Application of pridopidine to treatment of teenager huntington's disease

Abstract

Provided herein is a method of treating teenager Huntington's disease in a subject in need thereof, the method comprising orally administering a pharmaceutical composition comprising pridopidine and / or an analog thereof or a pharmaceutically acceptable salt thereof.

Description

Field of the Invention

[0001] Provided herein is a method for treating juvenile Huntington's disease, comprising orally administering a pharmaceutical composition comprising pridopidine and / or an analog thereof or a pharmaceutically acceptable salt thereof. Background of the Invention

[0002] Huntington's disease Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant inheritance pattern. Symptoms typically begin between the ages of 40 and 60, and the disease progresses over 10 to 30 years, ultimately leading to death. The prevalence of HD in the general population is approximately 10 per 100,000 people, and approximately 100,000 people worldwide. Approximately 5% of HD subjects develop clinical features before the age of 20, and these are classified as juvenile-onset HD (JHD). The prevalence of JHD is approximately 0.5 per 100,000 people.

[0003] Adult-onset HD and JHD share the same pathogenic mutation: an expansion of at least 36 CAG repeats in the HTT gene. However, the number of repeats is highly variable and correlates with disease severity and progression (higher repeat lengths are associated with earlier onset). JHD is associated with a large number of CAG repeats, typically exceeding 50. Furthermore, significant phenotypic differences exist between adult-onset HD and JHD.

[0004] HD is associated with a triad of motor, behavioral, and cognitive symptoms. Movement disorders are the defining characteristic of the disease. Disability and disease severity are most correlated with negative functional and motor features, such as decreased functional ability and impairment of fine motor skills and coarse motor coordination skills, including speech difficulties, gait, and postural dysfunction (Mahant et al., Huntington's disease: clinical correlates of disability and progression. Neurology. 2003 Oct 28; 61(8): 1085-92. doi: 10.1212 / 01.wnl.0000086373.32347.16. PMID: 14581669).

[0005] In contrast to adult-onset HD, which is primarily associated with chorea as a defining motor feature, JHD manifests with motor symptoms, including rigidity, dystonia, and bradykinesia, as well as behavioral problems and developmental delays. JHD patients suffer from more severe symptoms and faster disease progression (Quarrell et al., Managing juvenile Huntington's disease. Neurodegener Dis Manag. 2013 Jun 1;3(3):10.2217 / nmt.13.18).

[0006] Neuropathologically, JHD is primarily characterized by neuronal loss in the striatum and cortex. However, numerous other nuclei, including the globus pallidus, thalamus, hypothalamus, subthalamic nucleus, substantia nigra, and cerebellum, are also affected. Furthermore, diffusion tensor imaging has demonstrated white matter pathology in presymptomatic and early symptomatic patients (Raymond et al., Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience. 2011 Dec 15;198:252-73). JHD pathology is often more extensive and severe than typical adult-onset HD (Quarrell et al., 2013).

[0007] Many medications are prescribed to help manage the motor, cognitive, and behavioral problems associated with HD. However, these are symptom-specific. No registered medications are available to beneficially regulate the multifaceted symptoms of HD, which lead to the unstoppable motor, cognitive, and behavioral decline that occurs throughout the course of the disease.

[0008] The different manifestations of JHD mean that the treatments used to manage JHD and adult-onset HD may differ (Robertson, Lisa et al. "Current pharmacological management in juvenile Huntington's disease." PLoS currents 4 (2012). For example, the drugs tetrabenazine (TBZ) and deuterated tetrabenazine (dTBZ) are approved for treating chorea in adult-onset HD. However, because their safety and efficacy have not been proven in children, TBZ and dTBZ are not used in JHD.

[0009] In summary, there is no effective treatment for JHD, and patients have a progressive, uncontrolled, and unstoppable disease progression with worsening neurological status, loss of independence in daily activities, and premature death.

[0010] Because all current therapies are only symptomatic, a therapy that prevents or delays the progression of disability would represent a substantial improvement over currently available therapies. Therefore, there is a significant unmet medical need for the development of drugs to treat JHD.

[0011] Pridopidine Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine) (formerly known as ACR16) is a drug in clinical development for the treatment of HD. Pridopidine has high affinity and selectivity for the sigma-1 receptor (S1R, binding IC50 ~100 nM), with low affinity binding (in the micromolar range) for other receptors, including the dopamine D2 / D3 receptor.

[0012] The sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone protein involved in calcium homeostasis, cellular bioenergetics, neuroplasticity, and neuroprotection. SUMMARY OF THE INVENTION

[0013] In some embodiments, provided herein is a method of treating or reducing the progression of juvenile Huntington's disease (JHD) in a subject, comprising orally administering to the subject a pharmaceutical composition comprising pridopidine, an analog thereof, or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the Juvenile Huntington's disease subject has a mutation of 50 or more CAG repeats in the Huntington (Htt) gene. In some embodiments, the JHD subject has 55 or more CAG repeats.

[0015] In some embodiments, the JHD subject experiences symptom onset before age 16. In some embodiments, symptom onset is before age 18. In another embodiment, symptom onset is before age 20. In another embodiment, symptom onset is before age 21.

[0016] In some embodiments, the JHD subject is a pre-manifest or prodromal JHD subject.

[0017] The recently established Integrated Staging System (ISS) for HD defines specific stages based on different clinical markers and distinguishes between presymptomatic HD patients, prodromal HD patients, and manifest HD patients.

[0018] HD Integrated Scoring System (HD-ISS) In some embodiments, a prodromal JHD subject is characterized by an ISS stage of 1 or 2. In some embodiments, a presymptomatic JHD subject has an ISS score of 0.

[0019] The HD-ISS is an evidence-based staging system that is applicable to all stages of HD. The ISS defines marker assessments and cutoffs to identify key transitions in disease stage. The HD-ISS has 4 different stages. ISS Stage 0 (Presymptomatic) includes all HD gene carriers for whom there are no detectable changes in pathological markers, signs, or symptoms associated with HD. In ISS Stage 1, pathological changes indicative of the onset of neurodegeneration and specific signs can be detected, particularly changes in the volume of the caudate and putamen brain substructures. ISS Stage 2 is defined as the presence of clear clinical signs and symptoms (both cognitive and motor) without any decline in function. ISS Stage 3 (Manifested) is accompanied by a decline in functional ability or independence scales.

[0020] In some embodiments, provided herein is a method of maintaining or reducing one or more symptoms of juvenile Huntington's disease (JHD) in a subject, the method comprising orally administering to the subject a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof, wherein the one or more symptoms are selected from the group consisting of depression, anxiety, apathy, impulsivity, aggression, motor impairment, cognitive impairment, physical symptoms, seizures, psychiatric symptoms, mood symptoms, behavioral symptoms, and shortened lifespan.

[0021] In some embodiments, provided herein is a method for maintaining, improving, or reducing the decline in motor, cognitive, or behavioral function of a subject with juvenile Huntington's disease, the method comprising orally administering to the subject a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof. Detailed Description of the Invention

[0022] The present invention provides a method for treating juvenile Huntington's disease (JHD) in a subject or reducing its progression, the method comprising administering to the subject a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof.

[0023] Huntington's disease (HD) is caused by an expansion of cytosine-adenine-guanine (CAG) repeats within the coding region of the huntingtin (Htt) gene. The gene encodes a large protein (~350 kDa) called huntingtin (HTT), which is highly conserved and widely expressed throughout the body. The wild-type gene encodes a polyglutamine stretch ranging from 6 to 35 repeats near its amino terminus. HD is associated with 36 or more CAG repeats. This mutation results in a long polyglutamine stretch in the first exon of the huntingtin protein. When the number of repeats exceeds 39, clear clinical manifestations will occur, while the range of 36-39 results in incomplete penetrance or late onset of the disease. The negative correlation between the length of the CAG repeat and the age of onset has been well characterized, with the age of onset determined by the first motor manifestation. The longer the CAG repeat, the earlier the onset (Andrew et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993 Aug;4(4):398-403).In juvenile HD (JHD), onset occurs ≤ 20 years, and repeats frequently exceed 50 CAGs (Roos RA. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010 Dec 20;5:40; Raymond et al, Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function. Neuroscience. 2011 Dec 15;198:252-73; Quarrell et al, The Prevalence of Juvenile Huntington's Disease: A Review of the Literature and Meta-Analysis. PLoS Curr. 2012 Jul 20;4:e4f8606b742ef3; Telenius et al, Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum Mol Genet. 1993 Oct;2(10):1535-40.).

[0024] Neuropathologically, JHD is primarily characterized by neuronal loss in the striatum and cortex. However, numerous other nuclei, including the globus pallidus, thalamus, hypothalamus, subthalamic nucleus, substantia nigra, and cerebellum, are also affected. Furthermore, diffusion tensor imaging has demonstrated white matter pathology in presymptomatic and early symptomatic patients (Raymond et al., 2011). JHD pathology is often more extensive and severe than typical adult-onset HD (Quarrell et al., 2013).

[0025] The prevalence of JHD (onset age ≤ 20 years) is significantly lower than that of adult-onset HD. JHD is very rare and accounts for approximately 5% of all HD cases. When assuming a total HD prevalence of 10 per 100,000 people, this yields a conservative estimate of JHD prevalence of 0.5 per 100,000 people.

[0026] JHD JHD is defined as clinical onset ≤20 years of age. Childhood-onset JHD begins in the first decade of life (≤10 years), while adolescent-onset JHD begins in the second decade of life (11-20 years) (Quarrell et al., 2012; Quarrell et al., 2013). Due to the relative rarity of JHD, lack of awareness among physicians, complex and diverse symptom presentation, and nonspecific initial presentation, the diagnosis of JHD is often significantly delayed (Achenbach et al., Clinical Manifestation of Juvenile and Pediatric HD Patients: A Retrospective Case Series. Brain Sci. 2020 Jun 3;10(6):340; Ribaï et al., Psychiatric and cognitive difficulties as indicators of juvenile huntington disease onset in 29 patients. Arch Neurol. 2007 Jun;64(6):813-9). One study found that the average delay in diagnosis was 9 years (Ribai et al., 2007). Furthermore, JHD typically has more rapid progression and a shorter duration than adult-onset HD (Foroud et al., Differences in duration of Huntington's disease based on age at onset. J Neurol Neurosurg Psychiatry. 1999 Jan;66(1):52-6, Quarrell et al., 2013, Foroud T, Gray J, Ivashina J, Conneally PM. Differences in duration of Huntington's disease based on age at onset. J Neurol Neurosurg Psychiatry. 1999 Jan;66(1):52-6; Latimer et al., Neuropathological Comparison of Adult Onset and Juvenile Huntington's Disease with Cerebellar Atrophy: A Report of a Father and Son. J Huntingtons Dis. 2017;6(4):337-348).

[0027] Childhood-onset JHD The clinical features of JHD that manifests in the first decade of life (childhood-onset JHD) differ significantly from those of adult-onset HD, with a more severe and rapidly progressive phenotype. Clinical manifestations are typically one of the following: cognitive impairment (particularly executive function) with decreased school performance, and behavioral abnormalities. This condition is further exacerbated by speech and language problems.

[0028] In contrast to adult-onset HD, where the initial motor manifestations are hyperkinesia with chorea, patients with childhood-onset JHD have a different phenotype, with severe bradykinesia, rigidity, dystonia, and ataxia as their initial motor manifestations. Rigidity is a distinguishing feature of JHD that is not observed in adult-onset HD (Ribai et al., 2007; Quigley J. Juvenile Huntington's Disease: Diagnostic and Treatment Considerations for the Psychiatrist. Curr Psychiatry Rep. 2017 Feb;19(2):9).

[0029] In addition, epilepsy is common and may initially be confused with progressive myoclonic epilepsy in some patients (Thakor et al., Juvenile Huntington's disease masquerading as progressivemyoclonus epilepsy. Epilepsy Behav Rep. 2021 July 15;16:100470). Seizures occur in about one-third of JHD cases and are much more likely to occur in childhood-onset JHD than in adolescent-onset JHD (Cloud et al., Seizures in juvenile Huntington's disease: frequency and characterization in a multicenter cohort. Mov Disord. 2012 December;27(14):1797-800). The younger the age of onset, the greater the risk of epileptic seizures. Epileptic seizures are usually generalized tonic-clonic (Cloud et al., 2012). In the initial stages of the disease, seizures in childhood-onset JHD are usually well controlled. However, as the disease progresses, they become drug-resistant (Khair et al., Drug-Resistant Epilepsy in Children with Juvenile Huntington's Disease: A Challenging Case and BriefReview. Qatar Med J. 2020 Jul 14;2020(1):18. Gonzalez-Alegre P, Afifi AK. Clinical characteristics of childhood-onset (juvenile) Huntington disease:report of 12 patients and review of the literature. J Child Neurol. 2006 Mar;21(3):223-9). The initial manifestation of epileptic seizures is an additional distinguishing feature of JHD that is not observed in adult-onset HD.

[0030] The psychiatric symptom burden of JHD is substantial and includes depression, anxiety, impulsivity, and aggression (Quigley 2017). Conduct disturbances are a hallmark of childhood-onset JHD and are often the primary manifestation. These can be profoundly debilitating for the child and family, impacting interpersonal relationships and the ability to function socially and emotionally. Patients may initially be misdiagnosed with attention deficit hyperactivity disorder (ADHD) (Gonzalez-Alegre and Afifi, 2006).

[0031] Pubertal-onset JHD The clinical features of individuals with onset in the second decade (adolescent-onset JHD) show some phenotypic differences compared to the features of childhood onset. For example, although chorea is rarely observed when JHD first appears in the first decade, chorea may be observed in patients with onset in the second decade (adolescent-onset JHD) (Roos 2010; Quarrell et al., 2013; Oosterloo et al., Diagnosing Juvenile Huntington's Disease: An Explorative Study among Caregivers of Affected Children. Brain Sci. 2020 Mar 7; 10(3): 155). Seizures can also be observed in adolescent-onset HD (Cloud et al., 2012).

[0032] In adolescent-onset JHD, cognitive decline is often accompanied by a decline in school performance. There is a wide range of behavioral and psychiatric manifestations, including drug and alcohol abuse, depression with suicidal attempts, hyperactivity, or personality disorders (Nance MA. Clinical aspects of CAG repeat diseases. Brain Pathol. 1997 Jul;7(3):881-900; Ribai et al., 2007). As the disease progresses, it evolves into a phenotype similar to that of patients with childhood onset (Hansotia, Juvenile Huntington's chorea. Neurology. 1968 Mar;18(3):217-24; van Dijk JG et al., Juvenile Huntington disease. Hum Genet. 1986 Jul;73(3):235-9). Significant oropharyngeal dysfunction is often observed, and other features of adolescent-onset JHD can include rigidity, dystonia, and chorea.

[0033] The present invention provides a method for maintaining or reducing one or more symptoms of juvenile Huntington's disease in a subject, the method comprising administering to the subject a pharmaceutical composition comprising pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof. In embodiments, the one or more symptoms are selected from the group consisting of depression, anxiety, motor impairment, cognitive impairment, physical symptoms, psychiatric symptoms, mood symptoms, behavioral symptoms, impairment of the patient's functional ability, and shortened lifespan.

[0034] In one embodiment, provided herein is a method of maintaining, improving, or reducing decline in motor function in a human subject with juvenile Huntington's disease, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof.

[0035] In some embodiments, the method comprises maintaining, improving, or reducing decline in motor function in the subject.

[0036] In some embodiments, the method comprises reducing or alleviating seizures in a juvenile Huntington's disease subject.

[0037] In one embodiment, provided herein is a method for improving depression, preventing the worsening of depression, or reducing depression in a subject with Huntington's disease. In another embodiment, provided herein is a method for improving anxiety, preventing the worsening of anxiety, or reducing anxiety in a subject with Huntington's disease. In another embodiment, provided herein is a method for maintaining or reducing impulsivity in a subject with Huntington's disease. In another embodiment, provided herein is a method for improving aggression, preventing the worsening of aggression, or reducing aggression in a subject with Huntington's disease.

[0038] In one embodiment, provided herein is a method for maintaining or improving motor function impairment, or reducing its decline, in a subject with Huntington's disease. In one embodiment, provided herein is a method for maintaining or improving cognitive impairment, or reducing its decline, in a subject with Huntington's disease. In one embodiment, provided herein is a method for maintaining or improving memory impairment, or reducing its decline, in a subject with Huntington's disease. In one embodiment, provided herein is a method for maintaining or improving learning ability, or reducing its decline, in a subject with Huntington's disease.

[0039] In one embodiment, provided herein is a method for maintaining or improving physical symptoms, or reducing the decline thereof, in a subject with Huntington's disease. In one embodiment, provided herein is a method for maintaining or improving mental symptoms, or reducing the decline thereof, in a subject with Huntington's disease. In one embodiment, provided herein is a method for improving emotional symptoms, preventing the worsening of said emotional symptoms, or reducing said emotional symptoms in a subject with Huntington's disease. In one embodiment, provided herein is a method for maintaining or reducing behavioral symptoms in a subject with Huntington's disease. In one embodiment, provided herein is a method for maintaining shortened lifespan, improving shortened lifespan, or reducing the decline of shortened lifespan in a subject with Huntington's disease.

[0040] Also provided is a method for improving, maintaining, or slowing down the decline of a human patient's cognitive domain, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof, thereby improving, maintaining, or slowing down the decline of the human patient's cognitive domain. In some embodiments, the patient is a patient with juvenile Huntington's disease (JHD). The patient's cognitive domain can also be the patient's cognitive performance across multiple domains.

[0041] The cognitive domain of human patients can be for example measured by cognitive assessment battery test (the cognitive assessment battery) (CAB) and / or the Hopkins Verbal Learning Test (HVLT-R) of revision.Cognitive domain can also be measured by line connection test B (TMT-B).Cognitive domain can also be measured by HD cognitive assessment battery test (HD Cognitive Assessment Battery) (HD-CAB), which includes 6 tests.Cognitive measurement can also be measured by Wright International Performance Scale (Leiter International Performance Scale) and Peabody Picture Vocabulary Test (Peabody Picture Vocabulary Test).

[0042] Also provided is a method for improving or maintaining motor function in a human patient, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof, thereby improving the motor function of the human patient. In some embodiments, the improvement in motor function comprises less bradykinesia, improved ataxia and / or gait, less rigidity, less dystonia, and / or better coordination, eye movements, or hand movements. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0043] The present invention also provides a method for improving or maintaining the mobility of a human patient, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof, thereby improving or maintaining the mobility of the human patient. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0044] The present invention also provides a method for reducing or maintaining involuntary movements in a human patient, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof or a pharmaceutically acceptable salt thereof, thereby reducing or maintaining involuntary movements in the human patient. In some embodiments, the patient is a juvenile Huntington's disease (JHD) patient.

[0045] Motor ability can be measured by, for example, a score on the UHDRS Total Motor Score (TMS), a score on the UHDRS TMS minus chorea, or a score on the UHDRS TMS minus dystonia.

[0046] The present invention also provides a method for reducing or maintaining the level of dystonia in a human patient, the method comprising regularly orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof or a pharmaceutically acceptable salt thereof, thereby reducing or maintaining the level of dystonia in the human patient. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0047] The worsening of dystonia can also be slowed. Thus, the present invention provides a method for reducing, maintaining, or slowing the worsening of dystonia in a human patient, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof, thereby reducing, maintaining, or slowing the worsening of dystonia in the human patient. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0048] Dystonia in human patients can be measured using the UHDRS TMS dystonia score.

[0049] The present invention also provides a method for reducing or maintaining gait and balance in a human patient, the method comprising regularly orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof or a pharmaceutically acceptable salt thereof, thereby reducing or maintaining gait and balance in the human patient. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0050] Decline in gait and balance can also be slowed. Accordingly, the present invention provides a method for reducing, maintaining, or slowing decline in gait and balance in a human patient, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof, thereby reducing, maintaining, or slowing decline in gait and balance in the human patient. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0051] Gait and balance in human patients can be measured using the UHDRS TMS Gait and Balance Score.

[0052] The present invention also provides a method for reducing or maintaining the level of chorea in a human patient, the method comprising periodically orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof, thereby reducing or maintaining the level of chorea in the human patient. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0053] The progression of chorea can also be slowed. Thus, the present invention provides a method for reducing, maintaining, or slowing the progression of chorea in a human patient, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof, thereby reducing, maintaining, or slowing the progression of chorea in the human patient. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0054] Chorea in human patients can be measured using the UHDRS TMS chorea score.

[0055] In some embodiments, the patient's motor function is assessed by digit kinesiography (finger tapping).In some embodiments, motor function is assessed by the quantitative motor (Q-motor) battery.

[0056] Quantitative-Motion (Q-Motion) Q-motion is an objective assessment of specific motor function that utilizes pre-calibrated, temperature-independent force and 3D position sensors to provide standardized, unbiased measurements.

[0057] The Q-motor test has recently been tested in children and has been shown to be sensitive to age-related changes in motor skills. Finger tapping speed is directly related to age, with young children tapping slower and more irregularly than older children (Van Der Plas et al. 2019). Therefore, it can be used to detect developmental delays.

[0058] In another embodiment, the JHD subjects have decreased Q-motion finger tapping velocity frequency, decreased Q-motion finger tapping inter-episode interval, decreased Q-motion finger tapping inter-tap interval, decreased Q-motion inter-peak interval, decreased Q-motion palm-down / palm-up hand tapping frequency, decreased Q-motion hand tapping inter-episode interval, decreased grip strength, decreased tongue strength, or any combination thereof, compared to healthy controls.

[0059] Also provided is a method for improving or maintaining motor ability of a human patient as assessed by Q-motor assessment, comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof, thereby improving the Q-motor ability of the human patient. In some embodiments, the improvement in motor ability comprises improved Q-motor finger tapping intervals, increased or maintained Q-motor inter-peak intervals, improved or maintained Q-motor palm-down / palm-up hand tapping frequency, improved or maintained Q-motor hand tapping inter-episode intervals, improved or maintained grip strength, improved or maintained tongue strength, or any combination thereof. In some embodiments, the patient is a juvenile Huntington's disease (HD) patient.

[0060] The present invention also provides a method for improving or maintaining the behavioral and / or psychiatric state of a human patient, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or an analog thereof or a pharmaceutically acceptable salt thereof, thereby improving or maintaining the behavioral and / or psychiatric state of the human patient. In some embodiments, the patient is a patient with juvenile Huntington's disease (JHD).

[0061] The behavior and / or psychotic state of a human patient can be measured by, for example, a problem behavior assessment (PBA) total score. The behavior and / or psychotic state of a human patient can also be measured by a problem behavior assessment of depression. The behavior and / or psychotic state of a human patient can also be measured by a problem behavior assessment of irritability. The behavior and / or psychotic state of a human patient can also be measured by a problem behavior assessment of lack of initiative or apathy. The behavior and / or psychotic state of a human patient can also be measured by a problem behavior assessment of, for example, obsessive-compulsive disorder. The behavior and / or psychotic state of a human patient can also be measured by a problem behavior assessment of lost behavior.

[0062] Also provided is a method for improving apathy or apathy in a human HD patient, or reducing the decline thereof, the method comprising orally administering to the patient a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof, thereby improving the patient's apathy or apathy, or reducing the decline thereof. In some embodiments, the patient is a juvenile Huntington's disease (JHD) patient.

[0063] In some embodiments, the present invention also provides a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof for use in: (a) delaying the onset of HD or slowing the clinical progression of HD in JHD patients, (b) reducing dystonia or maintaining the level of dystonia in JHD patients, (c) treating limb dystonia in JHD patients, (d) preventing slowing, reduction in amplitude, or impairment in finger tapping ability in JHD patients, and / or preventing slowed or irregular performance in the palm down-palm up hand test, (e) improving or maintaining gait and balance in JHD patients, (f) improving or maintaining independence in human patients with JHD, (g) improving or maintaining cognitive performance in human patients across multiple domains in JHD patients, (h) reducing the severity of sustained or intermittent muscle contractions associated with dystonia in human patients in need thereof, (i) improving or maintaining (i) improving, maintaining, or reducing the decline in a JHD patient's motor ability, (ii) reducing or maintaining the level of chorea in a JHD patient, (iii) improving, maintaining, or reducing the decline in a JHD patient's behavioral and / or psychiatric state, (iv) reducing or maintaining involuntary movements in a JHD patient, (v) improving or maintaining a JHD patient's mobility, (v) improving or maintaining a JHD patient's ability to perform physical tasks, (v) improving or maintaining a JHD patient's quality of life, (v) improving, maintaining, or reducing the decline in a JHD patient's gait and balance, (v) improving, maintaining, or reducing the decline in a JHD patient's independence, (v) improving, maintaining, or reducing the decline in a JHD patient's cognitive performance in various areas, (v) reducing, maintaining, or reducing the increase in chorea in a JHD patient, wherein the pharmaceutical composition is orally administered to the patient such that a dose of 0.5 mg to 300 mg of pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof, is administered to the patient daily.

[0064] In an embodiment, one or more symptoms are measured by: Clinician's Interview-based Impression of Change plus Caregiver Input (CIBIC-Plus), Physical Disability Score (PDS), Clinical Global Impression of Change (CGI-C), Unified Huntington's Disease Rating Scale (UHDRS) Independence Score (IS), HD-Quality of Life Scale (HD-QoL), Multiple Sclerosis Walking Scale (MSWS-12), Physical Performance Test (PPT), Hand Motor Score, Gait and Balance Score, Quantitative Motor (Q-Motor) Assessment, Timed Up and Go (TUG) Assessment, Cognitive Assessment Battery (CAB), Symbol Digit Modalities Test (SDMT), Stroop word reading test, Montreal Cognitive Assessment (MoCA) scale, Trail Making Test B assessment, or Problem Behavior Assessment-Short Form (PBA-s). In another embodiment, one or more symptoms are measured by EQ5D-5L, Walk-12, or the modified Physical Performance Test (mPPT).

[0065] In embodiments, treating Juvenile Huntington's disease in a subject comprises reducing the subject's motor impairment symptoms as measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS).

[0066] In embodiments, treating Juvenile Huntington's disease in a subject comprises reducing the subject's motor impairment symptoms as measured by the Unified Huntington's Disease Rating Scale (UHDRS) modified motor score (mMS).

[0067] In embodiments, treating Juvenile Huntington's disease in a subject comprises reducing the subject's motor impairment symptoms as measured by the Unified Huntington's Disease Rating Scale (UHDRS)-Chorea score.

[0068] In embodiments, treating Juvenile Huntington's disease in a subject comprises reducing the subject's motor impairment symptoms as measured by the Unified Huntington's Disease Rating Scale (UHDRS)-Dystonia Score.

[0069] As used herein, "reducing the decline in adolescent HD" includes assessing the progression of HD using any of the scales and scores disclosed herein, wherein the rate of progression of adolescent HD as assessed by the methods described herein is reduced in a subject after administration of pridopidine and / or its analogs or pharmaceutically acceptable salts thereof for a period of time compared to a subject not receiving the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof for the same period of time.

[0070] In some embodiments, the present invention provides a method of treating or slowing the progression of juvenile HD in a subject, the method comprising administering to the subject a pharmaceutical composition comprising pridopidine and / or an analog thereof, or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, progression of HD is defined by a change in ISS stage 1 to stage 2. In another embodiment, progression is defined as a change in ISS stage 2 to stage 3. In some embodiments, treating, slowing, or delaying the progression of HD is measured by no change in the ISS scale. In some embodiments, treating or ameliorating HD is defined as a change in ISS stage from 3 to 2 or from 2 to 1.

[0072] In some embodiments, reducing the decline in the progression of HD in adolescents comprises slowing the patient's motor deterioration compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof over the same period of time. In some embodiments, reducing the decline in the progression of HD in adolescents comprises improving the patient's motor function compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof over the same period of time. In some embodiments, reducing the decline in the progression of HD comprises slowing the patient's motor deterioration and improving motor function compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof over the same period of time.

[0073] In some embodiments, reducing the decline in the progression of HD in adolescents comprises slowing the patient's cognitive deterioration compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof over the same period of time. In some embodiments, reducing the decline in the progression of HD in adolescents comprises improving the patient's cognitive function compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof over the same period of time. In some embodiments, reducing the decline in the progression of HD comprises slowing the patient's cognitive deterioration and improving the patient's cognitive function compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof over the same period of time.

[0074] In some embodiments, reducing the decline in the progression of HD in adolescents comprises slowing the worsening of the patient's psychosis or behavior compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof during the same period. In some embodiments, reducing the decline in the progression of HD in adolescents comprises improving the patient's psychosis or behavioral functioning compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof during the same period. In some embodiments, reducing the decline in the progression of HD comprises slowing the worsening of the patient's psychosis or behavior and improving the patient's psychosis or behavioral functioning compared to a subject who did not receive the same treatment with pridopidine and / or its analogs or pharmaceutically acceptable salts thereof during the same period.

[0075] In some embodiments, reducing the decline in progression of juvenile HD comprises slowing or preventing the frequency of seizures in the patient compared to a subject not receiving the same treatment with pridopidine and / or its analog or pharmaceutically acceptable salt thereof for the same period of time.

[0076] In some embodiments, the time period is between 6 and 60 months. In some embodiments, the time period is between 12 and 60 months. In some embodiments, the time period is between 24 and 60 months. In some embodiments, the time period is between 36 and 60 months. In some embodiments, the time period is between 48 and 60 months. In some embodiments, the time period is between 24 and 48 months. In some embodiments, the time period is between 36 and 48 months. In some embodiments, the time period is between 36 and 60 months. In some embodiments, the time period is between 48 and 60 months. In some embodiments, the time period is 6 months. In some embodiments, the time period is 12 months. In some embodiments, the time period is 24 months. In some embodiments, the time period is 36 months. In some embodiments, the time period is 48 months. In some embodiments, the time period is 60 months. In some embodiments, the time period is at least 6 months. In some embodiments, the time period is at least 12 months. In some embodiments, the time period is at least 24 months. In some embodiments, the time period is at least 36 months. In some embodiments, the period of time is at least 48 months. In some embodiments, the period of time is at least 60 months.

[0077] In some embodiments, administration of pridopidine results in a delay or reduction in deterioration of structural, functional, and metabolic measures in the brain. In some embodiments, these measures are assessed by volumetric magnetic resonance imaging (MRI), functional MRI (fMRI), and using 18 F-fluoro-2-deoxy-D-glucose (18 FDG-PET metabolic imaging was used to evaluate the

[0078] Neurofilament light protein (NfL) can be used as a biomarker for neurodegeneration in HD patients (Byrne et al., Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. Lancet Neurol. 2017 Aug;16(8):601-609.). NfL concentrations in plasma have been found to increase with the progression of HD disease. Elevated NfL concentrations are associated with decreased volumes of the caudate nucleus and putamen. Therefore, NfL concentrations in the plasma of HD patients may provide a means for assessing and predicting neurological damage in HD patients (Byrne et al., Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. Lancet Neurol. 2017 Aug;16(8):601-609). Furthermore, results suggest that NfL in blood can provide a reliable estimate of NfL concentration in CSF (Byrne et al., Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington's disease: a retrospective cohort analysis. Lancet Neurol. 2017 Aug;16(8):601-609).

[0079] Plasma NfL levels in subjects with JHD were significantly higher than in healthy controls, approximately 7-fold. Furthermore, plasma NfL levels in JHD subjects were significantly higher than in HD subjects (approximately 1.5-fold higher than in adolescent HD gene carriers with predicted symptom onset <20 years, with a false discovery rate (FDR) <0.0001) (Byrne et al., Neurofilament Light Protein as a Potential Blood Biomarker for Huntington's Disease in Children. Mov Disord. 2022 Jul;37(7):1526-1531).

[0080] The present invention also provides a method for maintaining, reducing, or mitigating increases in neurofilament light chain protein concentration in a JHD patient, comprising regularly orally administering a pharmaceutical composition comprising pridopidine to the patient, such that a dose of 0.5 mg to 300 mg of pridopidine is administered to the patient daily, thereby maintaining, reducing, or mitigating increases in neurofilament light chain protein concentration in the human patient. In one embodiment, the dose is 0.5 mg to 5 mg bid. In another embodiment, the dose is 0.5 mg to 10 mg bid. In some embodiments, the dose is 1 mg to 20 mg bid. In some embodiments, the dose is 5 mg to 40 mg bid. In one embodiment, increases in neurofilament light chain protein concentration in the human patient are mitigated. In another embodiment, neurofilament light chain protein concentration in the human patient is maintained or reduced.

[0081] The present invention also provides a method for predicting clinical responsiveness to pridopidine therapy in a subject with JHD, the method comprising administering an amount of pridopidine and assessing the amount of neurofilament light chain protein in the subject, thereby predicting clinical responsiveness to pridopidine.

[0082] In one embodiment, the method further comprises predicting a positive clinical responsiveness to pridopidine if the amount of neurofilament light chain protein decreases compared to baseline after administration of pridopidine to the subject. In one embodiment, the method further comprises predicting a positive clinical responsiveness to pridopidine if the amount of neurofilament light chain protein remains relative to baseline after administration of pridopidine to the subject. In this paragraph, baseline is the amount of neurofilament light chain protein before administration of pridopidine.

[0083] In one embodiment, if the amount of the biomarker is above a reference value, the subject is identified as a pridopidine responder. In another embodiment, if the amount of the biomarker is below a reference value, the subject is identified as a pridopidine responder.

[0084] In some embodiments, the biomarker is mutant huntingtin (mHtt).

[0085] In embodiments, the biomarker is a sigma-1 receptor (S1R). In another embodiment, the biomarker is glial fibrillary acidic protein (GFAP). In embodiments, the biomarker is tau. In another embodiment, the biomarker is phosphorylated tau. In some embodiments, the biomarker is an inflammatory marker, i.e., a proinflammatory cytokine, a complement factor, or a complement inhibitor such as clusterin, or a marker of microglial activation. In embodiments, the biomarker is interleukin 6 (IL-6). In another embodiment, the biomarker is chitinase 3-like protein 1 (CHI3L1 or YKL-40).

[0086] In some embodiments, the biomarker is a metabolic marker. In embodiments, the biomarker is HDL-cholesterol, LDL-cholesterol, or 24(H) hydroxycholesterol.

[0087] In some embodiments, the biomarker is a neuroendocrine marker. In some embodiments, the biomarker is melatonin. In another embodiment, the biomarker is cortisol.

[0088] In some embodiments, the biomarker is a marker of oxidative stress. In embodiments, increased lipid peroxidation is a biomarker. In another embodiment, F2-isoprostane is a biomarker of lipid peroxidation.

[0089] In some embodiments, the biomarker is an endogenous opioid peptide. In one embodiment, the biomarker is proenkephalin (PENK). In one embodiment, the biomarker is prodynorphin (PDYN).

[0090] In some embodiments, the biomarker is a small RNA. In some embodiments, the biomarker is a micro RNA.

[0091] The present invention also provides use of a certain amount of pridopidine and / or its analogues or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating juvenile HD in a subject or slowing its progression, wherein the medicament is formulated for oral administration at a daily dose of 0.5 mg to 300 mg of pridopidine and / or its analogues or pharmaceutically acceptable salts thereof.

[0092] In an embodiment, the methods disclosed herein comprise orally administering a composition comprising between 0.5 mg and 300 mg of pridopidine and / or its analogs or pharmaceutically acceptable salts thereof per day. In an embodiment, the methods disclosed herein comprise orally administering a composition comprising between 5 mg and 100 mg of pridopidine and / or its analogs or pharmaceutically acceptable salts thereof per day. In an embodiment, the methods disclosed herein comprise orally administering a composition comprising between 10 mg and 300 mg of pridopidine and / or its analogs or pharmaceutically acceptable salts thereof per day. In another embodiment, the method comprises administering between 10 mg and 100 mg of pridopidine and / or its analogs or pharmaceutically acceptable salts thereof per day. In another embodiment, 0.5 mg / day-50 mg / day, 22.5 mg / day-200 mg / day, 45 mg / day-150 mg / day, 90 mg / day-300 mg / day, or 150 mg / day-300 mg / day of pridopidine and / or its analogs or pharmaceutically acceptable salts thereof.

[0093] In an embodiment, the method comprises administering a composition comprising a unit dose of pridopidine, an analog thereof, or a pharmaceutically acceptable salt thereof, between 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 22.5 mg, 45 mg, 67.5 mg, and administering once a day, twice a day, three times a day, once a week, twice a week, or three times a week. In another embodiment, administration continues for at least 12 weeks, at least 26 weeks, at least 52 weeks, at least 65 weeks, at least 78 weeks, at least 24 months, at least 36 months, at least 48 months, or at least 60 months. In some embodiments, treatment continues for more than 60 months. In other embodiments, treatment continues for more than 120 months.

[0094] In some embodiments of the compositions and methods of use thereof, a 0.5 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 1 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 2.5 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 5 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 10 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 22.5 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 30 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 45 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 60 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 67.5 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 90 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 120 mg dose of pridopidine is administered to the patient / subject daily. In some embodiments of the compositions and methods of use thereof, a 135 mg dose of pridopidine is administered to the patient / subject daily. In preferred embodiments of the methods disclosed above, the 45 mg dose of pridopidine administered to the patient daily is administered to the patient at 22.5 mg bid. In preferred embodiments of the methods disclosed above, the 90 mg dose of pridopidine administered to the patient daily is administered to the patient at 45 mg bid.

[0095] In some embodiments of the methods and uses for treating JHD, or in embodiments of the methods and uses for treating a subject at risk of developing JHD, the AUC0-24 achieved is equivalent to the AUC0-24 achieved in adult HD patients receiving 45 mg bid pridopidine. In some embodiments, the AUC0-24 is 1,000 h*g / mL to 5,000 h*g / mL, 3,000 h*g / mL to 6,000 h*g / mL, 5,000 h*g / mL to 10,000 h*g / mL, 6,000 h*g / mL to 12,000 h*g / mL, or up to 15,000 h*g / mL.

[0096] In some embodiments of the methods and uses for treating JHD, or in embodiments of the methods and uses for treating subjects at risk of developing JHD, the Cmax achieved is equivalent to the Cmax achieved in adult HD patients receiving 45 mg bid pridopidine. In some embodiments, the Cmax is 50 ng / mL to 250 ng / mL, 100 ng / mL to 500 ng / mL, 200 ng / mL to 700 ng / mL, 300 ng / mL to 800 ng / mL, or 500 ng / mL to 1000 ng / mL. In some embodiments, the Cmax is up to 1200 ng / mL.

[0097] As used herein, the term "AUC" refers to the area under the plasma, serum, or blood concentration versus time curve. "AUC0-t" refers to the area under the plasma, serum, or blood concentration versus time curve, where t (hours) is the time point of the last measurement. "AUC at infinity" refers to the area under the plasma, serum, or blood concentration versus time curve extrapolated to infinity. AUC 24，ss It refers to the area under the concentration-time curve from 0 to 24 hours at steady state. The unit is expressed in h*g / mL.

[0098] As used herein, the term "Cmax" refers to the maximum plasma, serum, or blood concentration of a drug, such as pridopidine or a pharmaceutically acceptable salt thereof, following administration of the drug.

[0099] In some embodiments, 0.5 mg of pridopidine is administered to the patient once a day (qd) for about one to two weeks, and 1 mg of pridopidine is administered bid thereafter. In some embodiments, 1 mg of pridopidine is administered to the patient once a day (qd) for about one to two weeks, and 2 mg of pridopidine is administered bid thereafter. In some embodiments, 2.5 mg of pridopidine is administered to the patient once a day (qd) for about one to two weeks, and 5 mg of pridopidine is administered bid thereafter. In some embodiments, 5 mg of pridopidine is administered to the patient once a day (qd) for about one to two weeks, and 10 mg of pridopidine is administered bid thereafter. In some embodiments, 10 mg of pridopidine is administered to the patient once a day (qd) for about one to two weeks, and 10 mg of pridopidine is administered bid thereafter. In some embodiments, 25 mg of pridopidine is administered to the patient once a day (qd) for about one to two weeks, and 25 mg of pridopidine is administered bid thereafter. In some embodiments, 30 mg of pridopidine is administered to the patient once daily (qd) for about one to two weeks, and 30 mg of pridopidine is administered bid thereafter. In some embodiments, 45 mg of pridopidine is administered to the patient once daily (qd) for about one to two weeks, and 45 mg of pridopidine is administered bid thereafter. In some embodiments of the methods disclosed above, administration continues for at least 12 weeks, at least 26 weeks, at least 52 weeks, at least 65 weeks, or at least 78 weeks. In some embodiments of the methods disclosed above, administration continues for 52 weeks or 78 weeks. In some embodiments of the methods disclosed above, the HD patient has been diagnosed with having at least 50 CAG repeats in the Huntington gene. In some embodiments of the methods disclosed above, the HD patient is less than 21 years old. In some embodiments, the HD patient is a Juvenile Huntington's disease (JHD) patient. In some embodiments, the Juvenile HD patient is less than 21 years old. In some embodiments, the Juvenile HD patient is less than 20 years old. In other embodiments, the Juvenile HD patient is 18 years old or younger.

[0100] In embodiments of the methods of the present invention, the subject is less than 21 years old. In embodiments of the methods of the present invention, the subject is less than 18 years old. In embodiments of the methods of the present invention, the subject is between 1 and 21 years old, 1 and 20 years old, 1 and 19 years old, 1 and 18 years old, 5 and 18 years old, or 10 and 18 years old. In another embodiment, the subject is human. In another embodiment, the subject is a human male or a human female.

[0101] In an embodiment of the method of the invention, the subject has a UHDRS-TMS score of ≥ 25 prior to starting treatment.

[0102] In embodiments of the methods of the present invention, the subject has ≥50 CAG repeats in the Huntington gene. In embodiments of the methods of the present invention, the subject has ≥55 CAG repeats in the Huntington gene. In embodiments of the methods of the present invention, the subject has ≥60 CAG repeats in the Huntington gene. In embodiments of the methods of the present invention, the subject has ≥50 CAG repeats in the Huntington gene and the subject is less than 21 years old, less than 20 years old, or less than 18 years old.

[0103] Pharmaceutically acceptable salts The active compound for use according to the present invention can be provided in any form suitable for expected use. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts and prodrugs or prodrug forms (pre-or prodrug form) of the compound of the present invention. The example of pharmaceutically acceptable addition salts includes, but is not limited to, nontoxic inorganic acid addition salts and organic acid addition salts, such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formates, acetates, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, pamoate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, mesylate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, p-toluenesulfonate etc. Such salts can be formed by the procedures well known and described in the art.

[0104] Pridopidine analogs In some embodiments, the composition for use in the methods of the present invention comprises a combination of pridopidine or a pharmaceutically acceptable salt thereof and at least one of its analogs Compounds 1-8 or a pharmaceutically acceptable salt thereof: (Compound 1), (Compound 2), (Compound 3), (Compound 4), (Compound 6), (Compound 5), (Compound 7), or (Compound 8); Wherein, the weight ratio between pridopidine or its pharmaceutically acceptable salt and at least one of compounds 1-8 or its pharmaceutically acceptable salt is in the range of 1:0.00001 to 1:0.001. In other embodiments, the weight ratio between pridopidine or its pharmaceutically acceptable salt and at least one of compounds 1-8 or its pharmaceutically acceptable salt is in the range of 1:0.0001 to 1:0.1. In other embodiments, the weight ratio between pridopidine or its pharmaceutically acceptable salt and at least one of compounds 1-8 or its pharmaceutically acceptable salt is in the range of 1:0.005 to 1:0.1. In other embodiments, the weight ratio between pridopidine or its pharmaceutically acceptable salt and at least one of compounds 1-8 or its pharmaceutically acceptable salt is in the range of 1:0.0001 to 1:0.005.

[0105] In some embodiments, the composition for use in the methods of the present invention comprises a combination of a certain amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 1 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of a certain amount of pridopidine or a pharmaceutically acceptable salt thereof and compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of a certain amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 2 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of a certain amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 3 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of a certain amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 4 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of a certain amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 5 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of an amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 6 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of an amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 7 or a pharmaceutically acceptable salt thereof. In other embodiments, the composition for use in the methods of the present invention comprises a combination of an amount of pridopidine or a pharmaceutically acceptable salt thereof and at least compound 8 or a pharmaceutically acceptable salt thereof.

[0106] In other embodiments, pridopidine analogs Compounds 1-8 and methods for their preparation can be found in US Pat. Nos. 10,130,621 and 10,406,145, the entire contents of each of which are hereby incorporated by reference.

[0107] In an embodiment, pharmaceutically acceptable salts of pridopidine include hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, pamoate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, or p-toluenesulfonate.

[0108] In an embodiment, pharmaceutically acceptable salts of compounds 1-8 include hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, pamoate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, or p-toluenesulfonate.

[0109] Pharmaceutical composition Although the compounds for use according to the invention can be administered in the form of raw compounds, it is preferred to incorporate the active ingredient, optionally in the form of a physiologically acceptable salt, into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other customary pharmaceutical auxiliaries.

[0110] In an embodiment, the present invention provides a pharmaceutical composition comprising an active compound and / or its analog or pharmaceutically acceptable salt or derivative thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic ingredients known and used in the art. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0111] Pharmaceutical composition of the present invention can be used by any convenient approach that is suitable for required therapy.Preferred route of administration comprises oral administration, particularly with tablet, with capsule, with dragee, with multi-particulate, with pearl, with granule, with powder or with liquid form administration, and parenteral administration, particularly cutaneous, subcutaneous, intramuscular or intravenous injection.Pharmaceutical composition of the present invention can be manufactured by technical staff by using standard method and conventional technique that are suitable for the preparation of expectation.When desired, can adopt the composition that is suitable for giving the sustained release of active component.

[0112] Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).

[0113] As used herein, "effective" as an amount effective to achieve the purpose means an amount of a component commensurate with a reasonable benefit / risk ratio that is sufficient to produce the indicated therapeutic response without excessive adverse side effects (such as toxicity, irritation, or allergic reaction) when used in the manner of the present disclosure. For example, an amount effective to treat a movement disorder. The specific effective amount varies with factors such as the specific condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of treatment, the nature of concurrent therapy (if any), and the specific formulation employed, as well as the structure of the compound or its derivative.

[0114] As used herein, the amount of pridopidine, as measured in milligrams, refers to the number of milligrams of pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine) present in the preparation, regardless of the form of the preparation. For example, a unit dose containing "90 mg of pridopidine" means that the amount of pridopidine in the preparation is 90 mg, regardless of the form of the preparation. Thus, when in the form of a salt, such as pridopidine hydrochloride, the weight of the salt form required to provide a dose of 90 mg of pridopidine will be greater than 90 mg due to the presence of the salt.

[0115] As used herein, "treat" or "treating" encompasses, for example, reducing the symptoms of a disorder and / or disease, inducing inhibition, regression, or stagnation of a disorder and / or disease. As used herein, "inhibition" of a subject's disease progression or disease complications means preventing or reducing the subject's disease progression and / or disease complications.

[0116] The present invention will be better understood by reference to the following experimental details, but one skilled in the art will readily appreciate that the specific experiments detailed are merely illustrative of the invention more fully described in the appended claims.

[0117] Example Example 1: Clinical study evaluating the pharmacokinetics, safety and efficacy of pridopidine in adolescent HD patients A double-blind, placebo-controlled trial was conducted in children and adolescents aged 2-17 years to evaluate the pharmacokinetics, safety, and efficacy of pridopidine. Inclusion criteria included a UHDRS TMS score >10. A total of 24-30 male and female patients (aged 2 years and older) with adolescent and childhood-onset JHD were planned to be enrolled (a maximum of 24 adolescent JHD patients (aged 10-17 years) and a minimum of 6 childhood JHD patients (aged 2-10 years)).

[0118] This study was conducted in two consecutive parts. Part 1 (4 weeks) was conducted to determine the dose to be used in Part 2 (52 weeks).

[0119] Pridopidine is administered orally twice daily at a single dose level expected to produce a C between 200 ng / ml and 800 ng / ml in pediatric JHD patients. max and / or AUC of 1000 h × ng / ml-10,000 h × ng / ml 0-24 exposure.

[0120] Part 1 included 6 patients treated for a total of 4 weeks (based on the dose estimated in the PopPK model) (once daily (qd) dose escalation for 2 weeks, followed by twice daily (bid) (full daily dose) for 2 weeks). Once all 6 patients completed their participation in Part 1 (and reached steady state at the full dose) and data from their 4-week PK profiles were collected, a PK analysis was performed to confirm the appropriate dose to use in Part 2.

[0121] In Part 2 of the study, subjects were enrolled after completion of the PK analysis of Part 1. Part 2 patients were treated at the dose level confirmed after the Part 1 PK analysis.

[0122] The safety and tolerability of pridopidine were assessed throughout the study by continuous collection of adverse events and evaluation of safety laboratory assessments, the Columbia-Suicide Severity Rating Scale (C-SSRS), and ECG monitoring at specific visits.

[0123] Primary endpoint: The effects of pridopidine on motor function were assessed using the Unified Huntington's Disease Rating Scale (UHDRS)-Total Motor Score (TMS). The UHDRS-TMS was assessed at baseline (day 1) and at weeks 4, 13, 26, and 52.

[0124] PK analyses were performed at baseline and at each study visit (2 hours post-dose) for all subjects.

[0125] Secondary endpoints: The effect of pridopidine on plasma neurofilament light chain (NfL) protein, a disease biomarker, was evaluated at baseline and at weeks 13, 26, and 52.

[0126] The effects of pridopidine on imaging parameters were evaluated using volumetric magnetic resonance imaging (MRI) of the caudate nucleus and putamen, functional MRI (fMRI), and metabolic imaging using 18F-fluoro-2-deoxy-D-glucose (18FDG)-PET. Imaging was performed at baseline and at weeks 26 and 52.

[0127] The effects of pridopidine on motor function were assessed using quantitative motor (Q-Motor) finger tapping (digital kinesiography).

[0128] The effects of pridopidine on cognition were evaluated using the Wright International Performance Scale and the Peabody Picture Vocabulary Test.

[0129] Seizure frequency and duration.

[0130] Pediatric Quality of Life Scale (PedsQL).

[0131] The effect of pridopidine on psychiatric measures was evaluated using the Problem Behavior Assessment-Short Form (PBA-S). The safety and tolerability of pridopidine were assessed during the 52-week treatment period by continuously collecting adverse events (AEs) and by continuously collecting adverse events and the Columbia-Suicide Severity Rating Scale (C-SSRS) assessed at each clinic visit throughout the study. In addition, safety laboratory parameter assessments and electrocardiogram (ECG) monitoring were performed on day 1 and at weeks 4, 13, 26, and 52.

[0132] The PK of pridopidine and its major metabolites were assessed during the 52-week treatment period. For all patients, PK analysis was performed at baseline and at each study visit (2 hours after administration). A complete PK analysis was performed on the first 6 patients in Part 1 of the study at baseline (Day 1), Week 2 (when steady state was reached once a day), and Week 4 (when full dose twice a day was reached at steady state). PK samples were collected at the following time points: t=0 (before administration), 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, 12 hours, and 24 hours after administration.

[0133] Example 2: Case study: Pridopidine treatment of HD patients with CAG ≥ 50: This case study reports the effects of pridopidine 45 mg twice daily in patients with a CAG ≥ 50, which is associated with HD in adolescents. The effects of pridopidine were compared with those of placebo in patients with a CAG ≥ 50 (n = 4).

[0134] In the following methods and results, 45 mg bid pridopidine refers to a composition comprising pridopidine HCl with compound 1 (from pridopidine, in the range of 0.07% w / w-0.09% w / w) and compound 4 (from pridopidine, in the range of 0.10% w / w-0.12% w / w). 45 mg refers to the base form of pridopidine.

[0135] method: All patients began treatment with a 2-week titration period (45 mg once daily) followed by full-dose treatment for 63-78 weeks.

[0136] Efficacy was evaluated using the following clinical endpoints: change from baseline to Week 78 on the composite UHDRS (cUHDRS) total score, Total Functional Capacity (UHDRS-TFC) score, and the Stroop Word Reading (SWR) test for cognitive assessment.

[0137] result: UHDRS-TFC Rating: The UHDRS-TFC score is a commonly used and regulatory-approved clinical scale used to assess the functional ability of subjects with HD and monitor disease progression and severity over time. The score ranges from 0 to 13, with higher scores indicating better functional ability. A score of 13 means the individual is fully functional with no signs of impairment, while a score of 0 indicates complete dependence on others for daily activities.

[0138] All participants in this study had CAG repeats greater than or equal to 50. Participants receiving placebo demonstrated a decrease in TFC at all time points evaluated. For up to 78 weeks, the HD participant (n=1) receiving pridopidine 45 mg bid showed significant improvement in TFC compared to the HD participant in the placebo group (n=4) (Table 1). Pridopidine and compounds 1 and 4 demonstrated a positive treatment effect compared to placebo, with a change of 2.99 points at 26 weeks, a change of 3.06 points at 39 weeks, a change of 3.00 points at 52 weeks, a change of 2.90 points at 65 weeks, and a change of 3.45 points at 78 weeks relative to placebo (a positive change indicates improvement) (Table 1).

[0139] Table 1: Pridopidine improves TFC compared to placebo in adolescent HD patients with CAG repeat length >= 50 for up to 78 weeks

[0140] Data are from study cases. Pridopidine 45 mg bid in combination with compounds 1 and 4 and placebo in CAG Effects in HD patients with complex length >= 50 and no antidopaminergic drugs. A positive change in TFC indicates improvement.

[0141] cUHDRS: The comprehensive unified Huntington's disease rating scale (cUHDRS) is a clinical scale used to assess the severity and progression of Huntington's disease (HD).

[0142] The cUHDRS is a comprehensive scale that assesses overall progress in key independent aspects of HD: functional ability, motor symptoms, and cognitive function. The cUHDRS includes four subscales: Total Functional Capacity (TFC), Total Motor Score (TMS), and two cognitive measures: the Symbol Digit Modalities Test (SDMT) and the Stroop Word Reading (SWR) test.

[0143] The cUHDRS showed excellent test-retest reliability (ICC=0.96) and was superior to its individual components in sensitivity to disease stage and provided greater statistical power to detect clinical benefit longitudinally (Schobel, Scott A., et al. "Motor, cognitive, and functional declines contribute to a single progressive factor in early HD." Neurology 89.24 (2017): 2495-2502).

[0144] The cUHDRS score is a validated scale for tracking disease progression and assessing treatment effectiveness in subjects with HD. Higher cUHDRS scores indicate better overall disease status. By measuring multiple domains, the cUHDRS provides a comprehensive and integrated assessment of disease stage.

[0145] All participants in this study had CAG repeats greater than or equal to 50. Participants taking placebo showed a predictable decrease in cUHDRS at each time point up to 78 weeks. Pridopidine and compounds 1 and 4 (n=1) showed a positive treatment effect on cUHDRS up to 78 weeks compared to placebo (n=4). Pridopidine and compounds 1 and 4 showed a positive treatment effect compared to placebo, with a change of 2.52 points at 26 weeks, a change of 2.66 points at 39 weeks, a change of 2.49 points at 52 weeks, a change of 2.32 points at 65 weeks, and a change of 2.52 points at 78 weeks relative to placebo (positive change indicates improvement) (Table 2).

[0146] Table 2: Pridopidine improves overall disease progression compared to placebo in adolescent HD patients with a CAG repeat length >= 50, as measured by the cUHDRS, up to 78 weeks

[0147] Data are from study cases. Pridopidine 45 mg bid in combination with compounds 1 and 4 and placebo in CAG Effects in HD patients with complex length >= 50 and no antidopaminergic medication. Positive changes indicate improvement.

[0148] SWR Rating: The Stroop Word Reading (SWR) test is a validated and widely used clinical measure of cognitive function. The SWR assesses the ability to inhibit cognitive distractions and is commonly used to evaluate executive function, including cognitive flexibility and attentional control.

[0149] During the SWR test, individuals are asked to read a list of color names printed in colored ink, where the ink color does not match the word. This creates a cognitive conflict and requires inhibiting prepotent responses to read the word, making the test challenging.

[0150] The SWR score is determined by assessing the time taken to read a list of words and the number of errors made. Higher scores on the SWR test indicate better cognitive ability.

[0151] Participants with HD with a CAG repeat length ≥50 were treated with pridopidine 45 mg bid (n=1) or placebo (n=4) for 78 weeks. Participants receiving placebo showed a predictable, significant decline in cognitive function as assessed by SWR. However, patients treated with pridopidine and compounds 1 and 4 showed a positive treatment effect at each time point for up to 78 weeks compared to placebo. Compared to placebo, pridopidine and compounds 1 and 4 showed a positive treatment effect, with a change of 14.58 points at 26 weeks, a change of 15.38 points at 39 weeks, a change of 15.44 points at 52 weeks, a change of 12.35 points at 65 weeks, and a change of 14.28 points at 78 weeks (positive changes indicate improvement) relative to placebo (Table 3).

[0152] Table 3: Pridopidine improves cognitive function compared to placebo in adolescent HD patients with CAG repeat length >= 50 for up to 78 weeks

[0153] Data are from a case study. Pridopidine 45 mg bid in combination with compounds 1 and 4 and placebo in CAG Effects in HD patients with complex length >= 50 and no antidopaminergic medication. Positive changes indicate improvement.

[0154] Summarize In adolescent HD patients with a CAG repeat length of ≥50, pridopidine 45 mg bid demonstrated significant improvements in functional ability, cognitive function, and disease progression for up to 78 weeks.

Claims

1. A method for treating juvenile Huntington's disease in a subject or reducing its progression, comprising orally administering to the subject a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof.

2. A method of maintaining or reducing one or more symptoms or signs of juvenile Huntington's disease (JHD) in a subject, comprising orally administering to the subject a pharmaceutical composition comprising pridopidine and / or its analogs or pharmaceutically acceptable salts thereof, wherein the one or more symptoms or signs are selected from the group consisting of motor impairment, cognitive impairment, physical symptoms, mental symptoms, emotional symptoms, behavioral symptoms, psychotic symptoms, depression, anxiety, aggression, impulsivity, seizures, and shortened lifespan.

3. The method of claim 2, wherein the symptom or sign of adolescent HD comprises motor function.

4. The method of claim 2, wherein the symptom or sign of juvenile HD comprises cognitive function in a juvenile Huntington's disease subject.

5. The method of claim 2, wherein the symptom or sign of juvenile HD comprises behavioral function of a juvenile Huntington's disease subject.

6. The method of claim 2, wherein the symptoms or signs of juvenile HD include psychotic features in a juvenile Huntington's disease subject.

7. The method according to any one of claims 1 to 6, wherein the composition further comprises at least one pridopidine analog compound 1-8 or a pharmaceutically acceptable salt thereof: (Compound 1), (Compound 2), (Compound 3), (Compound 4), (Compound 6), (Compound 5), (Compound 7), or (Compound 8).

8. The method of any one of claims 1-7, wherein the human patient experiences symptom onset before the age of 20 years.

9. The method of any one of claims 1-8, wherein the human patient has ≥50 CAG repeats in the Huntington's gene.

10. The method of any one of claims 1-8, wherein the pharmaceutical composition is administered once a day, twice a day, or three times a day.

11. The method of any one of claims 1-3, wherein the human patient's motor function impairment is measured by the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS).

12. The method of any one of claims 1-3, wherein the human patient's motor impairment is assessed by a quantitative motor (Q-motor) test battery.

13. The method of any one of claims 1-12, wherein the method further comprises administering a pharmaceutical composition comprising an antiseizure drug, an antidepressant, an anxiolytic, tetrabenazine, deutetrabenazine, or a mutant huntingtin (mHtt) lowering agent.

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