Pharmaceutical composition comprising bevantolol for the treatment of mental disorders

Abstract

The present invention relates to a pharmaceutical composition comprising bevantolol or a pharmaceutically acceptable salt thereof for use in the treatment of mental disorders. Further provided herein is the use of said composition in the treatment of a hyperkinetic disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder.

Description

[0001] New PCT Patent Application

[0002] SOM Innovation Biotech, S. A.

[0003] Vossius Ref.: AJ3848 PCT BS

[0004] PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF MENTAL DISORDERS

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to a pharmaceutical composition comprising bevantolol or a pharmaceutically acceptable salt thereof for use in the treatment of mental disorders. Further provided herein is the use of said composition in the treatment of a hyperkinetic disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder.

[0007] BACKGROUND OF THE INVENTION

[0008] Mental disorders encompass a broad range of conditions that affect an individual's emotional, psychological, and social well-being, often leading to significant impairments in daily functioning. These disorders include, but are not limited to, depressive disorders, psychotic disorders, anxiety disorders, neurodevelopmental disorders, impulse control disorders, cognitive disorders, and / or bipolar disorders. Mental disorders can result from a combination of genetic, biological, environmental, and psychological factors. Some mental disorders, such as depressive disorders, have a high prevalence in patients with neurological disorders such as hyperkinetic movement disorders, which involve abnormal, involuntary movements that can be associated with disruptions in brain function.

[0009] Both mental disorders and hyperkinetic movement disorders are closely associated with imbalances in neurotransmitter systems, which play a critical role in regulating mood, behavior, and motor function. In mental disorders, such as depression and bipolar disorders, dysregulation of neurotransmitters like serotonin, dopamine, and norepinephrine has beenimplicated in the pathophysiology of these conditions, affecting emotional and cognitive processing. Similarly, hyperkinetic movement disorders, such as chorea associated with Huntington's disease or tardive dyskinesia, are often linked to abnormalities in dopamine transmission, which impacts motor control and can lead to involuntary movements. In both cases, the underlying neurotransmitter imbalances contribute to the manifestation of symptoms, whether emotional and cognitive in mental disorders or motor-related in hyperkinetic movement disorders.

[0010] One of the key proteins involved in maintaining neurotransmitter balance is the vesicular monoamine transporter (VMAT). VMATs plays a crucial role in the pathophysiology of mental disorders and hyperkinetic movement disorders by regulating the storage and release of key neurotransmitters, such as dopamine and serotonin, within the brain. VMATs transport neurotransmitters into synaptic vesicles, where they are stored until released into the synaptic cleft in response to neuronal activity. Dysregulation or dysfunction of VMATs can lead to imbalances in neurotransmitter availability and has been implicated in various mental disorders including schizophrenia, ADHS, psychotic disorders, contributing to a wide range of psychiatric and movement-related symptoms. The role of VMATs has been investigated in several mental disorders including: schizophrenia (Connolly et al., Psychopharmacology, 2024; 241, 225-241), addiction (Lee et al., Pharmacol Exp Ther., 2019; 371(2):526-543), ADHD (Warlick et al., Psychopharmacology (Berl), 2024; 241(11):2191-2203), and bipolar disorder (Zubieta et al., Biol Psychiatry, 2001; 15;49(2):110-6).

[0011] In the context of hyperkinetic movement disorders, pharmacological inhibition of VMAT2 has been established as a standard treatment with notable VMAT2 inhibitors such as tetrabenazine, deutetrabenazine, valbenazine. Additional inhibition of VMAT1 is associated with some antipsychotics like Ziprasidone or Reserpine (which binds to VMAt1 in an irreversible way). The VMAT2 inhibitors reduce the symptoms of hyperkinetic movement disorders by depleting presynaptic dopamine in neurons through VMAT isoform 2 (VMAT2) inhibition, which normally translocates monoamines from the cytoplasm into the synaptic vesicles for storage. Consequently, less vesicular dopamine is available for synaptic signaling, and the dopamine that remains in the cytoplasm is rapidly degraded by monoamine oxidases. The complete depletion of dopamine (and likely of serotonin) results in the common sideeffects of the VMAT2 inhibitors tetrabenazine and its derivatives deutetrabenazine and valbenazine, including parkinsonism and increased risk for worsening of depression and suicidality (Frank et al. CNS Drugs, 2022; 36(11):1207-1216) leading to a Black Box Warning for their use in Huntington's patients.

[0012] There is currently no drug that can treat both movement disorders and neuropsychiatric disorders. This is particularly relevant since movement disorders and neuropsychiatric disorders including mood disorders often co-exist. For example, one of the most common mental disorder associated with Huntington's disease is depression. Accordingly, pharmaceutical treatment of hyperkinetic movement disorders with VMAT2 inhibitors that exacerbate depression and suicidality poses a serious safety risk for patients.

[0013] These previous findings highlight the importance of dopamine and serotonin regulation and consequently, the unmet need for treatments that restore neurotransmitter balance without the undesired side effects associated with dopamine and / or serotonin depletion.

[0014] SUMMARY OF THE INVENTION

[0015] The present invention is characterized in the herein provided embodiments and claims. In particular, the present invention relates, inter alia, to the following embodiments:

[0016] 1. A pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of one or more mental disorders in a subject.

[0017] 2. The pharmaceutical composition for use according to embodiment 1, wherein the mental disorder is an anxiety disorder and / or a depressive disorder, preferably wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed anxiety-depressive disorder, and / or secondary depression.The pharmaceutical composition for use according to embodiment 1 or 2, wherein the mental disorder is a psychotic disorder, mood disorder, anxiety disorder, neurodevelopmental disorder, impulse control disorder, cognitive disorder, and / or bipolar disorder.

[0018] The pharmaceutical composition for use according any one of embodiments 1 to 3, wherein the mental disorder is selected from: schizophrenia, schizoaffective disorder, psychosis, psychosis associated with a neurodegenerative disease, obsessive-compulsive disorder, generalized anxiety disorder, social anxiety disorder, specific phobia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, addiction, and / or dementia.

[0019] The pharmaceutical composition for use according to embodiment 2 wherein the subject is a subject having a hyperkinetic movement disorder.

[0020] The pharmaceutical composition for use according to embodiment 5, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, dystonia syndromes, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.

[0021] The pharmaceutical composition for use according to embodiment 5 or 6, wherein the hyperkinetic movement disorder is associated with Huntington's disease.

[0022] The pharmaceutical composition for use according to any one of embodiments 5 to 7, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

[0023] The pharmaceutical composition for use according to any one of embodiments 5 to 8,wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0024] A pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder.

[0025] The pharmaceutical composition for use according to embodiment 10, wherein administering the pharmaceutical composition results in an improved depression score.

[0026] The pharmaceutical composition for use according to embodiment 10 or 11, wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed anxiety-depressive disorder, and / or secondary depression.

[0027] The pharmaceutical composition for use according to embodiment 10 to 12, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.

[0028] The pharmaceutical composition for use according to embodiment 10 to 13, wherein the hyperkinetic movement disorder is associated with Huntington's disease.

[0029] The pharmaceutical composition for use according to any one of embodiments 10 to 14, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.The pharmaceutical composition for use according to any one of embodiments 10 to 15, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0030] The pharmaceutical composition for use according to any one of embodiments 1 to 16, wherein the pharmaceutical composition is administered orally, preferably as a tablet or a capsule.

[0031] The pharmaceutical composition for use according to any one of embodiments 1 to 17, wherein said pharmaceutical composition is administered at a daily dose of about 1 mg to about 3000 mg bevantolol.

[0032] The pharmaceutical composition for use according to embodiment 18, wherein said pharmaceutical composition is administered twice daily at a dose of about 0.5 mg to about 1500 mg bevantolol.

[0033] The pharmaceutical composition for use according to embodiment 18 or 19, wherein said pharmaceutical composition is administered twice daily at a dose of about 300 mg bevantolol.

[0034] The pharmaceutical composition for use according to any one of embodiments 1 to 20, wherein said pharmaceutical composition comprises bevantolol hydrochloride.

[0035] The pharmaceutical composition for use according to any one of embodiments 1 to 21, wherein the bevantolol comprised in the composition inhibits VMAT2 and VMAT1.

[0036] The pharmaceutical composition for use according to any one of embodiments 1 to 22, wherein the bevantolol comprised in the composition inhibits dopamine uptake more efficiently than serotonin uptake via VMAT2.

[0037] The pharmaceutical composition for use according to embodiment 23, wherein thebevantolol comprised in the composition reduces vesicular dopamine, and serotonin.

[0038] 25. A method of treating or preventing one or more mental disorders in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof.

[0039] 26. The method according to embodiment 25, wherein the mental disorder is a depressive disorder, preferably wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed anxiety-depressive disorder, secondary depression and schizophrenia negative symptoms

[0040] 27. The method according to embodiment 25 or 26, wherein the mental disorder is a psychotic disorder, anxiety disorder, neurodevelopmental disorder, impulse control disorder, cognitive disorder and / or bipolar disorder.

[0041] 28. The method according to any one of embodiments 25 to 27, wherein the mental disorder is selected from: schizophrenia, schizoaffective disorder, psychosis, psychosis associated with a neurodegenerative disease, obsessive-compulsive disorder, generalized anxiety disorder, social anxiety disorder, specific phobia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, addiction, and / or dementia.

[0042] 29. The method according to embodiment 26, wherein the subject is a subject having a hyperkinetic movement disorder.

[0043] 30. The method according to embodiment 29, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.31. The method according to any one of embodiments 29 or 30, wherein the hyperkinetic disorder is associated with Huntington's disease.

[0044] 32. The method according to any one of embodiments 29 to 31, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, and / or tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

[0045] 33. The method according to any one of embodiments 29 to 32, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0046] 34. A method of treating or preventing a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder, the method comprising administering to the subject a pharmaceutically effective amount of a pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof.

[0047] 35. The method according to embodiment 34, wherein administering the pharmaceutical composition results in an improved depression score.

[0048] 36. The method according to embodiment 34 or 35, wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed anxiety-depressive disorder, secondary depression and schizophrenia negative symptoms.

[0049] 37. The method according to embodiment 34 to 36, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome,restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.

[0050] 38. The method according to embodiment 34 to 37, wherein the hyperkinetic movement disorder is associated with Huntington's disease.

[0051] 39. The method according to any one of embodiments 34 to 38, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

[0052] 40. The method according to any one of embodiments 34 to 39, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0053] 41. The method according to any one of embodiments 25 to 40, wherein the pharmaceutical composition is administered orally, preferably as a tablet or a capsule.

[0054] 42. The method according to any one of embodiments 25 to 41, wherein said pharmaceutical composition is administered at a daily dose of about 1 mg to about 3000 mg bevantolol.

[0055] 43. The method according to embodiment 42, wherein said pharmaceutical composition is administered twice daily at a dose of about 0.5 mg to about 1500 mg bevantolol.

[0056] 44. The method according to embodiment 42 or 43, wherein said pharmaceutical composition is administered twice daily at a dose of about 300 mg bevantolol.

[0057] 45. The method according to any one of embodiments 25 to 44, wherein said pharmaceutical composition comprises bevantolol hydrochloride.46. The method according to any one of embodiments 25 to 45, wherein the bevantolol comprised in the composition inhibits VMAT2 and VMAT1.

[0058] 47. The method according to any one of embodiments 25 to 46, wherein the bevantolol comprised in the composition inhibits dopamine uptake more efficiently than serotonin uptake via VMAT2.

[0059] 48. The method according to embodiment 47, wherein the bevantolol comprised in the composition reduces vesicular dopamine, and serotonin.

[0060] Accordingly, in a particular embodiment, the invention relates to a pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of one or more mental disorders in a subject.

[0061] The present invention is based on the surprising finding that a pharmaceutical composition comprising bevantolol reduced depression scores in patients with Huntington's disease (Figure 7). This finding is highly surprising, given that other VMAT inhibitors, such as tetrabenazine, were previously reported to result in severe side effects including depression and suicidality (Frank et al. CNS Drugs, 2022; 36(11):1207-1216). In contrast, in a previous randomized controlled study with bevantolol in Huntington's patients, no negative effects of bevantolol on depression were observed (Gamez et al., Br J Clin Pharmacol, 2023; 89(5):1656-1664). However, only in the study underlying the present invention, it was surprisingly found that bevantolol even shows to alleviate depression.

[0062] This beneficial and previously unknown activity of bevantolol can likely be explained by the unique inhibitory properties of bevantolol on VMAT molecules, which differ markedly from that of other VMAT2 inhibitors such as tetrabenazine and its derivatives deutetrabenazine and valbenazine, the standard of care for chorea and tardive dyskinesia, or reserpine, an irreversible VMAT2 and VMAT1 inhibitor. In particular, the inventors have found that bevantolol inhibits dopamine and serotonin transport by VMAT2 at a reduced level compared to other VMAT inhibitors such as tetrabenazine or reserpine (Figures 1 to 4) and thus does not result in depletion of dopamine and / or serotonin levels. Consequently, side effects associatedwith dopamine and / or serotonin depletion, such as depression, cognitive impairment and anxiety, which have been reported for tetrabenazine, are not to be expected in patients treated with bevantolol. Without being bound to theory, these unique inhibitory properties of bevantolol can be explained by the finding in Example 3 that bevantolol binds to a unique binding pocket on VMAT2.

[0063] Given the specific pharmacological properties of bevantolol in rebalancing the levels of neurotransmitters in the different areas of the brain covered by the concomitant effect on VMAT2 and VMAT1 (VMAT1 is located in the substantia nigra, hippocampus, thalamus, amygdala and frontal lobe and VMAT2 located primarily in the basal ganglia (Hansson, et al., 1998; Lohoff, et al., 2006; Multani, et al., 2013), in particular dopamine and serotonin, it is plausible that bevantolol can also be used for the treatment of other mental disorders associated with dysregulated dopamine and / or serotonin levels.

[0064] Dysregulation of neurotransmitters such as dopamine and / or serotonin has been implicated in several mental disorders, including depressive disorders (Ressler et al., Depress Anxiety.

[0065] 2000; 12 Suppl 1:2-19), bipolar disorders (Ashok et al. 2017, Mol Psychiatry, 2017; 22(5):666-679), anxiety disorders (Gordon et al., Neuromolecular Med. 2004; 5(l):27-40), schizophrenia (Ginovart et al., Handb Exp Pharmacol., 2012; (212):27-52 and Canul-Medina et al., Front. Psychiatry, 2024; 15:1436906), autism spectrum disorders (Paval et al., Dev Neurosci., 2021; 43(2):73-83), Attention Deficit Hyperactivity Disorders (ADHD) (Volkow et al., JAMA, 2009; 302(10):1084-91), addiction (Volkow et al., J Neurosci., 2006; 26(24):6583-8), and dementia (Lanctot et al., J Neuropsychiatry Clin Neurosci., 2001; 13(1):5-21). In addition, neurologic disorders such as hyperkinetic movement disorders also have been associated with a disbalance of dopamine and serotonin levels (Jankovic et al., Expert Opin Pharmacother., 2016; 17(18):2461-2470 and Smit et al., Neurosci Biobehav Rev., 2016; 65:264-75).

[0066] The pharmaceutical composition according to the invention comprises as an active ingredient the compound bevantolol, preferably wherein said compound is bevantolol hydrochloride.

[0067] Bevantolol is a beta-adrenergic antagonist (beta-blocker) that selectively inhibits beta-1 adrenergic receptors. It was initially proposed for the treatment of hypertension and certaincardiac arrhythmias and offers reduced side effects compared to non-selective beta-blockers. Later, bevantolol has also been proposed for the treatment of hyperkinetic movement disorders due to its VMAT2 inhibiting activity (WO 2014 / 202646).

[0068] Additionally, bevantolol has been proposed for use in the treatment of symptoms of depression or anxiety associated with depression, anxiety disorder, or neurological disorder (JP 2022 138903 A). However, no experimental data supporting the purported medical use has been provided. In consequence, JP 2022 138903 A is also silent as to the surprising technical effects reported herein, as well as the dosage regimens disclosed herein.

[0069] WO 2016 / 133989 A1 proposes the use of bevantolol in the treatment of hyperkinetic movement disorders. However, WO 2016 / 133989 A1 provides no supporting experimental data.

[0070] Bevantolol is the name commonly used for (RS)-[2-(3,4-dimethoxyphenyl)ethyl][2-hydroxy-3-(3-methylphenoxy)propyl]amine (CAS RN 59170-23-9) having the following structure:

[0071]

[0072] Bevantolol has a chiral center and can exist as two stereoisomers, an R-enantiomer and an S-enantiomer. As used herein, the term "stereoisomer" refers to all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), and mixtures of mirror image isomers (racemates, racemic mixtures). The present invention relates to each of these stereoisomers and also mixtures thereof.

[0073] That is, in certain embodiments, the bevantolol comprised in the pharmaceutical composition for use according to the invention may be S-bevantolol.

[0074] In certain embodiments, the bevantolol comprised in the pharmaceutical composition for use according to the invention may be R-bevantolol.

[0075] In certain embodiments, the bevantolol comprised in the pharmaceutical composition for use according to the invention may comprise a mixture of R-bevantolol and S-bevantolol. Theracemic mixture may comprise R-bevantolol and S-bevantolol in any suitable ratio. In certain embodiments, the bevantolol comprised in the pharmaceutical composition for use according to the invention may comprise a racemic mixture of R-bevantolol and S-bevantolol.

[0076] Enantiomers can be separated by conventional techniques such as chromatography or fractional crystallization. Optical isomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediates or on compounds of the invention. Optically pure isomers can also be individually obtained using enantiospecific synthesis.

[0077] In certain embodiments, the pharmaceutical composition for use according to the invention may comprise a pharmaceutically acceptable salt of bevantolol.

[0078] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids which are, within the scope of medical judgement, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0079] Within the present invention, the pharmaceutically acceptable salt of bevantolol may be any suitable salt. It is, however, preferred that the pharmaceutically acceptable salt of bevantolol is bevantolol hydrochloride.

[0080] The term "pharmaceutical composition" as used herein refers to a formulation that contains an active ingredient, such as bevantolol or a pharmaceutically acceptable salt thereof, combined with one or more pharmaceutically acceptable excipients or carriers.

[0081] In certain embodiments, the pharmaceutical composition comprising bevantolol is used for the treatment or prevention of one or more mental disorder, preferably a mental disorder associated with dysregulated levels of dopamine and / or serotonin in the brain.

[0082] As used herein, the term "mental disorder" includes disorders that may be diagnosed by a mental health professional as psychological or psychiatric in nature. This includes disorders that may be diagnosed by reference to the Diagnostic and Statistical Manuals of Mental Disorders (DSM-5). Examples for mental disorders include, but are not limited to: depressivedisorders, psychotic disorders, anxiety disorders, mood disorders, neurodevelopmental disorders, impulse control disorders, cognitive disorders, and / or bipolar disorders.

[0083] Preferably, the mental disorder is at least in part characterized by dopamine and / or serotonin dysregulation. The present invention is based on the surprising effect, that the pharmaceutical composition comprising bevantolol can restore neurotransmitter balance by reducing dopamine and serotonin levels without depletion of either one. In contrast to other VMAT inhibitors such as tetrabenazine or reserpine which mediate a strong reduction or depletion of dopamine and serotonin levels, the pharmaceutical composition of the present invention only mediates a mild reduction. Said mild reduction aids in the restoration of neurotransmitter levels and does not induce side effects such as depression, anxiety, and dementia as with other VMAT inhibitors.

[0084] Thus, in a particular embodiment, the invention relates to a pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of one or more mental disorders in a subject, wherein bevantolol normalizes and / or restores the neurotransmitter levels in the brain.

[0085] In the context of the present application, the expression "normalize or restore neurotransmitter levels in the brain" refers to the ability of bevantolol, or a pharmaceutically acceptable salt thereof, to adjust the concentrations of neurotransmitters to their absolute and relative optimal physiological levels, thereby achieving a balanced state that supports normal brain function. This process involves correcting any imbalances of neurotransmitters, preferably dopamine and serotonin, which are implicated in the pathophysiology of mental disorders, specifically in the corticostriatal loops and cortico-subthalamic-pallidal-thalamo-cortical loops. The goal is to bring these neurotransmitter levels to a state comparable to that found in healthy subjects, or at least to a more normal range, thereby alleviating symptoms associated with such disorders and promoting mental health and stability.

[0086] The specific dopamine and serotonin reducing profile of the pharmaceutical composition of the present invention, makes it suitable for the treatment of mental disorders which are at least in part characterized by dopamine and / or serotonin dysregulation. Exemplary mentaldisorders with dysregulated dopamine and / or serotonin levels include but are not limited to: mood disorder, depressive disorder, bipolar disorder, psychotic disorder, anxiety disorder, neurodevelopmental disorder, impulse control disorder, and / or cognitive disorder. Specific disorders which can be treated by the pharmaceutical composition of the present invention include but are not limited to: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed-anxiety depressive disorder, schizophrenia schizoaffective disorder, schizophreniform disorder, schizoid disorders, schizotypal disorders, schizoaffective psychosis, psychosis, delusional disorder, psychosis associated with affective disorders, brief psychotic disorder, shared psychotic disorder, psychosis associated with another disorder (such as major depressive disorder, bipolar disorder, Alzheimer's disease and traumatic stress syndrome), substance-induced psychosis (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine), acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition, attention deficit hyperactivity disorder, autism spectrum disorder, Rett syndrome, Fragile X syndrome, eating disorder, addiction, amnesia, dementia, delirium, amnestic disorder, substance-induced persisting delirium, dementia associated with HIV disease, dementia associated with Huntington's disease, dementia associated with Parkinson's disease, Parkinsonian-ALS dementia complex, dementia associated with Alzheimer's type, age-related cognitive decline, and mild cognitive impairment.

[0087] It is preferred herein that the mental disorder to be treated with the pharmaceutical composition comprising bevantolol is a depressive disorder.

[0088] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the mental disorder, preferably wherein the mental disorder is a depressive disorder, preferably wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression,dysthymic disorder, seasonal affective disorder, mixed-anxiety depressive disorder, and / or secondary depression.

[0089] In a preferred embodiment, the depressive disorder is selected from: major depressive disorder, minor depressive disorder, persistent depressive disorder, and / or treatment resistant depression.

[0090] In a more preferred embodiment, the depressive disorder is selected from: major depressive disorder, persistent depressive disorder, and treatment resistant depression.

[0091] In a most preferred embodiment, the depressive disorder is major depressive disorder.

[0092] As used herein, the term "depressive disorder" refers to a mood disorder characterized by a predominantly sad or depressed mood, accompanied by psychological and / or physical symptoms. The depressive disorder may be, without limitation major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed-anxiety depressive disorder, and / or secondary depression.

[0093] In some embodiments, the depressive disorder may be associated with or develop as a result of another underlying disorder. Such depressive disorders may be defined as "secondary depressive disorders" or "secondary depression" and are included within the term "depressive disorder". Exemplary disorders which can lead to secondary depressive disorders include but are not limited to: chronic disorders, neurological disorders, autoimmune disorders, endocrine disorders, chronic infectious disorders, and / or sleep disorders.

[0094] Specific disorders which can lead to secondary depressive disorders include but are not limited to: diabetes, heart disease, cancer, chronic pain conditions (e.g., arthritis, fibromyalgia, back pain), Huntington's disease, Parkinson's disease, multiple sclerosis, Alzheimer's disease, Fragile X syndrome, dementia, lupus, rheumatoid arthritis, hypothyroidism, Cushing's syndrome, adrenal insufficiency, HIV / aids, chronic hepatitis C, sleep apnea, and insomnia.

[0095] In some embodiments, the depressive disorder is associated with or results from a neurological disorder. In such embodiments, the neurological disorder may be aneurodegenerative disorder such as Huntington's disease, Alzheimer's disease, and / or Parkinson's disease.

[0096] In some embodiments, the depressive disorder may be associated with or result from a neurological disorder associated with a hyperkinetic movement disorder, such as Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome. It is known in the art that subjects with a neurological disorder, particularly a neurological disorder associated with a hyperkinetic movement disorder, have an elevated risk of developing depression.

[0097] In one aspect, the pharmaceutical composition comprising bevantolol to be used herein causes less side effects compared to conventional therapies of neurodegenerative disorder (in particular Huntington's disease), such as VMAT2 inhibitors, like tetrabenazine, deutetrabenazine and / or valbenazine. For example, a pharmaceutical composition comprising bevantolol to be used herein does not cause an increased risk of suicidality and / or does not cause a worsening of depression (e.g. when compared to the patient's status prior to treatment). If preceded by conventional therapies of neurodegenerative disorder (in particular Huntington's disease), such as VMAT2 inhibitors, like tetrabenazine, deutetrabenazine and / or valbenazine, treatment with the pharmaceutical composition comprising bevantolol to be used herein may even be used to reduce side effects (e.g. increased risk of suicidality and / or (worsening of) depression) caused by the preceding therapy (e.g. caused by VMAT2 inhibitors, like tetrabenazine, deutetrabenazine and / or valbenazine).

[0098] Generally, treatment with the pharmaceutical composition comprising bevantolol to be used herein lacks or minimizes side effects (e. g. depression, somnolence, parkinsonism, akathisia and / or fatigue).

[0099] The term "conventional VMAT2 inhibitor" and the like as used herein refers to VMAT2 inhibitor with the proviso that the VMAT2 inhibitor is not bevantolol.

[0100] The pharmaceutical composition comprising bevantolol to be used herein may show no worsening of depression (or even improvement of depression / depressive symptoms e.g. if patients have mild depression at baseline / priorto start of treatment), no increased suicidality,no somnolence (e.g. according to the Epworth Sleepiness scale (ESS)) or improvement in the daytime sleepiness, no fatigue or falls (e.g. compared to placebo), no akathisia (e.g. according to Barnes Akathisia rating scale) and / or no changes in cognitive function (e.g. according to MoCA).

[0101] As used herein, the term "neurodegenerative disorder" refers to a central nervous system (CNS) disorder that is characterized by the death of neurons in one or more regions of the nervous system and the subsequent functional impairment of the affected parties. Examples of neurodegenerative disorders include, but are not limited to: Alzheimer's disease, Parkinson's disease, and Huntington's disease.

[0102] As used herein, the term " Alzheimer's disease" refers to a progressive disease initially manifesting itself with partial amnesia, and later restlessness, disorientation, aphasia, agnosia or apraxia (cognitive decline), dementia and sometimes euphoria or depressions. The disease typically starts at 40 to 90 years of age and predominantly affects females. As to its prevalence, estimations are about 13% of the population above 65 years age. Patients with Alzheimer's disease have an elevated risk for depressive disorders compared to the general population.

[0103] As used herein the term " Huntington's disease" refers to a dominantly inherited neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. The cause of Huntington's disease is mutations in the gene encoding for huntingtin, and it is the most common genetic cause of abnormal involuntary writhing movements called chorea, which is why the disease used to be called Huntington's chorea. Thus, the term " Huntington's disease" and " Huntington's chorea" have the same meaning and are used interchangeably. Patients with Huntington's disease have an elevated risk for depressive disorders compared to general population.

[0104] As used herein the term " Wilson's disease" refers to a genetic disorder which causes dysfunctional copper metabolism and manifest as hepatic cirrhosis and basal ganglia damage. The condition is due to mutations in the Wilson disease protein (ATP7B) gene and the initial manifestations of the disorder are neurologic in about 40% of patients. The pathologicabnormalities in the brain are primarily in the basal ganglia, with cavitary necrosis of the putamen and caudate, associated with neuronal loss, axonal degeneration and astrocytosis. In addition, there is cortical atrophy. In Wilson's disease prevalence of depressive disorders is significantly higher compared to the general population.

[0105] As used herein the term " Tourette syndrome" refers to a neurologic disorder manifested by motor and vocal or phonic tics usually starting during childhood and often accompanied by some comorbid behavioral problems such as obsessive-compulsive disorder or attentiondeficit hyperactivity disorder. Tics are defined as involuntary, sudden, rapid, recurrent, nonrhythmic movement (motor tics) and vocalisations (vocal or phonic tics). Preliminary evidence from neurochemical and neuroimaging investigations suggests a primary role for dysfunction of the dopaminergic pathways within the cortico-striato-cortico-frontal circuitry. Patients with Tourette syndrome have an elevated risk for developing a depressive disorder compared to the general population.

[0106] As used herein the term "tardive dyskinesia" is a disorder characterized by involuntary, repetitive body movements and can result from the treatment with dopamine receptorblocking agents. The principal site affected by classic tardive dyskinesia is the face, particularly around the mouth, typically called oral-buccal-facial dyskinesia. The limbs and trunk are affected less often than the mouth. The tardive dyskinesia syndromes tend to appear late in the course of treatment, hence the term tardive. The symptoms can occur when the patient is taking these drugs or within a period of time after stopping the treatment. Patients with tardive dyskinesia have an elevated risk of developing a depressive disorder compared to the general population.

[0107] As used herein the term "restless legs syndrome" refers to a disorder characterized by a deep, ill-defined discomfort or dysesthesia in the legs, which arises during prolonged rest, or when the patient is drowsy and trying to fall asleep, especially at night. The most commonly associated medical condition is iron deficiency although there is also evidence to suggest that the disorder in many if not most patients is transmitted as an autosomal dominant trait.As used herein the term "progressive supranuclear palsy" refers to a rare neurodegenerative disorder characterized by the gradual deterioration of balance, movement, vision, speech, and cognition, caused by damage to brain regions that control these functions, particularly the brainstem and basal ganglia.

[0108] The term "multiple system atrophy" refers to a rare, progressive neurodegenerative disorder that affects the autonomic nervous system, movement, and coordination, leading to symptoms such as balance problems, rigidity, and difficulty with speech and swallowing.

[0109] The term "hyperekplexia" refers to a rare neurological disorder characterized by an exaggerated startle response to stimuli, often associated with muscle stiffness, spasms, and, in some cases, seizures.

[0110] The term "epilepsy" refers to a chronic neurological disorder characterized by recurrent, unprovoked seizures caused by abnormal neuronal activity in the brain, leading to a range of symptoms depending on the type and location of the seizures.

[0111] The term " Rett syndrome" refers to a rare genetic neurodevelopmental disorderthat primarily affects females, causing a period of normal development followed by a loss of motor and communication skills, along with repetitive hand movements and cognitive impairments.

[0112] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the mental disorder is a psychotic disorder, anxiety disorder, neurodevelopmental disorder, impulse control disorder, cognitive disorder, and / or bipolar disorder.

[0113] That is, in certain embodiments, the pharmaceutical composition comprising bevantolol may be used in the treatment of psychotic disorders.

[0114] As used herein the term "psychotic disorders" refers to a disorder characterized by abnormal thinking and perception, delusions and hallucinations, and the lack of ability to distinguish reality from fiction.In some embodiments, the mental disorder is a psychotic disorder, wherein the psychotic disorder is selected from: schizophrenia, schizoaffective disorder, catastrophic schizophrenia, schizophreniform disorder, schizoid disorders, schizotypal disorders, schizoaffective psychosis, psychosis, delusional disorder, psychosis associated with affective disorders, brief psychotic disorder, shared psychotic disorder, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, and / or substance-induced psychotic disorder.

[0115] In a preferred embodiment, the mental disorder is a psychotic disorder, wherein the psychotic disorder is selected from: schizophrenia, schizoaffective disorder, catastrophic schizophrenia, schizophreniform disorder, schizoid disorders, schizotypal disorders, schizoaffective psychosis, psychosis, delusional disorder, psychosis associated with affective disorders, brief psychotic disorder, psychotic depression, tardive psychosis, secondary psychotic disorder, and / or substance-induced psychotic disorder.

[0116] In a more preferred embodiment, the mental disorder is a psychotic disorder, wherein the psychotic disorder is selected from: schizophrenia, schizoaffective disorder, catastrophic schizophrenia, psychosis, delusional disorder, psychosis associated with affective disorders, psychotic depression, secondary psychotic disorder, and / or substance-induced psychotic disorder.

[0117] In a most preferred embodiment, the mental disorder is a psychotic disorder, wherein the psychotic disorder is schizophrenia, and / or psychosis.

[0118] In certain embodiments, the pharmaceutical composition comprising bevantolol may be used in the treatment of anxiety disorders.

[0119] As used herein the term "anxiety disorder" refers to a mental disorder characterized by significant distress and dysfunction due to feelings of apprehension, guilt, and / or fear.

[0120] In some embodiments, the mental disorder is an anxiety disorder, wherein the anxiety disorder is selected from: acute stress disorder, agoraphobia, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder, and / or anxiety due to a general medical condition.In a preferred embodiment, the mental disorder is an anxiety disorder, wherein the anxiety disorder is selected from: acute stress disorder, agoraphobia, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, social phobia, and / or specific phobia.

[0121] In more preferred embodiment, the mental disorder is an anxiety disorder, wherein the anxiety disorder is selected from: generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and / or specific phobia.

[0122] In a most preferred embodiment, the mental disorder is an anxiety disorder, wherein the anxiety disorder is generalized anxiety disorder, social anxiety disorder, and / or specific phobia.

[0123] In certain embodiments, the pharmaceutical composition comprising bevantolol may be used in the treatment of neurodevelopmental disorders.

[0124] As used herein the term "neurodevelopmental disorder" refers to mental disorders related to the development of the nervous system.

[0125] In some embodiments, the mental disorder is a neurodevelopmental disorder, wherein the neurodevelopmental disorder is selected from: attention deficit hyperactivity disorder, and / or autism spectrum disorder.

[0126] In some embodiments, the neurodevelopmental disorder results from a genetic disorder such as Rett syndrome, or Fragile X syndrome.

[0127] In certain embodiments, the pharmaceutical composition comprising bevantolol may be used in the treatment of impulse control disorders.

[0128] As used herein the term "impulse control disorder" refers to mental disorders involving the inability to control impulses and behaviors.

[0129] In some embodiments, the mental disorder is an impulse control disorder, wherein the impulse control disorder is addiction.

[0130] In certain embodiments, the pharmaceutical composition comprising bevantolol may be used in the treatment of cognitive disorders.

[0131] As used herein the term "cognitive disorder" refers to mental disorders wherein the cognitive abilities of a subject are decreased.In some embodiments, the mental disorder is a cognitive disorder, wherein the cognitive disorder is selected from: amnesia, dementia, delirium, amnestic disorder, substance-induced persisting delirium, dementia associated with HIV disease, dementia associated with Huntington's disease, dementia associated with Parkinson's disease, Parkinsonian-ALS dementia complex, dementia associated with Alzheimer's type, age-related cognitive decline, and / or mild cognitive impairment.

[0132] In a preferred embodiment, the mental disorder is a cognitive disorder, wherein the cognitive disorder is selected from: dementia, dementia associated with Huntington's disease, dementia associated with Parkinson's disease, Parkinsonian-ALS dementia complex, dementia associated with Alzheimer's type, and / or age-related cognitive decline.

[0133] In a more preferred embodiment, the mental disorder is a cognitive disorder, wherein the cognitive disorder is selected from: dementia, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, and / or age-related cognitive decline.

[0134] In a most preferred embodiment, the mental disorder is a cognitive disorder, wherein the cognitive disorder is dementia.

[0135] In certain embodiments, the pharmaceutical composition comprising bevantolol may be used in the treatment of bipolar disorders.

[0136] As used herein the term "bipolar disorder" is a mental health condition characterized by extreme mood swings, including episodes of elevated or irritable mood, and low mood or decreased energy.

[0137] In some embodiments, the mental disorder is a bipolar disorder, wherein the bipolar disorder is selected from: bipolar I disorder, bipolar II disorder and / or or cyclothymic disorder.

[0138] In a preferred embodiment, the mental disorder is a bipolar disorder, wherein the bipolar disorder is bipolar I disorder, or bipolar II disorder.

[0139] In some embodiments, the mental disorder may be associated with old age. Examples of age-related mental disorders include but are not limited to: dementia, vascular dementia, dementia related to a neurodegenerative disorder such as Alzheimer's disease, Lewy body dementia, depression, anxiety disorders, cognitive impairment, psychosis, bipolar disorder, sleep disorders.In some embodiments, the mental disorder is an eating disorder, wherein the eating disorder is anorexia nervosa, bulimia nervosa, and binge eating disorder.

[0140] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the mental disorder is selected from: schizophrenia, schizoaffective disorder, psychosis, psychosis associated with a neurodegenerative disease, obsessive-compulsive disorder, generalized anxiety disorder, social anxiety disorder, specific phobia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, addiction, and / or dementia.

[0141] The pharmaceutical composition according to the invention may be used for the treatment of one or more mental disorder. That is, the subject to be treated may also be a subject that has been diagnosed with two or more mental disorders. The subject to be treated may be diagnosed with any of the mental disorders disclosed herein above, in any suitable combination.

[0142] In certain embodiments, the subject to be treated is a subject that has been diagnosed with a depressive disorder and one or more of a psychotic disorder, an anxiety disorder, a neurodevelopmental disorder, an impulse control disorder, a cognitive disorder, and / or a bipolar disorder, as disclosed herein above.

[0143] In certain embodiments, the subject to be treated is a subject that has been diagnosed with a depressive disorder and a psychotic disorder as discloses herein above.

[0144] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the mental disorder is a depressive disorder and wherein the subject is having a hyperkinetic movement disorder.

[0145] That is, in certain embodiments, the invention relates to the use of a pharmaceutical composition comprising bevantolol in the treatment of a depressive disorder in a patient that has been diagnosed with a hyperkinetic movement disorder.The appended examples demonstrate that bevantolol can alleviate chorea in patients diagnosed with Huntington's disease, as evidenced by a reduced Total Maximal Chorea (TMC) score shown in Figure 6. Additionally, bevantolol simultaneously reduced the severity of depression in these patients, as indicated by a decreased Beck Depression Inventory (BDI) score in Figure 7.

[0146] The patient that is treated for a mental disorder may have any form of hyperkinetic movement disorder.

[0147] As used herein the term "hyperkinetic movement disorder" refers to a group of central nervous system conditions and / or diseases which involve an excess of involuntary movements.

[0148] Hyperkinetic movement disorders can be associated with neurological diseases such as Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.

[0149] Examples of hyperkinetic movement disorders include, but are not limited to: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

[0150] Thus, in a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.

[0151] In a preferred embodiment, the invention relates to the pharmaceutical composition of the invention, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, and / or tardive dyskinesia.In a more preferred embodiment, the invention relates to the pharmaceutical composition of the invention, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, and / or Tourette syndrome.

[0152] In a most preferred embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the hyperkinetic movement disorder is associated with Huntington's disease.

[0153] The pharmaceutical composition of the present invention is particularly suitable for use in the treatment of a depressive disorder in a subject having a hyperkinetic movement disorder, as bevantolol was demonstrated to reduce depression and depressive symptoms, while also reducing symptoms of the hyperkinetic movement disorder. The inventors of the present invention have surprisingly found that the pharmaceutical composition comprising bevantolol simultaneously reduces the symptoms of a hyperkinetic movement disorder and depression, contrary to other VMAT inhibitors such as tetrabenazine or reserpine which have been described to induce depression as a side effect.

[0154] Accordingly, it is understood that the present invention also relates the use of bevantolol or a pharmaceutical composition comprising bevantolol for use in the simultaneous treatment of a hyperkinetic movement disorder and depression / depressive symptoms, for example in the context of Huntington's disease.

[0155] Furthermore, the present inventors have surprisingly found that the pharmaceutical composition comprising bevantolol does not induce somnolence (i.e. sleepiness) and specifically daytime sleepiness, contrary to other VMAT2 inhibitors such as tetrabenazine which have been described to commonly induce somnolence as a side effect.

[0156] Additionally, the present inventors have surprisingly found that the pharmaceutical composition comprising bevantolol does not induce extrapyramidal symptoms, such as parkinsonism or dystonia, contrary to other VMAT2 inhibitors such as tetrabenazine which have been described to commonly induce somnolence as a side effect.

[0157] Additionally, the present inventors have surprisingly found that the pharmaceutical composition comprising bevantolol does not induce akathisia, contrary to other VMAT2inhibitors such as tetrabenazine which have been described to commonly induce akathisia as a side effect.

[0158] Additionally, the present inventors have surprisingly found that the pharmaceutical composition comprising bevantolol does not induce or worsen cognitive impairment, contrary to other VMAT2 inhibitors such as tetrabenazine which have been described to commonly induce or worsen cognitive impairment as a side effect.

[0159] Additionally, the present inventors have surprisingly found that the pharmaceutical composition comprising bevantolol does not induce QT prolongation, contrary to other VMAT2 inhibitors such as tetrabenazine which have been described to induce slight QT prolongation, or haloperidol which induces significant QT prolongation, as a side effect.

[0160] It is commonly understood that the term " QT prolongation" relates to a prolongation of the QT-intervall in an Electrocardiogram (ECG).

[0161] Accordingly, the present inventors have surprisingly found that the pharmaceutical composition comprising bevantolol does not exhibit the afore-mentioned side effects. It has, thus, surprisingly been found that the pharmaceutical composition comprising bevantolol is safer than established treatment approaches.

[0162] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

[0163] In a preferred embodiment, the invention relates to the pharmaceutical composition of the invention, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, and / or essential tremor.In a more preferred embodiment, the invention relates to the pharmaceutical composition of the invention, wherein the hyperkinetic movement disorder is selected from: ballism, chorea, and / or dystonia.

[0164] In a most preferred embodiment, the invention relates to the pharmaceutical composition of the invention, wherein the hyperkinetic movement disorder is chorea.

[0165] In some embodiments, the hyperkinetic movement disorder is associated with a neurological disorder such as Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.

[0166] In a preferred embodiment, the hyperkinetic movement disorder is associated with a neurological disorder selected from: Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, and / or tardive dyskinesia.

[0167] In a more preferred embodiment, the hyperkinetic movement disorder is associated with a neurological disorder selected from: Huntington's disease, Wilson's disease, and / or Tourette syndrome.

[0168] In a most preferred embodiment, the hyperkinetic movement disorder is associated with Huntington's disease.

[0169] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

[0170] That is, the pharmaceutical composition of the present invention is particularly suitable for use in the treatment of depressive disorders in subjects having chorea associated with Huntington's disease. In such embodiments, the depressive disorder may be selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression,dysthymic disorder, seasonal affective disorder, mixed-anxiety depressive disorder, and / or secondary depression.

[0171] In a particular embodiment, the invention relates to a pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder.

[0172] That is, the pharmaceutical composition of the invention may also be used for the treatment of a hyperkinetic movement disorder in a subject, wherein said subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder.

[0173] A depressive disorder may be diagnosed by a mental health professional with reference to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Typically, a depressive disorder is diagnosed when the symptoms reach a specific threshold and persist for at least two weeks. Various methods and techniques are available to skilled professionals for diagnosing a depressive disorder. These methods usually assess the status, severity, and progression of the condition, including responses to treatment or therapy. Techniques for diagnosing, assessing, and monitoring a depressive disorder may include clinician assessments, self-assessment or self-report questionnaires, and clinician-completed reports or questionnaires, alongside biochemical measurements. A variety of clinical measures of symptoms and mood are well known to those skilled in the art. The present disclosure contemplates the use of any such methods or techniques for diagnosing a depressive disorder and for assessing or monitoring these conditions. This can be part of an initial determination of an individual's suitability for treatment in accordance with the present disclosure or for evaluating the efficacy of a treatment as described herein.

[0174] The expression "at risk of developing a depressive disorder" as used herein refers to a subject who exhibits one or more risk factors that are known to increase the likelihood of developing a depressive disorder. These risk factors may include, but are not limited to, a family history of depression, previous episodes of depression, chronic medical conditions, significant life stressors, substance abuse, and certain personality traits or genetic predispositions.Identifying individuals at risk of developing a depressive disorder allows for early intervention and preventive measures, which can be crucial in mitigating the onset and severity of depressive symptoms.

[0175] Diagnosis and / or monitoring of a depressive disorder may comprise use of psychometric tests, which comprise self-assessment or self-reporting questionnaires, and clinician-completed reports or questionnaires.

[0176] Exemplary self-assessment or self-report questionnaires include but are not limited to: Depression and Anxiety Stress Scale (DASS), Outcome Questionnaire-45 (OQ45), Quality of Life in Depression Scale (QLDS), Beck's Depression Inventory (BDI), Warwick-Edinburgh Mental Well-Being Scale (WBS), Patient Health Questionnaire (PHQ, such as PHQ-9 and PHQ-2), Center for Epidemiologic Studies Depression Scale (CES-D), Major Depression Inventory (MDI), Zung Self-Rating Depression Scale (SDS), Geriatric Depression Scale (GDS).

[0177] Exemplary clinician-completed reports or questionnaires include but are not limited to: Mini International Neuropsychiatric Interview (MINI), Structured Clinical Interview for DSM Disorders (SCID), Hamilton Depression Rating Scale (HAM-D), Raskin Depression Rating Scale, Cornell Scale for Depression in Dementia (CASDD).

[0178] Biochemical measurements that may be employed to diagnose and / or monitor depressive disorders may include, but are not limited to: cortisol levels, thyroid function tests, serotonin levels, brain-derived neurotrophic factor, inflammatory markers (CRP, IL-6, TNF-α), vitamin D levels, omega-3 fatty acids, homocysteine levels, dopamine and norepinephrine levels, and gamma-aminobutyric acid (GABA) levels.

[0179] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the pharmaceutical composition results in an improved depression score.

[0180] That is, treatment of a subject having a depressive disorder with the composition comprising bevantolol preferably results in an improvement depression score.

[0181] The term "depression score" as used herein refers to a numerical value derived from standardized assessment tools designed to evaluate the severity and presence of depressivesymptoms in an individual. The depression score is used by healthcare professionals to diagnose depression, monitor changes over time, and evaluate the effectiveness of therapeutic interventions.

[0182] In some embodiments, the depression score may be determined using a psychometric test for measuring the severity of depression. This test may be selected from: Depression and Anxiety Stress Scale (DASS), the Outcome Quiestionnaire-45 (OQ45), Quality of Life in Depression Scale (QLDS, including a Quality of Life (QoL) score), the Beck's Depression Inventory (BDI), the Warwick-Edinburgh Mental Well-Being Scale (WBS), the Mini International Neuropsychiatric Interview (MINI), the Structured Clinical Interview for DSM Disorders (SCID), the Patient Health Questionnaire (PHQ, such as PHQ-9 and PHQ-2), Hamilton Depression Rating Scale (HAM-D), the Raskin Depression rating Scale, Center for Epidemiologic Studies Depression Scale (CES-D), Major Depression Inventory (MDI), Zung Self-Rating Depression Scale (SDS), Geriatric Depression Scale (GDS) and / or Cornell Scale for Depression in Dementia (CASDD).

[0183] In a preferred embodiment, the improvement of a depression score is measured using the Beck's Depression Inventory (BDI) test.

[0184] In a particular embodiment, the invention relates to the pharmaceutical composition for use in the prevention or treatment of a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder and wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed-anxiety depressive disorder, and / or secondary depression.

[0185] In some embodiments, the invention relates to the pharmaceutical composition for use in the prevention or treatment of a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder, wherein said depressive disorder is selected from: major depressive disorder, persistent depressive disorder, treatment resistant depression, seasonal affective disorder and bipolar disorder.In a preferred embodiment, said depressive disorder is selected from: major depressive disorder, persistent depressive disorder, treatment resistant depression and bipolar disorder.

[0186] In a more preferred embodiment, said depressive disorder is selected from: major depressive disorder, persistent depressive disorder, and treatment resistant depression.

[0187] In a most preferred embodiment, the depressive disorder is major depressive disorder.

[0188] In a particular embodiment, the invention relates to the pharmaceutical composition for use in the prevention or treatment of a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder, wherein said hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome.

[0189] In a preferred embodiment, said hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia.

[0190] In a more preferred embodiment, said hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome.

[0191] In a most preferred embodiment, said hyperkinetic movement disorder is associated with Huntington's disease.

[0192] In a particular embodiment, the invention relates to the pharmaceutical composition for use in the prevention or treatment of a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder, and wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

[0193] In a preferred embodiment, the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia,hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, and / or essential tremor.

[0194] In a more preferred embodiment, the hyperkinetic movement disorder is selected from: ballism, chorea, dystonia.

[0195] In a most preferred embodiment, the hyperkinetic movement disorder is chorea.

[0196] In a particular embodiment, the invention relates to the pharmaceutical composition for use in the treatment or prevention of chorea associated with Huntington's disease in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder.

[0197] The severity of hyperkinetic movement disorders such as chorea associated with Huntington's disease may be measured using motor rating scales or scores. Examples for motor rating scales and scores for the assessment hyperkinetic movement disorders, including chorea associated with Huntington's disease, include but are not limited to: Unified Huntington's Disease Rating Scale (UHDRS), Total Maximal Chorea (TMC), Motor Scale of the UHDRS, Huntington's Disease Rating Scale (HD Rating Scale), Total Functional Capacity Scale (TFC), Cambridge Neuropsychiatry Rating Scale for Huntington's Disease (CNS-R), Motor Abnormality Rating Scale (MARS), and Huntington's Disease Activities of Daily Living Scale (HD-ADL). Motor rating scales and scores for other hyperkinetic movement disorders include but are not limited to: Abnormal Involuntary Movement Scale (AIMS), Fahn-Marsden Dystonia Rating Scale (FMDRS), Jankovic Rating Scale for Tremor, Dyskinesia Rating Scale, Yale Global Tic Severity Scale (YGTSS), Motor Assessment Scale (MAS), and Dystonia Rating Scales.

[0198] In some embodiments, the invention relates to the pharmaceutical composition of the invention, wherein the pharmaceutical composition results in an improved motor rating scale or score.

[0199] In some embodiments, the motor rating scale or score is selected from: Unified Huntington's Disease Rating Scale (UHDRS), Total Maximal Chorea (TMC), Motor Scale of the UHDRS, Huntington's Disease Rating Scale (HD Rating Scale), Total Functional Capacity Scale (TFC), Cambridge Neuropsychiatry Rating Scale for Huntington's Disease (CNS-R), Motor Abnormality Rating Scale (MARS), and Huntington's Disease Activities of Daily Living Scale (HD-ADL), Abnormal Involuntary Movement Scale (AIMS), Fahn-Marsden Dystonia Rating Scale (FMDRS), Jankovic Rating Scale for Tremor, Dyskinesia Rating Scale, Yale Global Tic Severity Scale (YGTSS), Motor Assessment Scale (MAS), and Dystonia Rating Scales.

[0200] In some embodiments, the improvement of a movement disorder in a Huntington's disease subject is quantified using the Unified Huntington's Disease Rating Scale (UHDRS), Total Maximal Chorea (TMC) score, Motor Scale of the UHDRS, Huntington's Disease Rating Scale (HD Rating Scale), Total Functional Capacity Scale (TFC), Cambridge Neuropsychiatry Rating Scale for Huntington's Disease (CNS-R), Motor Abnormality Rating Scale (MARS), and Huntington's Disease Activities of Daily Living Scale (HD-ADL).

[0201] In a preferred embodiment, the improvement of a movement disorder in a Huntington's disease subject is quantified using the Total Maximal Chorea (TMC) score.

[0202] As used herein the terms "treating", "treatment" and the like refer to any applications which remedy, or otherwise hinder, retard, or reverse the progression of, a disorder or at least one symptom of a disease, including reducing the severity of a disorder. Thus, treatment does not necessarily imply that a subject is treated until complete elimination of, or recovery from, a disorder.

[0203] As used herein, the term "prevent" refers to taking measures to stop or avert the onset or progression of a disorder in a subject who may be at risk, predisposed, or exhibiting early signs or symptoms of the condition, but who has not yet been formally diagnosed with it. Prevention aims to maintain health and well-being by intervening before the disorder fully develops.

[0204] As used herein the term "disorder" is intended to be generally synonymous with, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition). All these terms reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.As used herein, the term "subject" refers to any human or nonhuman animal. The term "nonhuman animal" includes but is not limited to: vertebrates such as nonhuman primates, sheep, dogs, and rodents such as mice, rats and guinea pigs. In some embodiments, the subject is a human. The terms, "subject" and "patient" are used interchangeably herein.

[0205] In a particular embodiment of the invention, the pharmaceutical composition comprising bevantolol or a pharmaceutically acceptable salts thereof is administered to a patient. In such embodiments, the pharmaceutical composition of the invention is administered orally, preferably as a tablet or a capsule.

[0206] As used herein, the term "administered" refers to the act of delivering or applying a pharmaceutical composition or therapeutic agent to a subject, whether human or animal, by any suitable route to achieve a desired therapeutic effect. This includes, but is not limited to, oral, intravenous, intramuscular, subcutaneous, transdermal, inhalational, and topical routes of administration. The term encompasses both direct administration by a healthcare professional and self-administration by the subject.

[0207] Preferably, the composition for use according to the invention is administered orally.

[0208] In some embodiments, the invention relates to the pharmaceutical composition according to the invention, wherein the pharmaceutical composition is prepared for administration to a subject as an oral unit dosage form. In another embodiment of the invention, said pharmaceutical composition for use is an intraoral unit dosage form including sublingual and buccal. In a preferred embodiment, the pharmaceutical composition is a solid pharmaceutical composition which rapidly disintegrate in the mouth of a subject, upon insertion into the buccal pouch or upon placement under the tongue. Examples of oral dosage forms suitable for the present invention include but are not limited to: solid dosage forms like tablets, powders, capsules, sachets, as well as liquid syrups, gels, suspensions and elixirs. Pharmaceutically acceptable carriers and excipients suitable for use in the oral formulations disclosed herein include but are not limited to: diluents such as fillers and bulking agents, binders, lubricants, anti-caking agents, disintegrants, sweeteners, buffering agents, preservatives, solubility enhancers, isotonic agents, suspending and dispersing agents, wetting or emulsifying agents, flavors and aromas, thickening agents, and vehicles.In a particular embodiment, the composition for use according to the invention is a tablet or a capsule. Such tablets may, e.g. also be effervescent tablets.

[0209] In some embodiments, the invention relates to a pharmaceutical composition for use according to the invention, wherein the pharmaceutical composition is in the form of an inhalation unit dosage form, which is inhaled through the mouth or the nose, administered via an aerosol or a dry powder inhaler. Examples of inhalation dosage forms suitable for the present invention include but are not limited to: solutions, suspensions, and powders. Solutions and suspensions can be administered by atomizers, nebulizers, and vaporizing aerosol devices; and powders can be administered by insufflators or puffers. Pharmaceutically acceptable carriers and excipients suitable for use in the inhalation formulations disclosed herein include but are not limited to: preservatives, buffer salts, viscosity modifying agents, suspending agents, pH-adjusting agents, tonicity adjusting agent, solvent, co-solvent, surfactant and flavors.

[0210] In some embodiments, the inhalation unit dosage form of the invention may be in the form of pressurized dispersers of unit dose, bi-dose or multi-dose devices. The pressurized dispersers may further comprise at least one propellant agent. The propellant is the agent that supplies the necessary pressure within the aerosol, nebulizer or insufflator system to expel the material from the container. Propellants are commonly classified as liquefied or compressed gases having vapor pressures generally exceeding atmospheric pressure. Examples of suitable propellants for the present invention include but are not limited to: hydrocarbons, especially halogenated derivatives of methane, ethane, and propane, low molecular weight hydrocarbons such as the butanes and pentanes, and compressed gases such as carbon dioxide, nitrogen, and nitrous oxide. Mixtures of propellants are frequently used to obtain desirable pressure, delivery, and spray characteristics.

[0211] In another embodiment, the composition for use of the present invention is in form of a topical unit dosage form to be applied to the skin or mucous membranes of a patient to be treated. Examples of topical dosage forms suitable for the present invention include but are not limited to: transdermal patches, transdermal plasters, solutions, aerosols and non-aerosol sprays, creams, powders, lotions, gels, ointments, pastes, emulsions, pens or sticks.Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations disclosed herein include but are not limited to: an emollient, a thickener, a humectant, a pH-regulating agent, an antioxidant, a preservative agent, solubility enhancers, isotonic agents, suspending and dispersing agents, wetting or emulsifying agents, flavors and aromas, thickening agents, and vehicles or their mixtures.

[0212] The skilled person is aware that the individual dosage as well as the daily dosage of the pharmaceutical composition varies depending on the type and severity of the mental disorder, depressive disorder, and / or hyperkinetic movement disorder to be treated, and the specific patient response to the medication. Therefore, the exact individual dosage will be determined according to standard medical principles under the direction of a physician.

[0213] The pharmaceutical composition for use according to the invention is administered in an effective amount, which refers to a quantity sufficient to achieve the desired therapeutic effect in a subject. The effective amount will vary depending on factors such as the specific condition being treated, the severity of the condition, the subject's age, weight, and overall health, as well as the pharmacokinetics and pharmacodynamics of the active ingredient. The effective amount is determined by a healthcare professional and may involve titration to optimize the therapeutic outcome while minimizing potential side effects. This dosage ensures that the active ingredient is delivered at a concentration that is both safe and efficacious, providing the intended benefits of the treatment.

[0214] In a preferred embodiment, the present invention relates to the pharmaceutical composition for use according to the invention, wherein the pharmaceutical composition is administered once per day. In a more preferred embodiment, the pharmaceutical composition for use according to the invention is administered twice per day.

[0215] In some embodiments, the pharmaceutical composition for use according to the invention may be administered once or more than once per week.

[0216] In some embodiments, the pharmaceutical composition for use according to the invention may be formulated as a modified release dosage form, preferably a delayed release dosage.In such embodiments, the delayed release dosage may comprise a tablet core comprising an effective amount of bevantolol or a pharmaceutically acceptable salt thereof, the tablet core being surrounded by an outer surface, and an enteric coating completely covering the outer surface of the tablet core, the coating comprising an enteric polymer.

[0217] The enteric polymer may be selected from: a methacrylic acid / methacrylic acid ester copolymer, a methacrylic acid / acrylic acid ester copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate trimellitate, polyvinyl acetate phthalate, polyethylene oxide, and / or hydroxypropylmethylcellulose.

[0218] The present invention also relates to a deuterated derivative of bevantolol, i.e. bevantolol wherein one or more hydrogen atoms in the parent molecule are replaced by deuterium. It is commonly understood that incorporation of deuterium confers improved metabolic stability due to the kinetic isotope effect, resulting in a reduced rate of oxidative degradation and prolonged plasma half-life compared to non-deuterated drugs. Deuteration may lead to enhanced pharmacokinetic properties, allowing for decreased dosing frequency and reduced formation of undesirable metabolites, while maintaining the pharmacodynamic activity. The deuterated compound may be formulated as disclosed herein. The deuterated compound may be administered using the administration routes disclosed herein. It is understood that the deuterated compound may be used in the treatment for the diseases disclosed herein for bevantolol.

[0219] In some embodiments, the dosage form may further comprise one or more additional therapeutic agents suitable for the treatment of mental disorders, depressive disorders and / or hyperkinetic movement disorders.

[0220] In a particular embodiment, the present invention relates to the pharmaceutical composition for use according to the invention, wherein the effective daily dose of bevantolol ranges from 1 to 10,000 mg / day; preferably from 1 to 3,000 mg / day; more preferably from 100 to 1,000 mg / day; most preferably from 500 to 700 mg / day.

[0221] In some embodiments, the composition for use according to the invention is administered daily, wherein the daily dose of bevantolol is about 1 mg, about 10 mg, about 100 mg, about200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, about 8,000 mg, about 9,000 mg, or about 10,000 mg. In a preferred embodiment, said pharmaceutical composition is administered daily, wherein the daily dose of bevantolol is about 1 mg, about 10 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 2,000 mg, or about 3,000 mg. in a more preferred embodiment, said pharmaceutical composition is administered daily, wherein daily dose of bevantolol is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. In another preferred embodiment, said pharmaceutical composition is administered daily, wherein the daily dose of bevantolol is about 600 mg. In an alternative embodiment the daily dose of bevantolol is about 800 mg.

[0222] In a particular embodiment, said pharmaceutical composition is administered twice per day at a dose of bevantolol ranging from 0.5 mg to 5,000 mg. Preferably, said pharmaceutical composition is administered twice per day at a dose of bevantolol ranging from 0.5 mg and 1,500 mg. More preferably, said pharmaceutical composition is administered twice per day at a dose of bevantolol ranging from 50 mg and 500 mg. Most preferably, said pharmaceutical composition is administered twice per day at a dose of bevantolol ranging from 250 mg and 350 mg. In an alternative embodiment, the composition is administered twice per day at a dose of bevantolol ranging from 350 mg and 450 mg.

[0223] In some embodiments, said pharmaceutical composition is administered twice per day, with each dose comprising about 0.5 mg, about 5 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, about 3,000 mg, about 3,500 mg, about 4,000 mg, about 4,500 mg, or about 5,000 mg bevantolol. Preferably, said composition is administered twice per day, with each dose comprising about 0.5 mg, about 5 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg,about 900 mg, about 1,000 mg, or about 1,500 mg bevantolol. More preferably, said composition is administered twice per day, with each dose comprising about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg bevantolol. Most preferably, said composition is administered twice per day, with each dose comprising about 300 mg bevantolol.

[0224] In an alternative embodiment, said composition is administered twice per day, with each dose comprising about 400 mg bevantolol.

[0225] In some embodiments, said composition is administered multiple times per day, wherein the total daily dose of bevantolol is about 1 mg, about 10 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, about 6,000 mg, about 7,000 mg, about 8,000 mg, about 9,000 mg, or about 10,000 mg. Preferably, said pharmaceutical composition is administered multiple times per day, wherein the total daily dose of bevantolol is about 1 mg, about 10 mg, about 100 mg, about 200 mg, about 300 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1,000 mg, about 2,000 mg, or about 3,000 mg. More preferably, said pharmaceutical composition is administered multiple times per day, wherein the total daily dose of bevantolol is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1,000 mg. Most preferably, said pharmaceutical composition is administered multiple times per day, wherein the total daily dose of bevantolol is about 600 mg.

[0226] In an alternative embodiment, said pharmaceutical composition is administered multiple times per day, wherein the total daily dose of bevantolol is about 800 mg.

[0227] The pharmaceutical composition according to the present invention may be administered at different doses during the treatment initiation phase, maintenance phase and tapering phase. It is understood that typically the initiation phase is followed by the maintenance phase which in turn is followed by the tapering phase. Initiation phase and / or tapering phase may be optional.In the context of the present invention, the term "treatment initiation phase" (also referred to herein as "up-titration period" or "up-titration phase") refers to initial period of drug administration. Without being bound by a particular theory, this initial period of the treatment regimen may be at least 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, or more days. In one specific embodiment the treatment initiation phase is preferably 7 days (i.e. 1 week) or 14 days (i.e. 2 weeks).

[0228] It is commonly understood that the treatment regimen may comprise such a treatment initiation phase whenever a subject is first treated with the pharmaceutical composition according to the present invention, or whenever a subject has not been treated with the pharmaceutical composition according to the present invention for a certain period of time. The term "has not been treated for a certain period of time" may refer to treatment breaks or treatment intervals. Without being bound by theory this period of time during which a subject has not been treated with the pharmaceutical composition according to the present invention may be at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, or any duration in between, or more weeks. The optional treatment initiation phase may be repeated if the drug is not administered for at least about 3 weeks.

[0229] The treatment initiation dose (i.e. the dose to be administered during the treatment initiation phase) may be lower than the maintenance dose (i.e. the dose to be administered during the maintenance phase). For example, approx, half the dose of the maintenance dose may be administered as treatment initiation dose. As an example, the treatment initiation dose may be a daily dose of 300 mg if the maintenance dose is 600 mg per day (e.g. when administered at a dose of 300 mg BID (bis in die / twice daily).

[0230] A first treatment initiation phase may be followed by a second treatment initiation phase, where approx, double the dose of the dose administered during the first treatment initiation phase may be administered as treatment initiation dose. As an example, the treatment initiation dose in the first phase may be a daily dose of 300 mg and / or the treatment initiation dose in the second treatment initiation phase may be the double dose thereof (and correspond to the maintenance dose (e.g. 600 mg per day, for example, when administeredat a dose of 300 mg BID (bis in die / twice daily)). In other words, the "treatment initiation phase" may comprise administering a first treatment initiation dose during a first phase (e.g. a treatment initiation dose in the first phase (e.g. 1 week) may be a daily dose of 300 mg) which is followed by administering a second treatment initiation dose during a second phase (e.g. a treatment initiation dose in the second phase (e.g. 1 week) may be a daily dose of 600 mg) 600 mg per day, for example, when administered at a dose of 300 mg BID (bis in die / twice daily)). It may be considered that the second phase is not part of the treatment initiation phase, but of the subsequent phase (e.g. maintenance phase), in particular if the treatment initiation dose in the second treatment initiation phase corresponds to the maintenance dose.

[0231] The tapering dose (i.e. the dose to be administered during the tapering phase) may be lower than the maintenance dose (i.e. the dose to be administered during the maintenance phase). For example, between about 25% and about 75% of the maintenance dose may be administered as tapering dose, preferably between about 30% and 70% of the maintenance dose, more preferably between about 35% and 65% of the maintenance dose, even more preferably between about 40% and 60% of the maintenance dose, even more preferably between about 45% and 55% of the maintenance dose, most preferably about 50% of dose of the maintenance dose may be administered as tapering dose, e.g. in a first tapering phase. It is understood that the tapering dose may also be any range between the increments disclosed hereinabove. As an example, the tapering dose may be a daily dose of 300 mg if the maintenance dose is 600 mg per day (e.g. when administered at a dose of 300 mg BID (bis in die / twice daily)).

[0232] A first tapering phase may be followed by a second tapering phase, where approx, half the dose or less of the dose administered during the first tapering phase may be administered as tapering dose. As an example, the tapering dose in the first tapering phase may be a daily dose of 300 mg and / or the tapering dose in the second tapering phase may be 0 mg bevantolol per day (i.e. placebo treatment). In other words, the "tapering phase" may comprise administering a first tapering dose during a first phase (e.g. a tapering dose in the first phase (e.g. 1 week) may be a daily dose of 300 mg) which is followed by administering a second tapering dose during a second phase (e.g. a tapering dose in the second phase (e.g. 1 week) may be a daily dose of less than daily dose of 300 mg, e.g. 0 mg bevantolol per day). It may be considered that the second phase is not part of the tapering phase, but e.g. of the subsequentphase (e.g. follow-up phase or treatment break), in particular if no active agent is administered in the second phase (e.g. 0 mg bevantolol per day / e.g. placebo).

[0233] According to the present invention, the term "maintenance phase" refers to the main part of the treatment phase. The duration of the maintenance phase is not particularly limited, and it is commonly understood that the pharmaceutical composition according to the present invention may be administered as long as an objectively measurable treatment response is achieved, unless side effects are observed which prevent the subject from continuing therapy or which prompt the subject or clinician to discontinue treatment. Thus, it is understood that the maintenance phase may be at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 20 weeks, at least about 25 weeks, at least about 30 weeks, at least about 35 weeks, at least about 40 weeks, at least about 45 weeks, at least about 50 weeks, or more weeks.

[0234] Where treatment with the pharmaceutical composition is discontinued, either temporarily or permanently, a tapering phase may be employed. The tapering phase is also referred to herein as "down-titration period" or "down-titration phase". Without being bound by theory such a tapering phase may be at least 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, or more days. It is preferable for the tapering phase to last at least about 7 days (i.e. 1 week). During this tapering phase, the pharmaceutical composition according to the present invention may be administered at a dose which differs from the treatment maintenance dose. In one embodiment, the tapering dose is lower than the treatment maintenance dose. Without being bound by theory, the tapering phase may be repeated at different dose levels. For example, a first tapering phase for a period disclosed above, e.g. one week, at a defined dose may be followed up by a second tapering phase at a second, lower dose (i.e. lower dose than the dose in the first phase) for a period disclosed above, e.g. one week.Without being bound by theory, the dose during the treatment initiation and maintenance phase may be different or identical. For example, the dose employed during treatment initiation (i.e. treatment initiation dose) may be lower than the dose employed during the maintenance phase (i.e. maintenance dose), or the treatment initiation and maintenance doses may be identical. Where treatment initiation and maintenance doses are identical, this essentially corresponds to skipping the treatment initiation phase.

[0235] In one embodiment, the treatment initiation dose is lower than the maintenance dose. The considerations regarding dosages per day and / or administration recited herein above apply for treatment initiation and maintenance dose.

[0236] In one particular embodiment, the treatment initiation phase is 1 week at a treatment initiation dose of 300 mg bevantolol per day, the maintenance phase is 11 weeks at a maintenance dose of 300 mg BID (bis in die / twice daily) bevantolol per day (i.e. 600 mg per day), and the tapering phase is 1 week at a dose of 300 mg bevantolol per day, followed by a further tapering phase of 1 week at a dose of 0 mg bevantolol per day (i.e. placebo treatment). In another embodiment, the treatment initiation phase is 1 week at a treatment initiation dose of 300 mg bevantolol per day, and the maintenance phase is about 34 weeks at a dose of 300 mg bevantolol BID per day (i.e. 600 mg per day).

[0237] Furthermore, the maintenance dose may be adapted based on the presence of objectively measurable side effects associated with administration of the pharmaceutical composition according to the present invention. It is within the knowledge of the skilled clinician to determine the relevant side effects (see Example 7). Without being bound by theory, any of the doses recited above may be adapted in such scenario. For example, a reduced treatment maintenance dose may be administered (e.g a reduced dose compared to treatment maintenance dose described elsewhere herein), e.g. 500 mg per day, 450 mg per day, 400 mg per day, 350 mg per day, 300 mg per day, 250 mg per day, 200 mg per day, 150 mg per day, 100 mg per day, 50 mg per day, or any value in between. For example, a dose of 500 mg per day is a reduced dose compared to a dose of 600 mg per day. In one aspect a reducedtreatment maintenance dose may be administered, for example, 150 mg per day, 300 mg per day or 450 mg per day, preferably 300 mg per day.

[0238] Where side effects persist, a further dose reduction may be considered. Typically, such dose reductions are 50% of the previous dose. In case of side effects, tapering doses may be adapted in the same way.

[0239] In other words, the treatment may comprise administering a first dose which is lower than then a second dose (for example approx, half the dose of the second dose, e.g. 300 mg per day) for a period of time (e.g. approx. 1 week, exemplary periods are disclosed in context of the "treatment initiation phase which apply mutatis mutandis in this context) followed by administering a second dose (e.g. approx. 600 mg per day for example when administered at a dose of 300 mg BID (bis in die / twice daily)) for a period of time (e.g. approx. 12 weeks, followed by administering a third dose (for example approx, double the dose of the second dose, e.g. approx.. 300 mg per day) for a period of time.

[0240] Exemplary doses of the "first dose", "second dose" and "third dose" and respective periods of time for administration are disclosed herein in context of treatment initiation dose, maintenance dose and tapering dose which apply mutatis mutandis.

[0241] The treatment initiation dose (i.e. the dose to be administered during the treatment initiation phase) may be lower than the maintenance dose (i.e. the dose to be administered during the maintenance phase). For example, approx, half the dose of the maintenance dose may be administered as treatment initiation dose. As an example, the treatment initiation dose may be a daily dose of 300 mg if the maintenance dose is 600 mg per day (e.g. when administered at a dose of 300 mg BID (bis in die / twice daily)).

[0242] A first treatment initiation phase may be followed by a second treatment initiation phase, where approx, double the dose of the dose administered during the first treatment initiation phase may be administered as treatment initiation dose. As an example, the treatment initiation dose in the first phase may be a daily dose of 300 mg and / or the treatment initiation dose in the second treatment initiation phase may be the double dose thereof (and correspond to the maintenance dose (e.g. 600 mg per day, for example, when administered at a dose of 300 mg BID (bis in die / twice daily)). In other words, the "treatment initiation phase" may comprise administering a first treatment initiation dose during a first phase (e.g. a treatment initiation dose in the first phase (e.g. 1 week) may be a daily dose of 300 mg)which is followed by administering a second treatment initiation dose during a second phase (e.g. a treatment initiation dose in the second phase (e.g. 1 week) may be a daily dose of 600 mg) 600 mg per day, for example, when administered at a dose of 300 mg BID (bis in die / twice daily)). It may be considered that the second phase is not part of the treatment initiation phase, but of the subsequent phase (e.g. maintenance phase), in particular if the treatment initiation dose in the second treatment initiation phase corresponds to the maintenance dose.

[0243] The tapering dose (i.e. the dose to be administered during the tapering phase) may be lower than the maintenance dose (i.e. the dose to be administered during the maintenance phase). For example, between about 25% and about 75% of the maintenance dose may be administered as tapering dose, preferably between about 30% and 70% of the maintenance dose, more preferably between about 35% and 65% of the maintenance dose, even more preferably between about 40% and 60% of the maintenance dose, even more preferably between about 45% and 55% of the maintenance dose, most preferably about 50% of the maintenance dose may be administered as tapering dose, e.g. in a first tapering phase.. It is understood that the tapering dose may also be any range between the increments disclosed herein above. As an example, the tapering dose may be a daily dose of 300 mg if the maintenance dose is 600 mg per day (e.g. when administered at a dose of 300 mg BID (bis in die / twice daily)).

[0244] A first tapering phase may be followed by a second tapering phase, where approx, half the dose or less of the dose administered during the first tapering phase may be administered as tapering dose. As an example, the tapering dose in the first tapering phase may be a daily dose of 300 mg and / or the tapering dose in the second tapering phase may be 0 mg bevantolol per day. In other words, the "tapering phase" may comprise administering a first tapering dose during a first phase (e.g. a tapering dose in the first phase (e.g. 1 week) may be a daily dose of 300 mg) which is followed by administering a second tapering dose during a second phase (e.g. a tapering dose in the second phase (e.g. 1 week) may be a daily dose of less than daily dose of 300 mg, e.g. 0 mg bevantolol per day). It may be considered that the second phase is not part of the tapering phase, but e.g. of the subsequent phase (e.g. follow-up phase or treatment break), in particular if no active agent is administered in the second phase (e.g. 0 mg bevantolol per day).In some embodiments, a lower daily amount, preferably 1 mg to 600 mg of bevantolol hydrochloride, may be administered to a subject diagnosed with one or more mental disorders, preferably wherein said mental disorder is selected from: depressive disorder, psychotic disorder, anxiety disorder, neurodevelopmental disorder, impulse control disorder, cognitive disorder and / or bipolar disorder. In some embodiments, a higher daily amount, preferably 600 mg to 3,000 mg of bevantolol hydrochloride is administered to a subject, preferably wherein the subject has a hyperkinetic movement disorder, or wherein the subject has a hyperkinetic movement disorder and a depressive disorder, or wherein the subject has a hyperkinetic movement disorder and is at risk of developing a depressive disorder.

[0245] The pharmaceutical composition according to the present invention may further be used to alleviate one or more of the following symptoms associated with Huntington's disease, including chorea, depression, suicidality, anxiety, apathy, compulsive behavior, disruptive behavior, irritable behavior, and / or perseverative thinking, (see Example 6). It is commonly understood that amelioration of such symptoms is typically described as compared to baseline (i.e. the pre-treatment status), unless specified otherwise.

[0246] In one specific embodiment, treatment with the pharmaceutical composition according to the present invention leads to a significant improvement of chorea in a subject diagnosed with Huntington's disease, as well as one or more symptoms selected from the group consisting of depression, anxiety, apathy, compulsive behavior, disruptive behavior, irritable behavior, and perseverative thinking.

[0247] For example, treatment with the pharmaceutical composition according to the present invention may reduce depression. In one particular example, a reduction in depression symptoms as shown by a BDI mean score reduction of -3.32 ± SD 4.845 points was observed in HD patients diagnosed with baseline mild depression upon treatment with 600 mg / day bevantolol over the treatment course. In contrast, alternative treatment approaches (such as tetrabenazine), are known to increase symptoms of depression and / or are even contraindicated for use in patients diagnosed with depression and / or suicidal ideation.

[0248] Thus, the pharmaceutical composition according to the present invention may be used for the treatment of symptoms of depression (as defined herein). Specifically, the pharmaceuticalcomposition according to the present invention may be used for the treatment of symptoms of depression (as defined herein) in a subject diagnosed with hyperkinetic movement disorders, such as Huntington's disease.

[0249] Treatment with the pharmaceutical composition according to the present invention may alleviate symptoms of anxiety. In one specific example, anxiety symptoms improved by about -1.7 score points (mean score reduction of -1.7 ± SD 3.168) from baseline upon treatment with 400 mg / day bevantolol. Thus, the pharmaceutical composition according to the present invention may be used for the treatment of symptoms of anxiety (as defined herein). Specifically, the pharmaceutical composition according to the present invention may be used for the treatment of symptoms of anxiety (as defined herein) in a subject diagnosed with hyperkinetic movement disorders, such as Huntington's disease.

[0250] Treatment with the pharmaceutical composition according to the present invention may alleviate symptoms of apathy. In one specific example, apathy symptoms improved by about -0.33 score points (mean score reduction of -0.33 ± SD 2.378) from baseline upon treatment with 400 mg / day bevantolol, whereas apathy symptoms increased by +0.6 score points in the control group. Thus, the pharmaceutical composition according to the present invention may be used for the treatment of symptoms of anxiety (as defined herein). Specifically, the pharmaceutical composition according to the present invention may be used for the treatment of symptoms of anxiety (as defined herein) in a subject diagnosed with hyperkinetic movement disorders, such as Huntington's disease.

[0251] Treatment with the pharmaceutical composition according to the present invention may alleviate compulsive behavior. It is commonly known that "compulsive behavior" refers to repetitive actions or mental acts that a person feels driven to perform in response to an urge or according to rigid rules, often to reduce anxiety or prevent a feared event, even if the actions are excessive, irrational, or not connected in a realistic way to the intended outcome. In one specific example, compulsive behavior improved by about -0.15 score points (mean score reduction of -0.15 ± SD 0.700) from baseline upon treatment with 600 mg / day bevantolol. Thus, the pharmaceutical composition according to the present invention may be used for the treatment of compulsive behavior (as defined herein). Specifically, thepharmaceutical composition according to the present invention may be used for the treatment of compulsive behavior (as defined herein) in a subject diagnosed with hyperkinetic movement disorders, such as Huntington's disease.

[0252] Treatment with the pharmaceutical composition according to the present invention may alleviate disruptive behavior. It is understood that "disruptive behavior" refers to actions or conduct that significantly interrupts or interferes with the normal functioning, order, or harmony of a setting, such as a classroom, workplace, or social environment. This type of behavior often involves defiance, aggression, noncompliance, or rule-breaking, and can negatively impact others by causing distraction, conflict, or distress.

[0253] In one specific example, manifestations of disruptive behavior improved by about -0.58 score points (mean score reduction of -0.58 ± SD 2.297) from baseline upon treatment with 600 mg / day bevantolol. Thus, the pharmaceutical composition according to the present invention may be used for the treatment of disruptive behavior (as defined herein). Specifically, the pharmaceutical composition according to the present invention may be used for the treatment of disruptive behavior (as defined herein) in a subject diagnosed with hyperkinetic movement disorders, such as Huntington's disease.

[0254] Treatment with the pharmaceutical composition according to the present invention may alleviate irritable behavior. It is understood that "irritable behavior" refers to actions or responses characterized by a heightened tendency to become easily annoyed, frustrated, or angered, often in response to minor provocations or everyday situations. This type of behavior may manifest as impatience, snapping at others, moodiness, or an inability to tolerate frustration, and can affect interactions and relationships with others.

[0255] In one specific example, manifestations of irritable behavior improved by about -0.58 score points (mean score reduction of -0.68 ± SD 2.411) from baseline upon treatment with 600 mg / day bevantolol. Thus, the pharmaceutical composition according to the present invention may be used for the treatment of irritable behavior (as defined herein). Specifically, the pharmaceutical composition according to the present invention may be used for the treatment of irritable behavior (as defined herein) in a subject diagnosed with hyperkinetic movement disorders, such as Huntington's disease.Treatment with the pharmaceutical composition according to the present invention may alleviate perseverative thinking. It is understood that "perseverative thinking" refers to the repetitive and continuous focus on the same thought, idea, or theme, even when it is no longer relevant or productive. This type of thinking is characterized by difficulty in shifting attention away from certain thoughts, leading to a mental "stuckness" or rumination. Perseverative thinking is commonly observed in various psychological conditions.

[0256] In one specific example, perseverative thinking improved by about -0.58 score points (mean score reduction of -0.51 ± SD 2.077) from baseline upon treatment with 400 mg / day bevantolol. Thus, the pharmaceutical composition according to the present invention may be used for the treatment of symptoms of perseverative thinking (as defined herein). Specifically, the pharmaceutical composition according to the present invention may be used for the treatment of perseverative thinking (as defined herein) in a subject diagnosed with hyperkinetic movement disorders, such as Huntington's disease.

[0257] Treatment with the pharmaceutical composition according to the present invention may alleviate psychotic symptoms. It is understood that "psychotic symptoms" refer to a set of experiences and behaviors that indicate a loss of contact with reality, such as delusions, hallucinations and disorganized thinking.

[0258] In some embodiments, the invention relates to the pharmaceutical composition for use according to the invention, wherein said pharmaceutical composition further comprises or is administered in combination with one or more additional therapeutic agents.

[0259] That is, the pharmaceutical composition for use according to the present invention may be combined with one or more additional therapeutic agents for use in the treatment, prevention, control, amelioration, or reduction of risk of disorders for which the composition according to the invention may have utility, and / or where the combination may be safer or more efficacious than monotherapy.

[0260] As used herein, the term "additional therapeutic agents" refer to compounds and formulations thereof which may be combined with the pharmaceutical composition of the present invention and used for the treatment, prevention, control, amelioration, or reduction of risk of a disorder.In some embodiments, the invention relates to a combination therapy in which the pharmaceutical composition for use according to the invention is administered together with an additional therapeutic agent. Such combinations may be fixed dose combinations (the active ingredients that are to be combined are in the same pharmaceutical formulation) or free dose combinations (active ingredients are in separate pharmaceutical formulations).

[0261] In some embodiments, the invention relates to a combination of the composition for use according to the present invention with at least one other active compound, wherein the other active compound increases efficacy and / or safety of bevantolol. The active compounds of such a combination may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.

[0262] In some embodiments, the invention relates to a pharmaceutical composition for use according to the invention in combination with one or more additional therapeutic agents for use in the treatment of one or more mental disorders. In such embodiments, the pharmaceutical composition for use according to the invention may be combined with one or more therapeutic agents for use in the treatment of one or more mental disorders, preferably wherein the mental disorder is selected from: depressive disorder, bipolar disorder, schizophrenia, schizoaffective disorder, psychosis, psychosis associated with a neurodegenerative disease, obsessive-compulsive disorder, generalized anxiety disorder, social anxiety disorder, specific phobia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, addiction, and / or dementia.

[0263] In some embodiments, the invention relates to a pharmaceutical composition for use according to the invention in combination with one or more additional therapeutic agents for use in the treatment of one or more mental disorders, wherein said mental disorder is a depressive disorder. In such embodiments, the pharmaceutical composition for use according to the invention may be combined with one or more therapeutic agents for use in the treatment of a depressive disorder, for example wherein said therapeutic agent is an antidepressant selected from: selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), noradrenaline and specific serotonergic antidepressants (NASSAs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), serotonin antagonists and reuptake inhibitors (SARIs), monoamine oxidase inhibitors (MAOIs), norepinephrine reuptake inhibitors (NRIs), and atypical antipsychotics. Examples of SSRIs include but are not limited to: citalopram (Celexa, Cipramil), escitalopram (Lexapro, Cipralex), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox, Faverin), paroxetine (Paxil, Seroxat), sertraline (Zoloft, Lustral). Examples of SNRIs include but are not limited to: desvenlafaxine (Pristiq), duloxetine (Cymbalta), levomilnacipran (Fetzima), milnacipran (Ixel, Savella, Milnaneurax), venlafaxine (Effexor, Trevilor). Examples of NASSAs include but are not limited to: aptazapine (CGS-7525A), esmirtazapine (ORG-50,081), mianserin (Bolvidon, Norval, Tolvon), mirtazapine (Norset, Remeron, Avanza, Zispin), setiptiline / teciptiline (Tecipul). Examples for TCAs include but are not limited to: amitriptyline (Elavil, Endep), amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), amoxapine (Asendin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dibenzepin (Noveril, Victoril), dimetacrine (Istonil), dosulepin (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), lofepramine (Lomont, Gamanil), melitracen (Dixeran, Melixeran, Trausabun), nitroxazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxiptiline (Agedal, Elronon, Nogedal), pipofezine (Azafen / Azaphen), protriptyline (Vivactil), trimipramine (Surmontil). Examples for TECAs include but are not limited to: maprotiline (Ludiomil), mianserin (Tolvon), mirtazapine (Remeron), setiptiline (Tecipul). Examples for SARIs include but are not limited to: etoperidone (Axiomin, Etonin), lorpiprazole (Normarex), mepiprazole (Psigodal), nefazodone (Serzone, Nefadar), trazodone (Desyrel). Examples for MAOIs include but are not limited to: isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl, Zelapar, Emsam), metralindole (Inkazan), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), caroxazone (Surodil, Timostenil). Examples for NRIs include but are not limited to: reboxetine (Edronax), teniloxazine (Lucelan, Metatone), viloxazine (Qelbree, formerly Vivalan).

[0264] In some embodiments, the invention relates to the pharmaceutical composition for use according to the invention in combination with one or more additional therapeutic agents for use in the treatment of one or more mental disorders in a subject, wherein the mental disorder is selected from: psychotic disorder, anxiety disorder, neurodevelopmental disorder,impulse control disorder, cognitive disorder, and / or bipolar disorder. In such embodiments, the pharmaceutical composition for use according to the invention may be combined with one or more additional therapeutic agents for use in the treatment of one or more mental disorders in a subject, preferably wherein said therapeutic agents are selected from: antidepressants, antipsychotics, anti-anxiety medications (anxiolytics), mood stabilizing agents and stimulant medications. It is to be understood that some of the therapeutic agents may have redundant functions, for example, anti-depressants may be used for the treatment of a depressive disorder and an anxiety disorder. Examples for therapeutic agents for the treatment of mental disorders include but are not limited to: antidepressants as listed above; benzodiazepines such as clonazepam (Klonopin); azapirones such as alnespirone (S-20,499), binospirone (MDL-73,005), Buspirone (Buspar), Enilospirone (CERM-3,726), eptapirone (F-11,440), gepirone (Exxua), ipsapirone (TVX-Q-7,821), revospirone (BAY-VQ-7,813), tandospirone (Sediel), zalospirone (WY-47,846); beta-adrenoceptor antagonists such as propranolol; antipsychotics such as aripiprazole (Ability, Aristada), asenapine (Secuado, Saphris), brexpiprazole (Rexulti), cariprazine (Vraylar), clozapine (Clozaril, Versacloz), lloperidone (Fanapt), lumateperone (Caplyta), lurasidone (Latuda), olanzapine (Zyprexa, Lybalvi, Symbyax), quetiapine (Seroquel), paliperidone (Invega), pimavanserin (Nuplazid), risperidone (Perseris, Risperdal), ziprasidone (Geodon); acetyl cholinesterase inhibitors such as donepezil; anti-glutamatergic agents such as riluzole.

[0265] In some embodiments, the invention relates to the pharmaceutical composition for use according to the invention in combination with one or more additional therapeutic agents for the treatment of a subject that has been diagnosed with two or more mental disorders. In such embodiments, the pharmaceutical composition of the invention may be combined with one or more therapeutic agents, which on their own are suitable for use the therapy of the respective target disease. For instance, a subject may be diagnosed with a depressive disorder such as major depressive disorder, and a psychotic disorder such as schizophrenia. In such a case, the pharmaceutical composition of the invention may be combined, or administered in combination with one or more antidepressants and one or more antipsychotic agents.

[0266] In some embodiments, the invention relates to the pharmaceutical composition for use according to the invention, wherein said pharmaceutical composition is combined with oneor more additional therapeutic agents. It is to be understood that such combinations are effective not only when the active ingredients are used in a single composition, but also when used in two or more different compositions, either administered simultaneously, sequentially or separately after a certain period of time. It is further understood that said compositions can be prescribed to be used together with the other active ingredients in a combination therapy to prevent and / or treat one or more disorders, preferably mental disorders and / or hyperkinetic movement disorders.

[0267] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the bevantolol comprised in the pharmaceutical composition inhibits VMAT2 and VMAT1.

[0268] That is, the pharmaceutical composition of the present invention relies in part on the surprising finding that bevantolol binds to both, VMAT2 and VMAT1.

[0269] As used herein, " VMAT2" refers to human vesicular monoamine transporter isoform 2, an integral membrane protein that acts to transport monoamines, particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine, from cellular cytosol into synaptic vesicles.

[0270] " VMAT1" refers to human vesicular monoamine transporter isoform 1 which has similar function as VMAT2 but is found at higher density in different CNS regions.

[0271] VMAT1 is implicated in emotional brain circuits and the risk of psychopathology (Lohoff et al.

[0272] 2014). Without being bound by theory, the modulation of serotonin levels through the inhibition of VMAT1 by bevantolol may aid in restoring a healthy serotonin balance. Additionally, VMAT2 inhibition reduces dopamine levels, thereby the inhibitory effect on both VMAT1 and VMAT2 might contribute restoring dopamine balance in the cortico-striatal and cortico-subthalamic-pallidal-thalamo-cortical circuitries. Therefore, the therapeutic effect of the pharmaceutical composition of the present invention may be explained by the synergistic effect of bevantolol in restoring both dopamine and serotonin balance through the inhibition of VMAT2 and VMAT1. It is to be understood that the reduction of dopamine and serotonin levels and their subsequent rebalancing make the pharmaceutical composition of the presentinvention applicable to all disorders where dopamine and serotonin levels are dysregulated. Such disorders include, for example, mental disorders and hyperkinetic movement disorders.

[0273] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the bevantolol comprised in the pharmaceutical composition inhibits dopamine uptake more efficiently than serotonin uptake via VMAT2.

[0274] That is, bevantolol was demonstrated to result in a stronger inhibition of dopamine uptake than serotonin uptake via VMAT2. The inventors have surprisingly found that the inhibitory effect of bevantolol on dopamine uptake is stronger than the inhibitory effect of bevantolol on serotonin uptake by VMAT2. In other words, bevantolol reduces dopamine uptake by VMAT2 at an intermediate level, that is less efficient than tetrabenazine or reserpine, and bevantolol reduces serotonin uptake by VMAT2 at an even lower level. It is to be understood, that a moderate reduction of serotonin avoids side effects related to serotonin depletion such as depression, anxiety and memory loss. Thus, in certain embodiments, the pharmaceutical composition for use according to the invention inhibits serotonin uptake via VMAT2 less efficiently than tetrabenazine.

[0275] In a particular embodiment, the invention relates to the pharmaceutical composition for use according to the invention, wherein the bevantolol comprised in the composition reduces vesicular dopamine and serotonin.

[0276] That is, the pharmaceutical composition of the present invention reduces vesicular dopamine and serotonin by inhibition of VMAT2 and VMAT1. It is to be understood that the reduction of vesicular dopamine and serotonin caused by the composition for use according to the invention does not lead to their depletion and thus, does not induce side effects such as depression, parkinsonism, and fatigue.

[0277] The present invention also encompasses methods for the treatment of any of the diseases or disorders disclosed herein. These methods involve administering a therapeutically effective amount of the pharmaceutical composition to a subject in need thereof. The principles and details described above regarding the pharmaceutical composition, its combination withadditional therapeutic agents, and its therapeutic effects apply mutatis mutandis to these treatment methods, ensuring that the therapeutic strategies and benefits outlined are equally applicable to the methods of treatment encompassed by the present invention.

[0278] As used herein, the words "comprise", "comprising" and the like are to be construed in an inclusive sense, that is to say, in the sense of "including, but not limited to", as opposed to an exclusive or exhaustive sense. Likewise, the terms "include," "including" and "or" should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. Nevertheless, the compositions disclosed herein may lack any element that is not specifically disclosed herein. Thus, a disclosure of an embodiment using the term "comprising" includes a disclosure of embodiments "consisting essentially of" and "consisting of" the components identified.

[0279] All numerical ranges should be understood to include each integer, whole or fractions, within the range. Moreover, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0280] All percentages expressed herein are by weight of the total weight of the composition unless expressed otherwise. As used herein, "about," "approximately" and "substantially" are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1% to +1% of the referenced number, most preferably -0.1% to +0.1% of the referenced number.

[0281] As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0282] Unless defined otherwise, all technical and scientific terms have and should be given the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.The term "and / or" used in the context of " X and / or Y" should be interpreted as " X," or " Y," or " X and Y.". Similarly, "at least one of X or Y" should be interpreted as " X," or " Y," or "both X and Y.".

[0283] As used herein, the terms "example" and "such as," particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive. But, a disclosure of an embodiment using the term "example" and "such as" and "e.g." includes a disclosure of embodiments" where the terms are exclusive and / or comprehensive.

[0284] Those skilled in the art will understand that they can freely combine all features of the present invention disclosed herein. In particular, features described for the composition of the present invention may be combined with the uses and methods of the present invention and vice versa. Further, features described for different embodiments of the present invention may be combined.

[0285] Furthermore, where known equivalents exist to specific features, such equivalents are incorporated as if specifically referred in this specification. Further advantages and features of the present invention are apparent from the figures and non-limiting examples.

[0286] BRIEF DESCRIPTION OF FIGURES

[0287] Figure 1 shows the results from the 3H-DHTBZ binding assay. IC50 curve is shown for the displacement of 3H-DHTBZ in human VMAT2 expressing membrane vesicles by (A) bevantolol hydrochloride (SOM01), and (B) tetrabenazine (TBZ).

[0288] Figure 2 shows the results from the 3H-Reserpine binding assay. IC50 curve is shown for the displacement of 3H-Reserpine in human VMAT2 expressing membrane vesicles by (A) bevantolol hydrochloride (SOM01), (B) reserpine, and (C) tetrabenazine (TBZ).Figure 3 shows the results from the 3H-Dopamine (3H-DA) uptake assay. IC50 curve is shown for the inhibition of 3H-Dopamine (3H-DA) uptake in human VMAT2 expressing membrane vesicles by (A) bevantolol hydrochloride (SOM01), (B) tetrabenazine (TBZ), (C) reserpine, and (D) dopamine (DA).

[0289] Figure 4 shows the results from the 3H-Serotonin (5HT) uptake assay. IC50 curve is shown for the inhibition of 3H-Serotonin (5HT) uptake in human VMAT2 expressing membrane vesicles by (A) bevantolol hydrochloride (SOM01), (B) tetrabenazine (TBZ), (C) reserpine, and (D) serotonin (5HT).

[0290] Figure 5 shows the results for the rat VMAT1 inhibition assay. IC50 curve is shown for the inhibition of serotonin uptake into VMAT1 expressing membrane vesicles.

[0291] Figure 6 shows the reduction of chorea as measured by TMC score in Huntington's disease patients treated with SOM3355 (bevantolol hydrochloride).

[0292] Figure 7 shows the reduction of depression as measured by BDI score, in Huntington's disease patients treated with SOM3355 (bevantolol hydrochloride).EXAMPLES

[0293] Example 1: VMAT2 inhibitory profile of bevantolol and other inhibitors

[0294] Bevantolol was tested for its capacity to bind to human VMAT2 in comparison to the VMAT inhibitors tetrabenazine and reserpine using 3H-dihydrotetrabenazine (DHTBZ) and 3H-Reserpine binding assays. These assays are based on the displacement of radiolabeled 3H-DHTBZ and 3H-reserpine at different concentrations of bevantolol or other VMAT inhibitors. The inventors further tested the capacity of bevantolol to inhibit uptake of radiolabeled 3H-Dopamine (3H-DA) and 3H-Serotonin (3H-5HT) by human VMAT2 compared to other VMAT inhibitors.

[0295] Material and methods

[0296] Stable expression of human VMAT2 in cell lines

[0297] CHO-K1 cell or HEK293 cells were cultured respectively in F12K with 10% FBS and DMEM with 10 % FBS at 37°C. Cells were detached with trypsin and centrifuged at room temperature at 1000 rpm for 5 min to pellet cells. Cells were dispersed in culture medium and counted. 106HEK293 cells or 4*105CHO-K1 cells were seeded with 2mL culture medium to each well of a 6-well plate and placed in an incubator at 37°C with 5% CO2 overnight. Cells were transfected with 2 pg human VMAT2 plasmid (plRES2-EGFP containing the CDS sequence of human VMAT2 (NM_003054.6)) with FuGENE® HD, and incubated at 37°C, 5% CO2 for 24h. Culture medium was replaced with culture medium containing 600 ug / mL G418 for HEK293 and with culture medium containing 1200 ug / mL G418 for CHO-K1. Medium was replaced every three days until G418-resistant VMAT2 / HEK293 cells and VMAT2 / CHO-K1 cells were selected and expanded.

[0298] Preparation of VMAT2 containing vesicles

[0299] VMAT expressing cells were collected and suspended in 0.32 M sucrose. Cell suspension was homogenized at 13000 rpm and centrifuged at 2000 g for 10 min at 4°C. Cells were resuspended in 2 ml of 0.32 M sucrose, and exposed to osmotic shock by adding 7 ml water, and restored by adding 900 uL of 0.25 M HEPES buffer and 900ul of 1.0 M potassium tartratesolution after lmin. Lysate was centrifuged at 20000 g for 20 min at 4°C and 100 uL of 10 mM MgSO4, 100 uL of 0.25 M HEPES, and 100 uL of 1.0 M potassium tartrate solution was added to the supernatants and centrifuged at 87000 g for 60 min. Pellets of the human VMAT2 containing vesicles were collected and resuspend with assay buffer. Aliquots of vesicles were stored at

[0300] -80°C.

[0301] 3H-DHTBZ binding assay

[0302] lpL of bevantolol hydrochloride or tetrabenazine was transferred in serial dilutions (10 uM initial concentration with 8 doses of 1 / 5 dilutions) to assay plates with 1.5 pg human VMAT2 containing vesicles with 100 pL assay buffer (25 mM HEPES, 100 mM potassium tartrate, 5 mM MgSO4, 0.1 mM EDTA, and 0.05 mM EGTA, pH 7.4). 3H-DHTBZ was diluted with assay buffer to 9 nM and 100 pL was transferred to an assay plate to reach a final concentration of 4.5 nM. Plates were sealed and shaken at 300 rpm at RT for 60 min. Unifilter-96 GF / C filter plates were soaked with 50 pL of 0.3% PEI per well for at least 30 min at room temperature. Reaction mixture was filtered through GF / C plates using Perkin Elmer Filtermate Harvester, then each plate was washed for 6 times with cold wash buffer (25 mM HEPES, 100 mM potassium tartrate, 5 mM MgSO4, pH 7.4). Filter plates were dried ~1 hour at 50°C. Bottom of the filter plate wells was sealed using Perkin Elmer Unifilter-96 backing seal tape and 50 pL of Perkin Elmer Microscint 20 cocktail was added. 3H trapped on filter was counted using Perkin Elmer MicroBeta2 Reader.

[0303] 3H-Reserpine binding assay

[0304] lpL of bevantolol hydrochloride, reserpine or tetrabenazine was transferred in serial dilutions (10 uM initial concentration with 8 doses of 1 / 5 dilutions) to assay plates with 50 pg human VMAT2 containing vesicles with 100 pL assay buffer (25 mM HEPES, 100 mM potassium tartrate, 4 mM KCI, 2 mM MgSO4, 0.1 mM EDTA, and 0.05 mM EGTA, 3mM ATP, 0.5% BSA, pH 7.4). 3H-DHTBZ was diluted with assay buffer to 4 nM and 100 pL was transferred to an assay plate, to reach a final concentration of 2 nM. Plates were sealed and shaken at 300 rpm at 30°C for 60 min. Unifilter-96 GF / C filter plates were soaked with 50 pL of 0.5% BSA per well for at least 0.5 hour at room temperature. The reaction mixture was filtered through the GF / C plates using Perkin Elmer Filtermate Harvester and each plate was washed for 6 times withcold wash buffer (25 mM HEPES, 100 mM potassium tartrate, 5 mM MgSO4, 0.5% BSA, pH 7.4). Filter plates were dried for ~1 hour at 50°C. Bottom of the filter plate wells was sealed using Perkin Elmer Unifilter-96 backing seal tape and 50 pL of Perkin Elmer Microscint 20 cocktail was added. 3H trapped on filter was counted using Perkin Elmer MicroBeta2 Reader.

[0305] 3H-Dopamine (3H-DA) uptake assay

[0306] 1µL of bevantolol hydrochloride, dopamine, tetrabenazine or reserpine was transferred in serial dilutions (10 uM initial concentration with 8 doses of 1 / 5 dilutions) to assay plates with 10 pg vesicles and 100 pL assay buffer (25 mM HEPES, 100 mM potassium tartrate, 4mM KCI, 2 mM MgSO4, 0.1 mM EDTA, and 0.05 mM EGTA, 3mM ATP, 0.5% BSA, pH 7.4). 3H-Dopamine was diluted with assay bufferto 300 nM and 100 pL was transferred to the assay plate to reach a final concentration of 150 nM. Plates were sealed and shaken at 300 rpm at 30°C for 60 min. Unifilter-96 GF / C filter plates were soaked with 50 pL of 0.5 % BSA per well for at least 0.5 hour at room temperature. The reaction mixture was filtered through the GF / C plates using Perkin Elmer Filtermate Harvester, and then each plate was washed for 6 times with cold wash buffer (25 mM HEPES, 100 mM potassium tartrate, 5 mM MgSO4, 0.5% BSA, pH 7.4). Filter plates were dried for ~1 hour at 50°C. Bottom of the filter plate wells was sealed using Perkin Elmer Unifilter-96 backing seal tape and 50pL of Perkin Elmer Microscint 20 cocktail was added. 3H trapped on filter was counted using Perkin Elmer MicroBeta2 Reader.

[0307] 3H-Serotonin (3H-5HT) uptake assay

[0308] 1µL of bevantolol hydrochloride, serotonin, tetrabenazine or reserpine was transferred in serial dilutions (10 uM initial concentration with 8 doses of 1 / 5 dilutions) to assay plates with 5 µg vesicles and 100µL assay buffer (25 mM HEPES, 100 mM potassium tartrate, 4mM KCI, 2 mM MgSO4, 0.1 mM EDTA, and 0.05 mM EGTA, 3mM ATP,0.5%BSA, pH 7.4). 3H-Serotonin was diluted with assay buffer to 300 nM and 100µL were transferred to the assay plate to reach a final concentration of 150 nM. Plates were sealed and shaken at 300 rpm at 30°C for 60 min. Unifilter-96 GF / C filter plates were soaked with 50 pL of 0.5% BSA per well for at least 30 min at room temperature. The reaction mixture was filtered through the GF / C plates using Perkin Elmer Filtermate Harvester, and then each plate was washed for 6 times with cold wash buffer (25 mM HEPES, 100 mM potassium tartrate, 5 mM MgSO4, 0.5%BSA, pH 7.4). Filter plates were dried for ~1 hour at 50°C. Bottom of the filter plate wells was sealed using PerkinElmer Unifilter-96 backing seal tape and 50 pL of Perkin Elmer Microscint 20 cocktail was added. 3H trapped on filter was counted using Perkin Elmer MicroBeta2 Reader.

[0309] Results

[0310] Table 1: IC50 values of SOM3355 (bevantolol hydrochloride) in comparison to tetrabenazine and reserpine

[0311]

[0312] IC50 values from 3H-DHTBZ binding assay, 3H-Reserpine binding assay, 3H-Dopamine uptake assay and 3H-Serotonin uptake assay were determined (Figures 1 to 4 and table 1). The data show that bevantolol requires a much higher concentration (1353 nM) to displace DHTBZ compared to its analog tetrabenazine (19 nM). Likewise, displacement of 3H-Reserpine also required much higher concentrations of bevantolol (267 nM) than tetrabenazine (32 nM) or reserpine (1.1 nM). Bevantolol hydrochloride inhibited 3H-Dopamine uptake by human VMAT2 less efficiently than tetrabenazine (~2-fold), and much less efficiently than reserpine (~94-fold). For serotonin uptake inhibition, bevantolol inhibited 3H-Serotonin uptake to a lesser extent than tetrabenazine (~9-fold) and reserpine (~1200-fold). The inhibition of 3H-dopamine uptake (66 nM) by bevantolol hydrochloride was more efficient than inhibition of 3H-Serotonin uptake (600 nM).

[0313] The inefficient displacement of tetrabenazine and reserpine indicates that bevantolol binds to a different site on human VMAT2. Bevantolol has a reduced potency of inhibiting 3H-dopamine and 3H-Serotonin uptake by human VMAT2 compared to tetrabenazine and reserpine.

[0314] Example 2: VMAT1 inhibition by bevantolol hydrochloride

[0315] VMATl has a higher affinity for serotonin compared to VMAT2. To identify whether bevantolol hydrochloride inhibits serotonin uptake by VMATl the inventors determined the IC50 values of serotonin inhibition using a radiolabeled 3H-Serotonin uptake assay.

[0316] Material and methods

[0317] Preparation of membrane vesicles

[0318] Chinese hamster ovary cells were transfected with the rat cDNA of rat VMATl in the expression vector pcDM8 and with the geneticin resistance conferring expression plasmid pRcCMV by the calcium phosphate method (10 pg rVMATl / pCDM8 + 1 pg pRcCMV onto 2 million cells seeded on a 100 mm cell culture plate on day before), split 1:6 two days later, selected in 1 g / l geneticin in the medium (DMEM with 10% FBS, 50 pg / ml gentamicin and GlutaMax) added from day one after splitting and in 1 g / l geneticin plus ImM l-methyl-4-phenylpyridinium ion (MPP+) added from day 14 after transfection. Cell clones resistant to geneticin and MPP+ were transferred to multi-well plates and grown with the selecting geneticin and MPP+ on cell culture substrates with increasing surface (48-well, 24-well, 6-well, 60 mm, 100 mm and 150 mm plates). Confluent stably transfected cells from 8150 mm-plates, grown for more than one week in the absence of MPP+, were resuspended by trypsinization in the medium, centrifuged, the cell pellet resuspended in phosphate buffered saline, centrifuged again and resuspended in 2 ml of ice-cold 0.3M sucrose containing 25 mM Tris-HCI, pH 7.4, and 10 pM pargyline and protease-inhibitors (STP-PI) and sonicated with 5 pulses by a 5 mm probe at 10% of maximum intensity on ice. The cell homogenate was centrifuged at 16100 g for 10 min at 4°C and the resulting supernatant complemented with STP-PI to 4.1 ml (test of single concentrations of bevantolol hydrochloride in triplicates or concentrationdependence of uptake inhibition of 5 concentrations of bevantolol hydrochloride in triplicates) of final membrane vesicles and the preparation kept on ice until the immediately following uptake assay.3H-Serotonin (3H-5HT) uptake assay

[0319] Bevantolol hydrochloride was dissolved in DMSO at a concentration of 30 or 100 mM and diluted to a 30x stock solution with 0.13 M potassium phosphate, pH 7.4, which was the solvent for all the other constituents of the assay if not indicated differently. In triplicates, 1200 pl 0.13 M potassium phosphate, pH 7.4, or 1.25 pM reserpine was mixed with 50pl 30x bevantolol hydrochloride, 50pl 60 mM MgATP and 50 pl 3 pM 3H-Serotonin (serotonin containing 0.1 pCi [3H]-5-hydroxy tryptamine ([3H]5-HT)) in 0.3 mM ascorbic acid and 0.3 mM pargyline. Transport was initiated by placing the tubes in a 30°C water bath and adding 150 pl vesicular membrane preparation, and performed in a total volume of 1500 pl for 5 min at 30°C. Uptake was terminated by the addition of 2.5 ml ice-cold 0.13 M potassium phosphate, pH 7.4, immediate filtration under vacuum onto Whatman GF / B filter paper presoaked in 1% polyethylenimine, using a Brandel harvester. The filters were washed twice with additional 3ml of cold 0.13 M potassium phosphate, pH7.4. Filters were transferred to liquid scintillation tubes, mixed with 3 ml liquid scintillation cocktail, incubated for two hours at 50°C and vortexed vigorously before measurement of radioactivity in the liquid scintillation counter.

[0320] Calculation

[0321] Concentration dependence of uptake inhibition was fitted by non-linear regression to the equation uptake = min + (max-min) / (1+(conc / IC50)-Hillslope) with the constraint min = (uptake in the presence of 1 pM reserpine). Non-linear regression and plotting of the graphs were done using SigmaPlot for Windows Version 11.0.

[0322] Results

[0323] Bevantolol inhibits 3H-Serotonin uptake by rat VMAT1 at an IC50 of 0.044 ± 0.007uM (Figure 5).

[0324] Example 3: Bevantolol has a unique binding site on VMAT2

[0325] Based on the low displacement capacity of DHTBZ and reserpine by bevantolol, it was hypothesized that bevantolol may have a different binding site on human VMAT2 comparedto tetra benazine and reserpine. Thus, the inventors investigated the binding site of bevantolol on human VMAT2 using molecular modeling.

[0326] Material and methods

[0327] Induced Fit Docking

[0328] The human VMAT2 protein structure in a binding state with reserpine (8JTC) was retrieved from Protein Data Bank (PDB) and refined with the Protein Preparation Wizard in Maestro to assign protonation states and minimize the structure. Induced fit docking was performed using the Induced Fit Docking module in Glide. The top docking poses of bevantolol were ranked using GlideScore and analyzed for interactions with the receptor in PyMOL. Binding energies were calculated using the Prime MM-GBSA method, and the docking protocol was validated by redocking a known ligand and comparing the results to crystallographic data.

[0329] Results

[0330] Docking studies revealed that bevantolol binds to human VMAT2 in two main orientations: (1) similar position as reserpine and (2) a "unique pocket" opposite of where reserpine binds. Calculations revealed that bevantolol binds to the unique pocket with a slight preference.

[0331] The unique human VMAT2 binding site of bevantolol may explain its specific inhibitory profile forVMAT2-mediated uptake of dopamine and serotonin, and its reduced potency in displacing DHTBZ and reserpine.

[0332] Example 4: Reduction of chorea in Huntington's disease patients treated with bevantolol hydrochloride

[0333] To investigate whether the VMAT inhibitory profile of bevantolol hydrochloride could translate into a therapy for hyperkinetic movement disorders, the inventors studied the use of bevantolol for the treatment of chorea in Huntington's disease patients.

[0334] Material and methodsA randomized, placebo-controlled phase 2b study was performed in patients with chorea associated with Huntington's disease. Of the modified intent to treat population (N = 139) a total of 57 patients were not taking neuroleptics as concomitant medications, and had a baseline total maximum chorea (TMC) score >12. The TMC score is part of the Unified Huntington's Disease Rating Scale used to quantify the severity of chorea (involuntary, jerky movements) in individuals with Huntington's disease (Kieburtzet al., Mov Disord., 1996; 11(2): 136-42). The TMC score typically involves observing a patient's involuntary movements and rating their severity in seven body regions to measure the severity of chorea and its progression.

[0335] Patients were divided into 3 treatment groups: A group receiving placebo, a group receiving 200 mg SOM3355 (bevantolol hydrochloride) twice daily, and a group receiving 300 mg SOM3355 (bevantolol hydrochloride) twice daily. Patients were monitored over the course of 12 weeks for changes in TMC score from baseline.

[0336] Results

[0337] A statistically significant difference of the TMC score was observed in the group treated with 300 mg SOM3355 (bevantolol hydrochloride) twice daily compared to placebo at the end of the maintenance dose period with the score calculated as mean of TMC score at week 9 and week 10. The mean TMC score difference from baseline at end of maintenance dose period was -4.2, compared to -2.8 for the group treated with 200 mg SOM3355 (bevantolol hydrochloride) and -2.4 for the group that received the placebo (Figure 6).

[0338] The group treated with 300 mg SOM3355 (bevantolol hydrochloride) twice daily had a statistically significant TMC change of -1.78 compared to placebo based on a mixed model analysis (p = 0.03; IC [-3.40 - 0.16]).

[0339] Example 5: Reduction of depression in patients treated with bevantolol hydrochlorideTo investigate whether the VMATl and VMAT2 inhibitory profile of bevantolol hydrochloride could translate into a therapy for mental disorders associated with dopamine and serotonin dysregulation, the inventors studied the use of bevantolol in the treatment of depression in Huntington's disease patients in the same study described in example 4.

[0340] Material and methods

[0341] A randomized, placebo-controlled safety study was performed in 139 Huntington's disease patients. Patients were divided into 3 treatment groups: A group receiving placebo, a group receiving 200 mg SOM3355 (bevantolol hydrochloride) twice daily, and a group receiving 300 mg SOM3355 (bevantolol hydrochloride) twice daily. A part of patients was treated for depression at baseline: 44% (n = 21 / 48) in the group receiving placebo, 46% (n = 19 / 41) in the group receiving 200 mg SOM3355 (bevantolol hydrochloride) twice daily, and 54% (n = 27 / 50) in the group receiving 300 mg SOM3355 (bevantolol hydrochloride) twice daily. Patients were monitored over the course of 12 weeks for improvement in Beck's Depression Inventory (BDI) score. The BDI score is a standard tool for measuring the severity of depression based on a self-report questionnaire to determine the level of depressive symptoms (Beck et al., Arch Gen Psychiatry, 1961; 4:561-71).

[0342] Results

[0343] A reduction of the BDI score was observed in patients treated twice daily with 300 mg SOM3355 (bevantolol hydrochloride) (Figure 7). No case of depression worsening was observed in the study. Therefore, contrary to other known VMAT2 inhibitors, bevantolol hydrochloride does not induce or worsen depression but instead, reduces depression. Bevantolol hydrochloride can therefore be used in the therapy of depression and potentially, other mental disorders characterized by dysregulated dopamine and serotonin levels.Example 6: Comparative Assessment - Symptomatic benefits of SOM3355 vs. authorized drugs

[0344] Further symptomatic benefits of SOM3355 (bevantolol hydrochloride) were determined in the study population described in Example 5 and compared to previous reports for alternative drugs approved for the treatment of HD.

[0345] Methods:

[0346] Study participants were requested to answer a Problem Behavior Assessment-short form (PBA-s, Carlozzi et al, 2014). This semi-structured interview contained 11 items, each designed to measure the severity and frequency of certain behavioral neuropsychiatric symptoms frequently observed in HD: depression, suicidal ideation, anxiety, irritability, aggressive behavior, apathy, obsessive-compulsive symptoms, perseverative thinking, paranoid thinking, hallucinations, and disorientation. Severity and frequency were rated during the previous 4 weeks on a 5 point (0-4) scale for each symptom, individually. PBA-s was assessed at inclusion, at the interim visit (Visit 3 at the end of Week 6), and at the end of the maintenance dose (Visit 5 at the end of Week 10). All scores referred to in this Example, hereinafter refer to the PBA-s score unless another score is referred to.

[0347] Results:

[0348] Depression:

[0349] ■ SOM3355 (bevantolol hydrochloride) according to Beck's Depression Inventory (BDI) (and confirmed in the depression item of PBA): improvement of depressive symptoms in the SOM3355 600 mg / day treatment group with baseline score indicating a mild depression and BDI mean score reduction of -3.32 ± SD 4.845, with the most relevant changes at V4 and V5.

[0350] Suicidality

[0351] ■ SOM3355 (bevantolol hydrochloride) does not increase the risk of suicidality.

[0352] Anxiety

[0353] ■ SOM3355 (bevantolol hydrochloride) improvement at PBA in the 400mg treatment group with mean score reduction of -1.7 ± SD 3.168 (V3-V5) from baseline in patients with mild anxiety symptoms at baseline (600mg -0.4 placebo -0.2).Apathy

[0354] ■ SOM3355 (bevantolol hydrochloride): decrease at PBA of -0.33 ± SD 2.378 from baseline of the mean score in the 400mg group (while there was an increase in the placebo group +0.6)

[0355] Compulsive behaviour

[0356] ■ SOM3355 (bevantolol hydrochloride): slightly present at baseline in the 600 mg group and mild improvement with mean score reduction of -0.15 ± SD 0.700 (placebo increase).

[0357] Disruptive behaviour

[0358] ■ SOM3355 (bevantolol hydrochloride): minimal symptoms at baseline in the 600mg group that improved with mean score reduction of -0.58 ± SD 2.297.

[0359] Irritable behaviour

[0360] ■ SOM3355 (bevantolol hydrochloride): minimal symptoms at baseline in the 600mg group that improved with mean score reduction of -0.68 ± SD 2.411.

[0361] Perseverative Thinking

[0362] ■ SOM3355 (bevantolol hydrochloride): minimal symptoms at baseline in the 400mg group that improved with mean score reduction of -0.51 ± SD 2.077.

[0363] Psychotic symptoms

[0364] ■ SOM3355 (bevantolol hydrochloride): neither delusions nor hallucinations were present at baseline in the phase 2b study population. The mode of action with VMATl inhibition supports positive effect.

[0365] Treatment of cognitive impairment

[0366] ■ SOM3355 (bevantolol hydrochloride): Cognition was not impaired at baseline.

[0367] Baseline Montreal Cognitive Assessment (MoCA) value of 22 indicated the lower value of normal range. However, a minimal mean improvement of - 0.2 in the score was seen in the 600mg group while a minimal deterioration with mean increase of +0.2 was seen on placebo. The predominant pattern of HD cognitive impairment is a dysexecutive syndrome, reflecting early degeneration of fronto-striatal circuits - especially the caudate nucleus and its projections to the dorsolateral prefrontal cortex that manifests as slowed information processing and reduced working memory among other symptoms. Based on its specific polypharmachology and on preliminary evidence for propranolol in autism and Traumatic Brain Injury (TBI)SOM3355 (bevantolol hydrochloride) might have a positive effect on working memory.

[0368] Treatment of dysautonomia

[0369] ■ SOM3355 (bevantolol hydrochloride): reduction of baseline tachycardia and high blood pressure. Potential long-term benefit of p-blocking activity on the complex HD dysautonomia.

[0370] Disease modifying treatment

[0371] ■ SOM3355 (bevantolol hydrochloride): potential delay of HD onset and motor symptoms progression due to the |3 blocking activity.

[0372] Significant benefits provided by lack of exacerbation of HD symptoms, CNS safety, QTc and Drug–Drug Interaction (DDI) profile.

[0373] Somnolence

[0374] ■ SOM3355 (bevantolol hydrochloride): no somnolence. The ESS - sleepiness score - showed light sleepiness at baseline. There was a mean ESS score reduction in daytime sleepiness at V5, reaching -0.41 in in the 400 mg / day treatment group (and of 0.23 at V2 to -0.10 atV5.

[0375] Extrapyramidal symptoms (like parkinsonism, dystonia, akathisia)

[0376] ■ SOM3355 (bevantolol hydrochloride): no parkinsonism, dystonia, and akathisia. QTc prolongation

[0377] • SOM3355 (bevantolol hydrochloride) no effect.

[0378] DDI

[0379] • SOM3355 (bevantolol hydrochloride) Limited.

[0380] In summary, compared to the authorised drugs in HD, SOM3355 has:

[0381] • Proven benefit: Chorea.

[0382] • No risk of somnolence, depression, suicide, parkinsonism and akathisia.

[0383] • Preliminary benefit: improvement of depression, anxiety.

[0384] • Potential Benefits based on its pharmacology:

[0385] o Reduced Risks of Cognitive Impairment:

[0386] o Reduced Aggression:o Apathy.

[0387] o Akathisia.

[0388] o Tremor.

[0389] o Dysautonomia.

[0390] o Disease modifying.

[0391] Example 7: Treatment of Huntington's Disease subjects with choreic movements and other symptoms

[0392] Rationale

[0393] Huntington's disease (HD) is an inherited progressive neurodegenerative disease. Chorea, an involuntary jerky movement that is purposeless and abrupt, is one of the most prominent symptoms in HD. No effective disease-modifying therapies exist for HD, and treatment is symptomatic relief. Chorea is treated by tetrabenazine (TBZ), approved in Europe and the United States (US), and the long-acting derivative deutetrabenazine (deuTBZ) and the prodrug of the active metabolite of TBZ valbenazine, approved in the US only. Both drugs are derivatives of TBZ and all 3 are vesicular monoamine transporter type 2 (VMAT2) inhibitors depleting monoamines in presynaptic neurons. Depletion of dopamine reduces signaling across neural synapses, thus controlling the dyskinetic movements, such as chorea, but also causing significant adverse events, some of which are also HD disease manifestations that might be exacerbated. The labels of these compounds carry a black box warning by the Food and Drug Administration (FDA) and special warnings by the European Medicines Agency (EMA) since they can increase the risk of depression and suicidality in HD subjects.

[0394] SOM3355 is a selective β1-adrenergic blocker and provides functional inhibition of VMATl and VMAT2 with similar potency. It differs from TBZ by having a different binding site with a different profile substate affinity and inhibition such as 10 folds less potent on serotonin, leading to less risk of severe side effects. In line with these properties, in the phase 2b study including 139 subjects with HD, SOM3355 has shown efficacy on chorea at the dose of 600 mg / day administered twice daily, with no worsening of depressive symptoms and suicidality and overall good safety and tolerability. The most frequent treatment emergent adverse events, all but one mild or moderate, were expected, e.g. bradycardia. Moreover, the results of the pharmacokinetics (PK) sub-study and PK / pharmacodynamics (PD) assessment for up to 600 mg / day indicate that the 200 and 300 mg BID doses have similar effects on heart rate (HR)and diastolic blood pressure (DBP), and the higher dose only a mild effect on systolic blood pressure (SBP).

[0395] Based on the results of the Phase Ila and lib studies, a Phase III trial with SOM3355 300 mg dose administered twice per day (BID) for the treatment of chorea and other HD symptoms is performed to confirm the efficacy and safety profile in subjects with HD, followed by 9 months open label extension to assess long term safety.

[0396] Objectives

[0397] Primary Study Objective

[0398] Evaluate the efficacy of SOM3355 to reduce Huntington's chorea using the Unified Huntington's Disease Rating Scale (UHDRS®) Total Maximal Chorea (TMC) score. The efficacy of SOM3355300 mg BID compared to placebo is assessed based on the following endpoint:

[0399] • Change from baseline in the TMC score at Week 12.

[0400] Secondary Study Objective

[0401] To evaluate the efficacy of SOM3355 to reduce symptoms associated with HD compared with placebo based on the following endpoints:

[0402] Change from baseline in the following individual scales scores at Week 12 for the key secondary endpoints:

[0403] • Hospital Anxiety and Depression Scale (HADS)-Anxiety scale (clinician rated anxiety scale)

[0404] • Huntington's Disease Health Index (HD-HI) measuring quality of life in HD

[0405] • Problem Behavior Assessment short form (PBA-s) (11 items, each designed to measure the severity and frequency of behavioral neuropsychiatric symptoms that are frequent in HD)

[0406] • Clinical Global Impression of Change (CGI-C)

[0407] • Patient Global Impression of Change (PGI-C)

[0408] • Total Motor Score (TMS) of the UHDRS®

[0409] • Percentage of change in TMC score

[0410] • Percentage of subjects with TMC score change > -4.0 pointsTo evaluate the safety and tolerability of SOM3355 300 mg BID compared with placebo in HD subjects based on the following endpoints:

[0411] • Incidence and severity of adverse events, with severity determined according to the Adverse Event Severity Grading Scale

[0412] • Vital signs (including orthostatic blood pressure and pulse)

[0413] • Physical examinations

[0414] • Swallowing Disturbance Questionnaire (SDQ)

[0415] In addition, the change from baseline in the following individual scales at Week 12:

[0416] • 12-lead electrocardiogram (ECG)

[0417] • Clinical laboratory tests (hematology, clinical chemistry, and urinalysis)

[0418] • Columbia-Suicide Severity Rating Scale (C-SSRS)

[0419] • Cognitive UHDRS® (verbal fluency test, the Symbol Digit Modalities Test, and the Stroop Interference Test)

[0420] • Montgomery-Asberg Depression Rating Scale (MADRS) (clinician rated depression scale)

[0421] • Barnes Akathisia Rating Scale (BARS)

[0422] • UHDRS® parkinsonism score (total of the following UHDRS® motor items: finger taps, pronation / supination, rigidity, bradykinesia, gait, tandem gait and retropulsion pull test)

[0423] • Epworth Sleepiness Scale (ESS)

[0424] Study design

[0425] A Phase III, randomized, double-blind, placebo-controlled, parallel-group study is conducted to evaluate the efficacy, safety, and tolerability of SOM3355 at the dose of 300 mg BID (i.e.

[0426] 300 mg twice per day, corresponding to 600 mg daily) in subjects presenting chorea and other symptoms of Huntington's Disease, in a total of 136 subjects.

[0427] The expected duration of the double-blind study is approximately 18 weeks. The study includes a 2-week screening period, a 2-week up-titration period, a 10-week maintenance dose period, a 2-week down-titration period, and a final study visit, 2 weeks following the final dose of study drug (Figure 8). Following the end of the double-blind study visit, all subjectsstart the open label extension with 1 week up-titration period, continue with a maintenance dose period for additional 34 weeks until the end of week 52, and a final safety call 2 weeks following the final dose of the open label extension study drug.

[0428] Eligible participants are randomized 1:1 to SOM3355 or placebo treatment on Day 1 (baseline). The study is stratified by baseline TMC level (mild, moderate or severe). Study drug (SOM3355) is administered in a blinded fashion throughout the 14-week treatment period beginning on Day 1. The maximum doses during each week of the treatment period are shown in Table 2, below::

[0429] Table - Dosage and treatment regimen by treatment group and time interval Maintenance

[0430] Up-Titration Period Down-Titration Period Dose Period

[0431] Week 0- 1 1 -2 2 - 12 12 - 13 13 - 14 Treatment Placebo OD Placebo BID Placebo BID Placebo OD Placebo OD (Arm 1) (1 Tablet) (2 Tablets) (2 Tablets) (1 Tablet) (1 Tablet) SOM3355 SOM3355 SOM3355 SOM3355

[0432] Treatment Placebo OD 300 mg OD 300 mg BID 300 mg BID 300 mg OD (Arm 2) (1 Tablet)

[0433]

[0434] (1 Tablet) (2 Tablets) (2 Tablets) (1 Tablet)

[0435] All participants enter the open label extension at the start of Week 17, and receive SOM3355. Study treatment is administered as indicated in Table 3, below:

[0436] Table 3 -Treatment regimen during OLE

[0437] Up-Titration Period Maintenance Dose Period Week 17 - 18 18 -52 SOM3355 SOM3355 Treatment (OLE) 300 mg OD 300 mg BID

[0438]

[0439] (1 Tablet) (2 Tablets)

[0440] Subjects assume 1 tablet in the morning during Week 1 (study drug should be administered at approximately the same time each day during the study), 2 tablets, one in the morning and one in the evening, from the beginning of Week 2 to the end of Week 12 (at the same time in the morning and in the evening, i.e. every 12 hours), and 1 tablet each morning starting from Week 13 until the last day of treatment at the end of Week 14 (see Table 4). A follow-up visit occurs at Week 16, 2 weeks after the final dose of study drug. After the follow-up visit, subjects roll over to the open label extension. During the first week of the open label extension, SOM3355 is taken by all subjects at the dose of 300 mg OD (1 tablet in the morning), followed by a dose increase to 300 mg BID (i.e. 600 mg daily) from the second week and continued fornine months. If the dose of 300 mg BID is not tolerated, investigators can instruct the subjects to decrease the dose to 300 mg OD. The follow-up visit (V5, Week 16) also serves as the baseline visit for the open label extension (see Table5). In the open label extension phase of the study there is a visit (V6, Week 20) 1 month after V5, followed by visits at months 7, 9, 11 and 12 (or end of study visit), interspersed with safety calls at months 6, 8 and 10, and two weeks after the final dose of study drug. As much as possible, study visits should occur at approximately the same time as Day 1 (baseline) visit to standardize the time of day for the assessment of efficacy, safety, and drug exposure. Visits have a window of ± 2 days.

[0441] Inclusion criteria:

[0442] Eligibility criteria to participate in this study are:

[0443] 1. Males or females > 21 years old.

[0444] 2. Diagnosis of motor manifest HD at or before screening.

[0445] 3. Subjects with a diagnosis of HD determined by a movement disorders expert and confirmed by a number of huntingin (HTT) gene cytosine-adenosine-guanine (CAG) repeats >36 at or before baseline.

[0446] 4. Subjects must be ambulatory, but assistance devices are permitted.

[0447] 5. UHDRS® Total maximal chorea (TMC) score > 8 confirmed at screening and baseline.

[0448] Subjects with mild, moderate and severe chorea are included (stratified at randomization) according to the following definition:

[0449] • Mild chorea: Movements of arms and legs often, and torso and eyebrows occasionally; fall occasionally; need help with some daily activities; can drive and work with restrictions / accommodation.

[0450] • Moderate chorea: Movements of arms, legs, torso, and face very often; fall often;

[0451] can sit still in a chair; do not fall out of bed; need help with most daily activities; cannot drive or work.

[0452] • Severe chorea: Movements of arms, legs, torso, and face all the time; fall frequently; cannot sit still in a chair; fall out of bed; need help with all daily activities; cannot drive or work.

[0453] • > 50% of patients with additional symptoms according to HADS-Anxiety scale and PBA-s6. UHDRS® Total Functional Capacity (TFC) > 7

[0454] 7. Subjects of child-bearing potential must use a medically accepted effective method of contraception consistently while participating in the study until 30 days (females) or 90 days (males) after the last dose of the study drug. A female subject of childbearing potential is defined as a subject who is not surgically sterile and who has not been postmenopausal for at least 1 year prior to screening. A male subject of childbearing potential is defined as a subject who has not been vasectomized for at least 3 months prior to screening.

[0455] 8. Female subjects of childbearing potential must have a negative serum p-human chorionic gonadotropin (P-hCG) pregnancy test result at screening and a negative urine pregnancy test at Day 1.

[0456] 9. In the opinion of the Investigator, the subject must have adequate support to comply with the entire study requirements as described in the protocol (e.g. transportation to and from the trial site, self-rating scales, drug compliance, scheduled visits, etc.).

[0457] 10. Able and willing to provide written informed consent prior to any study-related procedure being performed at the screening visit.

[0458] 11. Subjects treated with VMAT2 inhibitors such as tetrabenazine, deutetrabenazine, or valbenazine are allowed if they had been stopped due to poor tolerability for > 2 months prior to randomization.

[0459] Exclusion Criteria:

[0460] Subjects are excluded from the study if any of the following criteria apply:

[0461] 1. Onset of HD symptoms prior to the age of 21 years, corresponding to juvenile forms of HD.

[0462] 2. HD subjects presenting rigid akinesia.

[0463] 3. Use of other VMAT2 inhibitors such as tetrabenazine, deutetrabenazine, or valbenazine within 2 months before enrollment, and use of other antichoreic treatment such as any neuroleptic within 2 months, or amantadine, memantine, riluzole within 1 month before enrollment and along the study.

[0464] 4. Have an inability to swallow the investigational medicinal product, based on clinical evaluation and interpretation of the SDQ score.Subjects who experienced severe depression or suicide attempt in the last 3 years despite documented antidepressive treatment at effective doses.

[0465] Severe untreated or under-treated medical or psychiatric illness such as active suicidal ideation or behavior according to C-SSRS or depression at screening or baseline. Subjects with stable well-controlled depression receiving antidepressant therapy may be enrolled if they have been on a stable dose for at least 2 months prior to baseline.

[0466] Subjects with a history of, or current, hypotension (SBP <110 mmHg), bradycardia (HR <50 bpm), or orthostatic hypotension as defined by the European Society of Hypertension (reduction in SBP >20 mmHg or in DBP >10 mmHg).

[0467] Other active clinically significant illness, including unstable cardiovascular disease, angina pectoris, congestive heart failure, pulmonary hypertension, peripheral arterial disease, history of pheochromocytoma, asthma, Chronic Obstructive Pulmonary Disease (COPD), diabetic ketoacidosis or metabolic acidosis, or neoplastic pathology, which could interfere with the study conduct, or counter-indicate the study treatment, or to place the subject at risk during the trial, or compromise their study participation.

[0468] Any significant serious abnormality in the ECG, e.g. recent myocardial infarction, significant sinus bradycardia (<50 bpm), atrioventricular block (grades I to III with PR >240 msec), sinoatrial block, atrial sinus disease or prolonged QTc interval at screening (ECG Bazett's corrected QT interval (QT / √ [HR / 60] >450 msec for males or >470 msec for females), or a known history of long QTc syndrome.

[0469] Have any of the following laboratory test abnormalities at screening:

[0470] a. Serum creatinine >1.5 times the upper limit of normal (ULN).

[0471] b. AST > 2.5 * ULN

[0472] c. ALT > 2.5 * ULN

[0473] d. GGT > 2.5 * ULN

[0474] e. Total bilirubin > 1.5 mg / dL

[0475] Have any of the following hematologic abnormalities at screening:

[0476] a. Hemoglobin < 10 g / dL

[0477] b. White blood cell (WBC) count < 3.0 * 10^3 / mm^3

[0478] c. Platelet count < 100,000 / mm^312. Subjects with severe hepatic impairment, severe renal impairment, or any other significant abnormality in the physical examination or clinical laboratory results that, in the Investigator's opinion, would not be compatible with study participation or represent a risk for the subject while in the study.

[0479] 13. Females who are pregnant or lactating, or who intend to become pregnant during the study period.

[0480] 14. Subjects with any allergies under desensitization, or a known allergy / hypersensitivity to any ingredients of the trial medication or placebo.

[0481] 15. Have a positive urine drug screen at screening (positive for amphetamines, barbiturates, phencyclidine, benzodiazepines, cocaine, or opiates), except for subjects who have a prescription for benzodiazepines or opiates.

[0482] 16. History of alcohol or substance abuse in the previous 12 months.

[0483] 17. Subjects participating in any other study, and the use of any investigational therapy, within 1 month prior to entry in this study.

[0484] Previous and concomitant medications

[0485] Prohibited treatments:

[0486] VMAT2 inhibitors such as tetrabenazine, deutetrabenazine, or valbenazine are forbidden within 2 months prior to randomization and at any time during the whole study.

[0487] First and second-generation antipsychotics / neuroleptics are forbidden within 2 months prior to randomization and at any time during the whole study.

[0488] The following treatments are forbidden within 1 month prior to randomization and during the whole study:

[0489] • All monoamine oxidase (MAO) inhibitors.

[0490] • Levodopa and dopa-agonist drugs: apomorphin, ropinirole, pramipexole, rotigotine.

[0491] • Reserpine.

[0492] • Glutamate antagonists: amantadine, memantine, riluzole.

[0493] • Anti-arrhythmic drugs inducing bradycardia: diltiazem, verapamil, amiodarone, digitalis, quinidine, sotalol, disopyramide.Any other -blocker antihypertensive medication: metoprolol, propranolol, atenolol...

[0494] Central antihypertensive treatments: clonidine, methyldopa, rilmenidine.

[0495] Authorized treatments:

[0496] Subjects treated with antihypertensive drugs such as diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or calcium blockers (dihydropyridines only) can continue their treatment at a stable dose during the whole study, with maximum of a dual combination of 2 antihypertensive drugs, and if the subject has stable blood pressure. Subjects treated for depression and stabilized with non-IMAO (inhibitors of MAO) antidepressants can continue their treatment at stable dose during the whole study. Allowed antidepressants are:

[0497] • SSRIs (selective serotonin reuptake inhibitors): fluoxetine, paroxetine (see precautions below), citalopram, sertraline.

[0498] • SNRIs (serotonin-noradrenaline reuptake inhibitors): duloxetine, venlafaxine. • TCAs (tricyclic antidepressants): amitriptyline, clomipramine, imipramine, nortriptyline, lofepramine.

[0499] Treatments to be used with precautions (because of risk of interactions):

[0500] • Alpha-blockers.

[0501] • Local beta-blockers (eye drop) or pilocarpine (eye drop).

[0502] • Anticholinesterase drugs: donepezil, rivastigmine.

[0503] • Strong CYP2D6 inhibitors (may increase the blood levels of SOM3355): paroxetine fluoxetine, quinidine, bupropion, dacomitinib, tipranavir.

[0504] Treatment

[0505] The study medication is provided in tablets of SOM3355 dosed at 300 mg or matching placebo. The tablets are identical in appearance to ensure that neither the subject nor the Investigator or the clinical staff know the exact nature of the study medication.

[0506] Subjects take one tablet in the morning during Week 1, one tablet twice per day, one in the morning and one in the evening (every 12 hours) from Week 2 to Week 12, and then one tablet in the morning from Week 13 to Week 14. In the open label extension, all subjects takeone tablet in the morning during Week 17 (300 mg OD) and then one in the morning and one in the evening (every 12 hours) from Week 18 (300 mg BID) for up to month 12. Tablets can be taken with food.

[0507] Sample size and statistical analyses

[0508] Sample size calculation

[0509] The planned sample size for this study is 58 subjects per treatment group, for a total of 116 subjects to be randomized in blinded-fashion in a 1:1 ratio i.e. 58 subjects in each treatment arm (SOM3355 600 mg / day or placebo). Based on a treatment difference of -1.75 points in the change from baseline of TMC score compared to placebo with a standard deviation of 2.88 (i.e. an effect size of 0.607), 58 subjects provide 90% power to detect this difference at the 0.05 two-sided significant level. These power calculations were based on results from the previous phase 2b trial that tested SOM3355 at the dose of 600 mg / day on chorea in HD subjects with TMC score as primary endpoint. To account for a 15% dropout rate, 68 subjects per treatment group (a total of 136 subjects) are enrolled.

[0510] An interim analysis for futility is planned when 68 subjects enrolled (approximately 50% of the total subjects) have completed Visit 4.

[0511] Statistical analysis

[0512] Descriptive statistics are presented by treatment group and overall. Variables included in descriptive analyses include demographics along with baseline values, post-baseline values, and changes from baseline for efficacy and safety outcomes. Categorical variables are summarized by counts and percentages. Continuous variables are summarized using mean, standard deviation, median, minimum, and maximum.

[0513] Primary Efficacy Endpoint

[0514] The primary efficacy endpoint for this study is the change in TMC score from baseline (Day 1 -Visit 1) to the end of treatment (Week 12 - Visit 4).

[0515] The primary efficacy analysis is based on the modified Intent-to-treat (mITT) population defined as all randomized subjects who received at least one dose of the study medication and had at least one post-baseline assessment of the TMC score.

[0516] The estimand for the primary efficacy analysis targets the difference between treatments in mean change from baseline to Week 12 in TMC scores. The population of interest is subjectswith HD with choreic movements. The key intercurrent event of use of prohibited concomitant medication is handled using the treatment policy strategy.

[0517] The primary analysis of the primary efficacy endpoint is based on a mixed-effect linear model for repeated measures (MM RM) to compare the active treatment group to placebo. The model includes the following factors: treatment group, visit, and treatment-by-visit interaction as fixed effects, and baseline TMC score as covariate. An unstructured variancecovariance matrix is used to model the within-subject errors. If no reliable results under the unstructured assumption can be obtained, the Toeplitz covariance structure, followed by the autoregressive and compound symmetry covariance structure are used. This model assumes that missing data arise from a missing at random (MAR) mechanism. Sensitivity to the MAR assumption is assessed in the sensitivity analysis.

[0518] The least square mean (LSM) estimate for each treatment group and difference in LSM estimates at end of maintenance dose between active treatment and placebo group with their confidence intervals is provided.

[0519] Sensitivity analyses on the primary efficacy estimand includes the following:

[0520] The primary efficacy analysis is repeated for the Per Protocol Population defined as all subjects who complete the study to Week 12 without any major protocol deviations that can influence the validity of the data for the primary efficacy variable.

[0521] The primary efficacy analysis is repeated on the ITT population assessing the impact of missing data under a missing not at random (MNAR) approach.

[0522] The primary efficacy analysis is done for subgroups of interest including

[0523] • Country: US sites vs non-US

[0524] • Baseline TMC score: < median, > median

[0525] Secondary Efficacy Endpoints

[0526] The following key secondary endpoints are assessed hierarchically in the following order: • HADS-Anxiety scale

[0527] • PBA-s

[0528] • CGI-C

[0529] • PGI-C

[0530] • HD-HI

[0531] TMS ofthe UHDRS'Percentage of change in TMC score

[0532] Percentage of subjects with TMC score change > -4.0 points

[0533] Secondary efficacy endpoints are analyzed using the mITT Population.

[0534] The family-wise Type I error rate is controlled among the multiplicity adjusted key secondary endpoints using a hierarchical testing strategy. If the primary endpoint of TMC score shows a significant difference (p < 0.05) between treatments in mean change from baseline to Week 12, key secondary endpoints are tested in the order listed. Significance at the 0.05 level is required to test the next endpoint in the testing sequence.

[0535] The estimands for the key secondary endpoints are defined similarly to those of the primary endpoint with the exception of the change in the endpoint component of the estimand. For continuous efficacy endpoints with longitudinal data, the same MMRM model, as described for the primary endpoint is performed. For other continuous efficacy endpoints measured at baseline and end of maintenance dose, an ANCOVA model is used.

[0536] Categorical efficacy endpoints are analyzed using a logistic regression model.

[0537] The type I error is set at 0.05 (two-sided) and the coverage level of confidence intervals to 95% for all secondary efficacy analyses. No multiplicity adjustment is applied for the statistical inferences of the secondary efficacy endpoints.

[0538] Safety Analysis

[0539] Safety is evaluated from reported adverse events, clinical laboratory values, vital signs, electrocardiograms (ECG), and other safety assessments as detailed in the schedule of assessments and outlined below. Safety analysis is based on the Safety Population, defined as all randomized subjects having received at least one dose of study treatment.

[0540] Adverse events (AEs):

[0541] All AEs summaries are restricted to Treatment Emergent Adverse Events (TEAEs), which are defined as any AE that occurs or worsens at or after the initiation of the study drug. The AEs are coded using the Medical Dictionary for Regulatory Activities (MedDRA) and tabulated by system organ class (SOC) and preferred term. Each AE summary is displayed by treatment group.

[0542] Number of AEs, frequency and percentage of subjects are reported. For intensity level, subjects are classified for the highest severity if they experienced several AEs.Onset time of AEs from initiation of study drug and AEs duration are also summarized.

[0543] Other safety endpoints:

[0544] • Incidence and severity of AEs, with severity determined according to the Adverse Event Severity Grading Scale

[0545] • Vital signs (including orthostatic blood pressure and pulse)

[0546] • Physical examinations

[0547] • SDQ

[0548] • Change from baseline in ECG parameters

[0549] • Change from baseline in Clinical laboratory tests (hematology, clinical chemistry, and urinalysis)

[0550] • Change from baseline in the C-SSRS

[0551] • Change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) • Change from baseline in the Barnes Akathisia Rating Scale (BARS)

[0552] • Cognitive UHDRS® measuring clinical symptoms in HD (verbal fluency test, the Symbol Digit Modalities Test, and the Stroop Interference Test)

[0553] • UHDRS® parkinsonism score (total of the following UHDRS® motor items: finger taps, pronation / supination, rigidity, bradykinesia, gait, tandem gait and retropulsion pull test) • Epworth Sleepiness Scale (ESS)

[0554] Open Label Extension

[0555] The same complete safety analysis is repeated in the open label extension. Additionally, efficacy is assessed using the open label extension baseline for all scales used in the doubleblind study.

[0556] Study duration and sites

[0557] The total duration of this double-blind study is up to 18 weeks, including 2 weeks for screening, 14 weeks of treatment, and a final study visit, 2 weeks following the final dose of study drug. The open label extension consists of 1 week up-titration and 34 weeks of maintenance treatment. The study is conducted in about 35 investigating sites.\ Kil \ ll \ 1 Sale!' < all 1 \ 2 \.? \ 4 Sa let ' call 2 \ 5

[0558] BiiM’line l iillun - 1 p I nd id' ( K.i mlmii i / .i l imi ) Dunn- 1 illation Period Screenin'* Maintenance Dose Period Sludx mid X 1 p- 1 illation ( I nd id' 1 realmenl I Period OI L. Baseline Dux 1) 14 h. " DI 1)14 2 d:r- - 1)28 2 days D5(> 2 da' - 1)84 2 days 1)98 2 days 1)112 2 da' - \X 8 M 12 1 n I* nineil cmiM'iil X 1 nclirii in mill excliriiui criteria X X < repeal X Ra lull >ini / a 1 ii in X Deinom aphics and medical lii-lm x X Pin sical mid iieuri>li>eic:il X

[0559]

[0560] X X X X

[0561] examination

[0562] \ ilul '.imi'. X X X X X X

[0563] 1 IIDRS 1 \l< Mine X X X X X X

[0564] < <. l-<. I’<.l-<. II WS. PUVx. X

[0565] X X X X IID-III

[0566] < -SSRS X X X X X X X X

[0567] 1 IIDRS l l ( X X X

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[0569] 1 IIDRS parIJiiMiiiiMii Min e. X X X X

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[0572] Bl.1 sample lor sale!' X X X X X X

[0573] 1 l ine ill’ll!* M i een X

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[0575] \iheiM1ex cuts X X X X X X X

[0576] < u-meilicalium X X X X X X X X

[0577] Dispell'-:! 1 i< m idXluih ilrim X X X X

[0578]

[0579] Drill* accuimlaliililx X cumplimice X X X X.....

[0580] Safety Call 3 Safetv Call 4 Safety Call 5 j 3'9 3 10 s.lfl B I.ill 0

[0581] Post Treatment Maintenance Dose Extension Period End of Treatment Observation- Follow-Up D140x2 days D210-2 days ■■■■jilM ■Ijfjljjjljl^ (jfBIIIIBI Week Month 5 (W20) Month 6 (W24) Month " (W30) Month 8 (M 34) Month 9 (W40) Month 10 (W44) Month 11 (W48) \b«n‘l« 12 W2» W54 Inforaied consent * Inclusion and exclusion criteria CAG repeat; Randomization, Demographics and medical history Pin 'k.il uhi m 'uol-i^ii.ii X X X X X examination A ltai signs X X X x X I DDRS' MJC X x X X X ( c,l <. PGI (. H M^. PB \.

[0582] X X X X X X x X x X X X X X X X X x

[0583]

[0584] M \BKx M)Q. I i; \Rs.

[0585] 1 11DR’*4P i:kiii-u>i['-m X X X X X

[0586] ( n«ni:iw I HDKs*

[0587] 00 X X X X X n Blood sample for safety X X X X X

[0588] Urine drug screen

[0589] Urine Pregnancy test in female

[0590] Adverse events X X X x X X X X X

[0591] Co-medications X X X X X X X X X

[0592] 1 Dispensation of study drug X X X X

[0593]

[0594] Di ’in.i« i •Hiiii.tlniib A. i ompli.im t- X X X X X

Claims

New PCT Patent ApplicationSOM BiotechVossius Ref.: AJ3848 PCT BSCLAIMS1. A pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of one or more mental disorders in a subject, wherein said pharmaceutical composition is to be administered twice daily at a dose of about 50 mg and 500 mg bevantolol.

2. The pharmaceutical composition for use according to claim 1, wherein the mental disorder is a depressive disorder, preferably wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed anxiety-depressive disorder, and / or secondary depression.

3. The pharmaceutical composition for use according to claim 1 or 2, wherein the mental disorder is a psychotic disorder, anxiety disorder, neurodevelopmental disorder, impulse control disorder, cognitive disorder, and / or bipolar disorder; and / or wherein the mental disorder is selected from: schizophrenia, schizoaffective disorder, psychosis, psychosis associated with a neurodegenerative disease, obsessive- compulsive disorder, generalized anxiety disorder, social anxiety disorder, specific phobia, post-traumatic stress disorder, attention deficit hyperactivity disorder, autism spectrum disorder, addiction, and / or dementia.

4. The pharmaceutical composition for use according to claim 2 wherein the subject is a subject having a hyperkinetic movement disorder.

5. The pharmaceutical composition for use according to claim 4, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourettesyndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome, in particular wherein the hyperkinetic movement disorder is associated with Huntington's disease.

6. The pharmaceutical composition for use according to claim 4 or 5, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

7. The pharmaceutical composition for use according to any one of claims 4 to 6, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

8. A pharmaceutical composition comprising bevantolol, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a hyperkinetic movement disorder in a subject, wherein the subject has been diagnosed with a depressive disorder or is at risk of developing a depressive disorder, in particular wherein administering the pharmaceutical composition results in an improved depression score.

9. The pharmaceutical composition for use according to claim 8, wherein the depressive disorder is selected from: major depressive disorder, minor depressive disorder, melancholic depression, atypical depression, catatonic depression, postpartum depression, treatment resistant depression, dysthymic disorder, seasonal affective disorder, mixed anxiety-depressive disorder, and / or secondary depression.

10. The pharmaceutical composition for use according to claim 8 or 9, wherein the hyperkinetic movement disorder is associated with Huntington's disease, Wilson's disease, Tourette syndrome, restless leg syndrome, tardive dyskinesia, progressive supranuclear palsy, multiple system atrophy, hyperekplexia, epilepsy, and / or Rett syndrome, in particular wherein the hyperkinetic movement disorder is associated with Huntington's disease.

11. The pharmaceutical composition for use according to any one of claims 8 to 10, wherein the hyperkinetic movement disorder is selected from: abdominal dyskinesias, akathisia, asynergia, ataxia, athetosis, ballism, chorea, dysmetria, dystonia, hemifacial spasm, jumpy stumps, moving toes and / or fingers, myoclonus, myokymia, myorhythmia, tics, tremors, seizures, epileptic seizures, spasticity, rigidity, paroxysmal dyskinesias, hypnogenic dyskinesia, and / or essential tremor.

12. The pharmaceutical composition for use according to any one of claims 8 to 11, wherein the hyperkinetic movement disorder is chorea associated with Huntington's disease.

13. The pharmaceutical composition for use according to any one of claims 1 to 12, wherein the pharmaceutical composition is administered orally, preferably as a tablet or a capsule; and / orwherein said pharmaceutical composition comprises bevantolol hydrochloride.

14. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein said pharmaceutical composition is to be administered twice daily at a dose of about 300 mg bevantolol.

15. The pharmaceutical composition for use according to any one of claims 1 to 13, wherein said pharmaceutical composition is to be administered twice daily at a dose of about 400 mg bevantolol.

16. The pharmaceutical composition for use according to any one of claims 1 to 15, wherein the bevantolol comprised in the composition inhibits VMAT2 and VMAT1; and / or wherein the bevantolol comprised in the composition inhibits dopamine uptake more efficiently than serotonin uptake via VMAT2; and / orwherein the bevantolol comprised in the composition reduces vesicular dopamine, and serotonin.

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