment arms over 12 weeks of treatment is shown in
As illustrated in
Furthermore, the statistically significant benefit of MIN-101 over placebo was also demonstrated on the PANSS total score (not significant for the 32 mg dose; p≤0.003 for the 64 mg dose), with effect sizes of 0.35 and 0.59, respectively.
Improvement in negative symptoms achieved by both doses of MIN-101 was also observed when the effect was measured using the BNSS total score, as shown in
MIN-101 was generally reported to be well tolerated, and the incidence and types of side effects did not differ significantly between the MIN-101 group and the placebo group. Based upon previous non-clinical and clinical experience, QTcF, a measurement of cardiac function, was closely monitored. Discontinuation criteria based on QTcF prolongation were incorporated in the protocol. Two patients out of 162 who received MIN-101 were discontinued based upon these criteria; both of these patients received the higher dose (64 mg). Unlike many currently marketed antipsychotic drugs, no metabolic adverse effects, no weight gain, no extra-pyramidal symptoms and no prolactin elevation were observed.
The invention has been described herein by reference to certain preferred embodiments. However, as particular variations thereon will become apparent to those skilled in the art, based on the disclosure set forth herein, the invention is not to be considered as limited thereto.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. In the specification and claims, the singular forms also include the plural unless the context clearly dictates otherwise.
It is to be understood that at least some of the descriptions of the invention have been simplified to focus on elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the invention. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the invention, a description of such elements is not provided herein.
Further, to the extent that the method does not rely on the particular order of steps set forth herein, the particular order of the steps should not be construed as limitation on the claims. The claims directed to the method of the present disclosure should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the steps may be varied and still remain within the spirit and scope of the present disclosure.
All patents, patent applications, references and publications cited herein are fully and completely incorporated by reference as if set forth in their entirety.
This application claims priority to, and the benefit of, U.S. Provisional Application No. 62/341,590, filed May 25, 2016, the entire content of which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2017/034030 | 5/23/2017 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62341590 | May 2016 | US |
