Patent Description:
Dystonia is a dynamic condition that often changes in severity depending on the posture assumed and on voluntary activity of the involved body area. Symptoms may progress into adjacent muscles and vary according to the type and location of the dystonia. Patients with dystonia may experience muscle spasms, cramping, pain, impaired vision (eyelid closure), chewing, speech, or swallowing, loss of coordination, and abnormal posture / gait. This feature of dystonia has challenged the development of rating scales with acceptable clinimetric properties. (Albanese 2013a).

The clinical characteristics of dystonia include: age at onset (from infancy to late adulthood), body distribution (focal, segmental or, generalized), and temporal pattern (static or progressive and variability related to voluntary actions or to diurnal fluctuations). Dystonia can be isolated or combined with another movement disorder, such as parkinsonism or myoclonus, or can be associated with other neurological or systemic manifestations. Isolated dystonia with onset in childhood tends to progress to generalization, whereas dystonia arising in adulthood usually remains focal or segmental.

Despite the identification of genetic mutations associated with dystonias, there remains uncertainty regarding the causative role of those gene variants. Many familial dystonia cases and the majority of sporadic dystonia cases cannot be explained by validated mutations in known dystonia gene. A list of genes for monogenic forms of isolated and combined dystonias is presented in Table <NUM> of Verbeek and Gasser. (Verbeek <NUM>). Additional genes responsible for inherited dystonias are listed in Albanese. (Albanese 2013a).

The classification of dystonia has evolved over time. The changing system for categorizing dystonia reflects, in part, an increased understanding of the various clinical manifestations and etiologies, but also the varied opinion on the merits and criteria for grouping certain disorders together. (Albanese 2013a).

The most common hereditary, primary dystonia is DYT1 dystonia caused by a genetic mutation (DYT1) which results in a defect in an ATP-binding protein called Torsin A. Torsin A is expressed at high levels in neuronal cytoplasm of specific neuronal populations in the adult human brain, including the substantia nigra (SN), thalamus, cerebellum, hippocampus, and neostriatum. The defective Torsin A protein creates a disruption in communication in neurons that control muscle movement and muscle control (Ozelius <NUM>; Albanese <NUM>).

The most common symptoms of DYT1 dystonia are dystonic muscle contractions causing posturing of a foot, leg, or arm. Dystonia is usually first apparent with specific actions such as writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present, except for postural arm tremor. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign (Ozelius <NUM>).

In most instances, DYT1 dystonia symptoms start with a focal dystonia as talipes equinovarus of one leg in early childhood, typically around <NUM> years of age. The dystonic posturing then gradually progresses with age to other extremities and trunk muscles by the early teens. Dystonia may also start in an arm. There is asymmetry to the dystonia, with involvement of the extremities on the dominant side along with the ipsilateral sternocleidomastoid muscle. In these patients, interlimb coordination and locomotive movements are not affected. Moreover, intellectual, mental, and psychological functions are completely intact in these patients (Ozelius <NUM>; Ozelius <NUM>; Albanese <NUM>).

Based on clinical characteristics, it has been proposed that DYT1 dystonia can be classified into two types: the postural type with appendicular and truncal dystonias, or the action type, which is associated with violent dyskinetic movements in addition to dystonic posture (Segawa <NUM>).

Pridopidine (<NUM>-[<NUM>-(methylsulfonyl)phenyl]-<NUM>-propyl-piperidine) (formerly known as ACR16) is a drug under development for treatment of Huntington's disease. Pridopidine has been shown to modulate motor activity by either suppressing hyperactivity or enhancing hypoactivity. The neuroprotective properties of pridopidine are suggested to be attributed to its high affinity to the Sigma-<NUM> receptor (S1R, binding IC50 ~ <NUM>), while the motor activity of pridopidine may be mediated primarily by its low-affinity, antagonistic activity at the dopamine D2 receptor (D2R) (binding IC50 ~ <NUM>) (Ponten <NUM>). Pridopidine shows low-affinity binding to additional receptors in the micromolar range.

The S1R is an endoplasmic reticulum (ER) chaperone protein which is implicated in cellular differentiation, neuroplasticity, neuroprotection and cognitive function in the brain. Recently, transcriptomic analysis of rat striatum showed that pridopidine treatment activates expression of the BDNF, dopamine receptor <NUM> (D1R), glucocorticoid receptor (GR), and the serine-threonine kinase protein kinase B (Akt)/phosphoinositide <NUM>-kinase (PI3K) pathways, known to promote neuronal plasticity and survival and to be impaired in HD. Moreover, pridopidine gene expression profile showed a reversed pattern of the HD disease gene expression profile in a Q175 knock-in (Q175 KI) HD mouse model (Geva <NUM>). Pridopidine also enhances secretion of the neuroprotective brain-derived neurotrophic factor (BDNF) in a neuroblastoma cell fine, in a S1R-dependent manner (Geva <NUM>). Michl et al. discloses the use of pridopidine in the pharmacological treatment of Huntington's disease (<NPL>).

The present invention provides a pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof for use in treating dystonia by periodic administration to a human subject afflicted with dystonia, wherein the subject has a Unified Huntington's Disease Rating Scale Total Motor Score dystonia (UHDRS-TMS-dystonia) rating of ≥<NUM>, and wherein the pridopidine is administered at a dosage of <NUM> bid to <NUM> bid.

In an embodiment, the dystonia is a primary dystonia, an isolated dystonia, a primary generalized dystonia, a genetic form of primary dystonia, a secondary dystonia, a combined dystonia, a focal dystonia, a segmental dystonia, a multifocal dystonia, a hemidystonia, a generalized dystonia, a paroxysmal dystonia or an early onset generalized dystonia.

In an embodiment, the dystonia is Torsion dystonia-<NUM> (DYT1) dystonia, DYT6 dystonia, or DYT-KMT2B (DYT28) dystonia.

In an embodiment, the DYT1 dystonia is postural type dystonia or action type dystonia.

In an embodiment, the secondary dystonia or the combined dystonia is Dopa-responsive dystonia, Myoclonus dystonia, X-linked dystonia-parkinsonism, or Rapid-onset dystonia-parkinsonism.

In an embodiment, the dystonia is action-specific dystonia or a task-specific dystonia, and/or the dystonia is Musician's dystonia.

In an embodiment, the dystonia is not caused by a pathology, for example the dystonia is not caused by a stroke, a traumatic brain injury, a lesion, a brain tumor, neurological tissue damage or neurological tissue degeneration.

In an embodiment, the subject has been confirmed to be afflicted with DYT1 or other primary genetic forms of dystonia by genetic testing; the subject has a <NUM>-base pair in-frame deletion within the coding region of the TOR1A (torsinA) gene located on chromosome 9q34; and/or the subject is not afflicted with Huntington's disease.

In an embodiment, the amount of pridopidine is effective to provide a clinically significant improvement in dystonia symptoms.

In an embodiment, the clinically significant improvement in dystonia symptoms is an at least a <NUM>% change from baseline in the subject administered pridopidine in comparison to a human patient not treated with pridopidine as measured by the dystonia items of the UHDRS scale.

In an embodiment, the amount of pridopidine is effective to reduce or maintain a level of one or more symptoms of the dystonia in the subject.

In an embodiment, the one or more symptoms are selected from involuntary limb movement or muscle contractions; twisted posture of the limbs or trunk; abnormal fixed posture of the limbs or trunk; talipes equinovarus; turning in of the leg; turning in of the arm; tremor of the hand, head, trunk or arms; dragging of the leg; torticollis; writer's cramp; and dystonia of trunk and/or extremities.

In an embodiment, the pridopidine is administered at a dosage of <NUM> bid, <NUM> bid or <NUM> bid.

In an embodiment, the pridopidine is administered at a unit dose of <NUM>, <NUM>, <NUM>, or <NUM> pridopidine.

In an embodiment, the pharmaceutical composition is administered orally.

In an embodiment, the pridopidine is in the form of pridopidine hydrochloride, hydrobromide, L-tartrate, nitrate, perchlorate, phosphate, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-<NUM>-sulphonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate or toluene-p-sulphonate salt.

The present invention is further illustrated by reference to the accompanying drawings. In the following brief descriptions of the figures and the corresponding figures, efficacy was assessed throughout the <NUM>-week period using Mixed Models Repeated Measures (MMRM) analyses of change from baseline in the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS TMS; TMS), the modified Physical Performance Test (mPPT), individual TMS subscales, functional, cognitive and other outcomes.

<FIG>: Pridopidine concentration in patient's blood (ng/mL; Mean (+/-sd) measured values). "Pre" means predose and "post" mean post dose. V2 means visit <NUM>, V3 means visit <NUM>, etc. Wk2 means second week, Wk3 means third week, etc.
<FIG>: Pridopidine concentration in patient's blood (ng/mL). Post-dose ("Cmax") (+/-sd) at Steady State. For <FIG>, a % coefficient of variation (CV) of around <NUM>% for measured values is considered adequate for this setting [<NUM>-<NUM> hours post dose, patient population, sparse sampling]. Variability is expected to decrease once true sampling times are taken into consideration. <FIG>: Total Motor Score (TMS) Change from Baseline (BL) with pridopidine administration. The <NUM> bid dose (circles) demonstrated the largest treatment effect. A decrease in TMS indicates an improvement. Table <NUM> below shows the P-Values corresponding to <FIG>.

<FIG>: Total Motor Score (TMS) - Change from Baseline (<NUM> pridopidine bid vs historical placebo in HART and MermaiHD clinical trials). There is about a <NUM> TMS point difference at week <NUM>. <FIG>: Change from baseline in TMS. <FIG>: Using historical placebo in HART and MermaiHD clinical trials, TMS (change from baseline) results are significant for both <NUM> pridopidine bid and <NUM> pridopidine bid. A lower number indicates improvement. <FIG>: Change from baseline UHDRS-TMS full analysis set plotted over time. PRIDE-HD replicates previous data in TMS changes from baseline as the change from baseline values were similar to those in HART and MermaiHD. In this graph, a decrease in TMS change from baseline indicates improvement. Dark line with diamonds represents placebo, dark line with open circles represents <NUM> bid, gray line with triangles represents <NUM> bid, gray line with diamonds represents <NUM> bid, line with squares represents <NUM> bid. The <NUM> bid dose demonstrated the largest treatment effect. <FIG> and <FIG>: Total Dystonia at week <NUM> (6a); at week <NUM> (6b); and at week <NUM> (6c) in patient groups administered different doses of pridopidine. Y-axis is change in dystonia from baseline. All data refer to adjusted means +SE of change in dystonia in full analysis set. A lower number indicates improvement. <FIG>: Change in Dystonia in limbs (UHDRS-dystonia limbs) at week <NUM>; <FIG>: Finger Taps and Pronate-Supinate (P/S) hands at week <NUM>; <FIG>: Finger Taps and P/S hands at week <NUM>. Finger Taps and Pronate-Supinate (P/S) hands is a combination of finger tapping (the ability to tap the fingers of both hands where <NUM> repetitions in <NUM> seconds is considered normal) with pronation/supination (the ability to rotate the forearm and hand such that the palm is down (pronation) and to rotate the forearm and hand such that the palm is up (supination) on both sides of the body). In the tables below, data and the P-Values corresponding to the figures are provided. N refers to number of patients. Wk26 refers to relevant score at week <NUM>. Wk52 refers to relevant score at week <NUM>. "Δ to placebo" refers to the difference in score from compared to placebo, specifically, the average change from baseline in the placebo group compared to the average change from baseline of the relevant group. "ALL" refers to pridopidine treated patients irrespective of disease stage. Y-axes are change from baseline for characteristic listed above the table. X-axes are dose whereby P means "placebo", <NUM> means "<NUM> bid," <NUM> means "<NUM> bid," <NUM> means "<NUM> bid," and <NUM> means "<NUM> bid. " In the figures, improvement is in the direction from bottom of the graph to top of the graph. For example, <FIG> shows the average difference in the UHDRS TMS score of the indicated group of patients (i.e. patients having a TFC score of <NUM>-<NUM> at baseline) between the score at baseline (prior to administration of pridopidine at week <NUM>) and the score after <NUM> weeks of administration of pridopidine (at week <NUM>). In this figure, the <NUM> bid dose shows the greatest improvement because its data point is the top most data point in the figure, showing an approximately <NUM> point improvement compared to baseline (i.e. a -<NUM> UHDRS TMS score at week <NUM> compared to baseline). The table below the description of <FIG> shows that the <NUM> bid group had <NUM> patients ("N" row) and an average UHDRS TMS score of <NUM> at baseline ("Baseline" row). The table below the description of <FIG> also shows that the <NUM> bid group's change from baseline (about -<NUM>, shown in figure, not shown in table) is <NUM> points better (-<NUM>) than the placebo group's change from placebo (about -<NUM>, shown in figure, not shown in table)("Δ to placebo" row). Additionally, the table below the description of <FIG> shows a p value of <NUM> for the <NUM> bid group ("p value" row). HD1 refers to an early stage Huntington's disease (HD) patient with a baseline Unified Huntington's Disease Rating Scale Total Functional Capacity (UHDRS-TFC; TFC) score of <NUM>-<NUM>. HD2 refers to an early stage HD patient with a baseline UHDRS-TFC score of <NUM>-<NUM>. <FIG>: Change from baseline in UHDRS TMS Week <NUM> ALL. The table below and <FIG> show no significant improvement in UHDRS TMS in all pridopidine treated patients at <NUM> weeks compared to placebo. Improvement is evidenced by a more negative value in the UHDRS TMS score.

<FIG>: Change from baseline in UHDRS TMS Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. (The UHDRS TMS score at week <NUM> of pridopidine treated patients with a baseline Total Functional Capacity (BL TFC) score of <NUM> to <NUM>). HD patients with a baseline TFC score of <NUM>-<NUM> are generally considered to be first stage (stage <NUM>) HD patients. The table below and <FIG> show trend towards improvement in UHDRS TMS in HD1 pridopidine treated patients at <NUM> weeks compared to placebo.

<FIG>: Change from baseline in UHDRS TMS Week <NUM> ALL. The table below and <FIG> show no significant improvement in UHDRS TMS in all pridopidine treated patients at <NUM> weeks, compared to placebo.

<FIG>: Change from baseline in UHDRS TMS Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show a trend towards improvement in UHDRS TMS in HD1 pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Gait and Balances Week <NUM>. The table below and <FIG> show no significant improvement in UHDRS TMS gait and balances in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Gait and Balances Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show a trend towards improvement in UHDRS TMS gait and balances in HD1 pridopidine treated patients at <NUM> weeks with significance for patients receiving <NUM> bid pridopidine.

<FIG>: Change from baseline in UHDRS TMS Chorea Week <NUM> ALL. The table below and <FIG> show no significant improvement in UHDRS TMS chorea in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Chorea Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show a trend towards improvement in UHDRS TMS chorea in HD1 pridopidine treated patients at <NUM> weeks with significance for patients receiving <NUM> bid pridopidine.

<FIG>: Change from baseline in UHDRS TMS Dystonia Week <NUM> ALL. The table below and <FIG> show a trend towards improvement in UHDRS TMS dystonia in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Dystonia Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show a trend towards improvement in UHDRS TMS dystonia in HD1 pridopidine treated patients at <NUM> weeks with significance for patients receiving <NUM> bid pridopidine.

<FIG>: Change from baseline in UHDRS TMS Dystonia Week <NUM>. The table below and <FIG> show a trend toward improvement in UHDRS TMS dystonia in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Involuntary Movements Week <NUM> ALL The table below and <FIG> show no significant improvement in UHDRS TMS Involuntary Movements in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Involuntary Movements Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show significant improvement in UHDRS TMS Involuntary Movements at <NUM> weeks in HD1 pridopidine treated patients receiving <NUM> bid, <NUM> bid and <NUM> bid pridopidine.

<FIG>: Change from baseline in UHDRS TMS Involuntary Movements Week <NUM> The table below and <FIG> show no significant improvement in UHDRS TMS Involuntary Movements in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Involuntary Movements Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show a trend towards improvement in UHDRS TMS Involuntary Movements in HD1 pridopidine treated patients at <NUM> weeks, in particular in <NUM> bid and <NUM> bid treated patients.

<FIG>: Change from baseline in UHDRS TMS Excluding Chorea Week <NUM>. The table below and <FIG> show no significant improvement in UHDRS TMS excluding chorea in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Excluding Chorea Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show a trend towards improvement in UHDRS TMS excluding chorea in HD1 pridopidine treated patients at <NUM> weeks, in particular in the <NUM> bid and <NUM> bid treated patients.

<FIG>: Change from baseline in UHDRS TMS Excluding Dystonia Week <NUM> ALL. The table below and <FIG> show no significant improvement in UHDRS TMS excluding dystonia in all pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Excluding Dystonia Week <NUM> Stage <NUM> BL TFC <NUM>-<NUM>. The table below and <FIG> show a trend towards improvement in UHDRS TMS excluding dystonia in HD1 pridopidine treated patients, at <NUM> weeks.

<FIG> show bar graphs of changes in UHDRS TMS Finger Tap scores in <NUM> and <NUM> week patient groups. <FIG>: Change from Baseline in UHDRS TMS Finger Taps ALL. Week <NUM>. The table below provides P-Values corresponding to <FIG>. The table below and <FIG> show no significant improvement in the UHDRS TMS finger taps in all pridopidine treated patients, at <NUM> weeks.

<FIG>: Change from Baseline in UHDRS TMS Finger Taps: Week <NUM> patients with baseline total functional capacity (BL TFC) ≥ <NUM> and CAG Repeats > <NUM>. The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show statistically significant improvement in the UHDRS TMS finger taps in <NUM> bid and <NUM> bid pridopidine treated patients having BL TFC greater than or equal to <NUM> and greater than <NUM> CAG repeats in their htt gene, at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Finger Taps: Week <NUM> patients with BL TFC ≥ <NUM>, CAG Repeats < <NUM> and patients who represent three least severe TMS quarters (BL TMS 1st <NUM> Qs). The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show statistically significant improvement in the UHDRS TMS finger taps in <NUM> bid and <NUM> bid pridopidine treated patients having BL TFC greater than or equal to <NUM> and less than <NUM> CAG repeats in their htt gene, at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Finger Taps: Patients who have completed <NUM> weeks of treatment: UHDRS TMS Finger Tap score at week <NUM>. The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show statistically significant improvement in the UHDRS TMS finger taps in <NUM> bid pridopidine treated patients who completed <NUM> weeks, at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Finger Taps: Patients who have completed <NUM> weeks of treatment: UHDRS TMS Finger Tap score at week <NUM>. The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show no significant improvement in the UHDRS TMS finger taps in ALL pridopidine treated patients, at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Finger Tapping + Pronate-Supinate Hands: Patients who have completed <NUM> weeks of treatment - score at week <NUM>. The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show statistically significant improvement in the UHDRS TMS finger taps and Pronate-Supinate Hands in <NUM> bid pridopidine treated patients who completed <NUM> weeks, at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Finger Tapping + Pronate-Supinate Hands: Patients who have completed <NUM> weeks of treatment - score at week <NUM>. The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show no significant improvement in the UHDRS TMS finger taps and Pronate-Supinate Hands in pridopidine treated patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Gait and Balance: Gait and balance scores at week <NUM> for patients with BL TFC ≥ <NUM>. The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show statistically significant improvement in the UHDRS TMS gait and balances in <NUM> bid pridopidine treated HD1 and HD2 patients at <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Gait and Balance: Gait and balance scores at week <NUM> for patients with BL TFC ≥ <NUM>. The table below provides the P-Values corresponding to <FIG>. The table below and <FIG> show no significant improvement in the UHDRS TMS gait and balances in pridopidine treated HD1 and HD2 patients at <NUM> weeks.

<FIG> provide bar graphs of changes in UHDRS TMS Dystonia scores in <NUM> and <NUM> week patient groups. <FIG>: Change from baseline in UHDRS TMS Dystonia ALL: UHDRS TMS Dystonia scores at week <NUM> in all patients. The table below provides the P-Values corresponding to <FIG>. No significant improvement is observed.

<FIG>: Change from baseline in UHDRS TMS Dystonia: UHDRS TMS Dystonia scores for patients with BL TFC ≥ <NUM> AND CAG Repeats < <NUM> at week <NUM>. The table below provides the P-Values corresponding to <FIG>. Patients with baseline TFC greater than or equal to <NUM>, show statistically significant improvement in the UHDRS TMS Dystonia score at <NUM> bid- <NUM> bid pridopidine for <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Dystonia: UHDRS TMS Dystonia scores for patients with CAG Repeats < <NUM> AND BL TMS 1st <NUM> Qs at week <NUM>. The table below provides the P-Values corresponding to <FIG>. Patients with baseline TMS who represent three least severe TMS quarters and less than <NUM> CAG repeats in their htt gene, show statistically significant improvement in the UHDRS TMS Dystonia score at <NUM> bid- <NUM> bid pridopidine for <NUM> weeks.

<FIG>: Change from baseline in UHDRS TMS Dystonia: UHDRS TMS Dystonia scores for patients with BL TFC ≥ <NUM> and CAG Repeats < <NUM> and BL TMS 1st <NUM> Qs at week <NUM>. The table below provides the P-Values corresponding to <FIG>. Patients with baseline TFC greater than or equal to <NUM>, baseline TMS representing three least severe TMS quarters and less than <NUM> CAG repeats in their htt gene, show statistically significant improvement in the UHDRS TMS Dystonia score at <NUM> bid <NUM> bid and <NUM> bid pridopidine for <NUM> weeks.

<FIG>: General information regarding Finger tapping (Q-motor tap measurements). <FIG> shows a drawing of subject's arm with tapper. <FIG> shows normal and aberrant tapping measurements. <FIG>: Q-motor tap measurements: A well-validated objective measure. (Bechtel <NUM>)
<FIG>: Q-Motor Tap-Speed-Frequency. <NUM> pridopidine administered bid demonstrated consistent improvement from baseline. The data for <NUM> pridopidine bid is shown by the top line in this graph and the data for the placebo is shown by the bottom line in this graph. Difference in p-value of <NUM> pridopidine bid from placebo was <NUM> at week <NUM>, <NUM> at week <NUM>, and <NUM> at week <NUM>. Increase in tap speed indicates improvement. The unit of measurement of the Y-axis is Frequency (Hz). <FIG>: Q-Motor Tap Speed Inter Onset interval (IOI). <NUM> pridopidine administered bid demonstrated consistent and significant improvement from baseline for <NUM> bid. The data for <NUM> pridopidine bid is shown by the bottom line in this graph and the data for the placebo is shown by the top line in this graph. Difference in p-value of <NUM> pridopidine bid from placebo was <NUM> at week <NUM>, <NUM> at week <NUM>, and <NUM> at week <NUM>. Decrease in inter tap interval indicates improvement. The unit of measurement of the Y-axis in <FIG> is Frequency (Hz). <FIG> shows change from baseline in Tap-Speed-Inter-Onset-interval-MN-Hand-L (sec) over time (weeks) for full analysis set. <FIG>: Improvement in objective pharmacodynamic measures of motor control: change from baseline in Q-Motor: Tap-Speed-Inter-Onset-interval-MN-Hand (sec), Week <NUM> FAS. The table below provides data and the P-Values corresponding to <FIG>. A trend towards improvement was noted in <NUM> bid treated patients.

<FIG>: Improvement in objective pharmacodynamic measures of motor control: change from baseline in Q-Motor: Tap-Speed-Inter-Onset-interval-MN-Hand (sec), Week <NUM> in pridopidine treated HD1 and HD2 patients. The table below provides the data and P-Values corresponding to <FIG>. A trend towards improvement was noted in all treatment arms.

<FIG>: Improvement in objective pharmacodynamic measures of motor control, change from baseline in Q-Motor: Pro-Sup-Frequency-MN-Hand (Hz), Week <NUM> FAS. The table below provides the data and P-Values corresponding to <FIG>. A trend towards improvement was noted in <NUM> bid treated patients.

<FIG>: Improvement in objective pharmacodynamic measures of motor control, change from baseline in Q-Motor: Pro-Sup-Frequency-MN-Hand (Hz), Week <NUM> Week <NUM> in pridopidine treated HD1 and HD2 patients. The table below provides the data and P-Values corresponding to <FIG>. A trend towards improvement was noted in <NUM> bid treated patients.

<FIG>: Change from baseline in UHDRS-TMS plotted over time in HD1 patients. Line with dark diamond represents placebo; line with open circle represents <NUM> bid, line with triangle represents <NUM> bid, line with grey diamond represents <NUM> bid, line with square represents <NUM> bid. <NUM> bid shows improvement in TMS score after <NUM> weeks. Y axis represents change from baseline in TMS from baseline, x axis represents treatment time in weeks. means ± SEM)
<FIG>: Comparison of patients with baseline (BL) dystonia score of ≥<NUM> at <NUM> weeks after dosage with either placebo, <NUM> pridopidine b. d, <NUM> pridopidine b. , <NUM> pridopidine b. , or <NUM> pridopidine b. Within the full analysis set, no clinically meaningful changes from baseline were noted for patients at Week <NUM> or Week <NUM> in the dystonia score across the placebo and all active treatment groups (not shown). In patients with a baseline total dystonia score≥<NUM> assessed at Week <NUM>, a directional clinical improvement in dystonia was noted for all treatment groups, with the greatest decreases observed for the <NUM>, <NUM>, and <NUM> bid treatment groups. <FIG>: Of those patients with baseline (BL) dystonia score of ≥<NUM> who completed <NUM> weeks of treatment with either placebo or <NUM> pridopidine b. , the percentage who were categorized based on the change in UHDRS TMS dystonia from BL to <NUM> weeks as responders (improved or no change, e.g. change ≥<NUM>) or non-responders (worsened, change < <NUM>). <FIG>: Of those patients with baseline (BL) dystonia score of ≥<NUM> who completed <NUM> weeks of treatment with either placebo or <NUM> pridopidine b. , the percentage who were categorized based on the change in UHDRS TMS dystonia from BL to <NUM> weeks as responders (improved, e.g. change ≥<NUM>) or non-responders (worsened or no change < <NUM>). Results of the Responder Analysis for dystonia items (<FIG>) further support this trend toward improvement by showing that a greater percentage of patients were categorized as Responders within the dystonia items in the <NUM> bid treatment group compared to the placebo group (<NUM> patients [<NUM>%] and <NUM> patients [<NUM>%], respectively in <FIG> and <NUM>% and <NUM>%, respectively in <FIG>). A similar trend of Responders was seen in the chorea + dystonia items in the <NUM> bid treatment group compared to the placebo group (<NUM> patients [<NUM>%] and <NUM> patients [<NUM>%], respectively) (not shown). <FIG>: Plot of change in UHDRS Dystonia score over time for subjects pooled from MermaiHD, HART and Pride-HD studies with baseline (BL) dystonia (≥<NUM>) who received either placebo or <NUM> pridopidine b. At Week <NUM>, patients taking <NUM> pridopidine b. d showed a statistically significant improvement in the dystonia score compared to those taking placebo. A trend toward this improvement was maintained at Week <NUM>. <FIG>: Of those PRIDE-HD patients with baseline (BL) dystonia score of ≥<NUM> who completed <NUM> weeks of treatment with either placebo or <NUM> pridopidine b. , the percentage who were categorized based on the change in UHDRS limb dystonia from BL to <NUM> weeks as responders (improved, e.g. change ≥<NUM>) or non-responders (worsened or no change < <NUM>).

A statistically significant greater percentage of patients were categorized as Responders for the UHDRS-Limb Dystonia item in the pridopidine <NUM> bid treatment group compared to the placebo group (<NUM>% and <NUM>%, respectively).

In some embodiments, the subject is not afflicted with Huntington's disease.

In some embodiments, the subject is not a Huntington's disease subject.

In one embodiment, the dystonia is a primary dystonia or an isolated dystonia. In another embodiment, the dystonia is a primary generalized dystonia. In another embodiment, the dystonia is a genetic form of primary dystonia. In another embodiment, the dystonia is an early onset generalized dystonia.

In one embodiment, the dystonia is Torsion dystonia-<NUM> (DYT1) dystonia. In another embodiment, the dystonia is DYT6 dystonia or DYT-KMT2B (DYT28) dystonia. In one embodiment, the DYT1 dystonia is postural type dystonia or action type dystonia.

In some embodiments, the dystonia is early onset dystonia or late onset dystonia. In some embodiments, the dystonia manifests at any age. In some embodiments, the dystonia is an early onset generalized dystonia (DYT1 and non-DYT1).

In some embodiments, the dystonia is an isolated or a combined dystonia.

In some embodiments, the dystonia is a secondary dystonia or a combined dystonia.

In one embodiment, the dystonia is Dopa-responsive dystonia, Myoclonus dystonia, X-linked dystonia-parkinsonism, or Rapid-onset dystonia-parkinsonism.

In some embodiments, the dystonia is a focal dystonia, a segmental dystonia, a multifocal dystonia, a hemidystonia or a generalized dystonia.

In one embodiment, the dystonia is a paroxysmal dystonia. In another embodiment the dystonia is action-specific dystonia or a task-specific dystonia. In one embodiment, the dystonia is Musician's dystonia.

In one embodiment, the dystonia is not caused by a pathology. In some embodiments, the pathology is a stroke, a traumatic brain injury, a lesion, a brain tumor, neurological tissue damage, or neurological tissue degeneration.

In some embodiments, the dystonia is Musician's dystonia, Dopa-responsive dystonia, Myoclonus dystonia, Paroxysmal dystonia and dyskinesia, X-linked dystonia-parkinsonisms, Rapid-onset dystonia-parkinsonisms, Primary dystonia, Secondary dystonia (including Huntington's dystonia), or Psychogenic dystonia.

In one embodiment, the dystonia is postural dystonia. In another embodiment, the dystonia is action dystonia.

In an embodiment, the subject has been confirmed to be afflicted with DYT1 or other primary genetic forms of dystonia by genetic testing. In an embodiment, the subject has a Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) score greater than <NUM>.

In one embodiment, the subject has a <NUM>-base pair in-frame deletion within the coding region of the TOR1A (torsinA) gene located on chromosome 9q34.

In one embodiment, the subject does not suffer from cognitive impairment. In another embodiment, the subject suffers from a cognitive impairment.

In an embodiment, the amount of pridopidine is effective to reduce or maintain a level of one or more symptoms of the dystonia in the subject. In an embodiment, the symptoms are measured by the Burke-Fahn-Marsden Dystonia Rating Scale or the Unified Dystonia Rating Scale. In another embodiment, the symptoms are measured by the Clinical Global Impression (CGI) scale, Patient Global Assessment score, Visual Analogue Score for pain, Patient Evaluation of Global Response, Burke-Fahn-Marsden Disability Scale (BFMDS), or the Health Related quality of life score (EQ-5D, SF-<NUM>).

In an embodiment, the one or more symptoms are selected from the group consisting of: involuntary limb movement or muscle contractions; twisted posture of the limbs or trunk; abnormal fixed posture of the limbs or trunk; talipes equinovarus; turning in of the leg; turning in of the arm; tremor of the hand, head, trunk or arms; dragging of the leg; torticollis; writer's cramp; and dystonia of trunk and/or extremities.

The amount of pridopidine is effective to provide a clinically significant improvement in dystonia symptoms. In an embodiment, the clinically significant improvement in dystonia symptoms is an at least a <NUM>% change from baseline in the subject administered pridopidine in comparison to a human patient not treated with pridopidine as measured by a rating scale used in clinical practice or clinical research. In an embodiment, the rating scale used in clinical practice or clinical research is the dystonia items of the UHDRS scale or the Burke-Fahn-Marsden Dystonia Rating Scale. In some embodiments, a clinically significant improvement in dystonia symptoms is considered to be at least a <NUM>% change from baseline in a pridopidine treated patient compared to placebo treated patient (a patient not receiving pridopidine) when measured using a rating scale used in clinical practice or clinical research such as, for example, the dystonia items of the UHDRS scale or BFMDRS. In some embodiments, a clinically significant improvement is at least a <NUM>% change from baseline, a <NUM>% change from baseline, a <NUM>% change from baseline or a greater than <NUM>% change from baseline.

In an embodiment, the subject is a human patient. In another embodiment, the subject is a mammal. In one embodiment, the periodic administration is oral.

In another embodiment, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> pridopidine is administered to the patient per day.

In an embodiment, the amount of pridopidine is administered by a unit dose of <NUM>, <NUM>, or <NUM> pridopidine.

In an embodiment, the pridopidine is in the form of pridopidine hydrochloride.

The composition may be provided as a package comprising:.

A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with dystonia may include:.

Combinations of the above-described embodiments are also within the scope of the invention.

Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. For instance, all combinations of the various elements described herein are within the scope of the invention. Additionally, the elements recited in the packaging and pharmaceutical composition embodiments can be used in the treatment embodiments described herein.

While the compositions for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredients, optionally in the form of physiologically acceptable salts, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.

In an embodiment, the pharmaceutical compositions comprise the active compounds or pharmaceutically acceptable salts or derivatives thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic ingredients know and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy. Preferred routes of administration include oral administration, in particular in tablet, in capsule, in dragé, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection. The pharmaceutical composition of the invention can be manufactured by the skilled person by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.

Further details on techniques for formulation and administration may be found in the latest edition of <NPL>).

As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.

The articles "a", "an" and "the" are non-limiting. For example, "the method" includes the broadest definition of the meaning of the phrase, which can be more than one method.

As used herein, "effective" as in an amount effective to achieve an end means the quantity of a component that is sufficient to yield an indicated therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this disclosure. For example, an amount effective to treat a movement disorder. The specific effective amount varies with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.

As used herein, to "treat" or "treating" encompasses, e.g., reducing a symptom, inducing inhibition, regression, or stasis of the disorder and/or disease. As used herein, "inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.

"Administering to the subject" or "administering to the (human) patient" means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition. The administration can be periodic administration.

As used herein, "periodic administration" means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc..

"Dystonia" as referred to herein is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation (Albanese 2013a).

As used herein, an "amount" or "dose" of pridopidine as measured in milligrams refers to the milligrams of pridopidine present in a preparation, regardless of the form of the preparation. A "dose of <NUM> pridopidine" means the amount of pridopidine acid in a preparation is <NUM>, regardless of the form of the preparation. Thus, when in the form of a salt, e.g. a pridopidine hydrochloride, the weight of the salt form necessary to provide a dose of <NUM> pridopidine would be greater than <NUM> due to the presence of the additional salt ion.

By any range disclosed herein, it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, for example, <NUM> to <NUM> means that <NUM>, <NUM>. <NUM>; <NUM>; <NUM>. <NUM>; and <NUM>, <NUM>. <NUM> unit amounts are included as embodiments of this invention.

As used herein, "pridopidine" means pridopidine base or a pharmaceutically acceptable salt thereof, as well as derivatives, for example deuterium-enriched version of pridopidine and salts. Examples of deuterium-enriched pridopidine and salts and their methods of preparation may be found in <CIT>, <CIT> and <CIT>. In certain embodiments, pridopidine is a pharmaceutically acceptable salt, such as the HCl salt or tartrate salt. Preferably, in any embodiments of the invention as described herein, the pridopidine is in the form of its hydrochloride salt.

"Deuterium-enriched" means that the abundance of deuterium at any relevant site of the compound is more than the abundance of deuterium naturally occurring at that site in an amount of the compound. The naturally occurring distribution of deuterium is about <NUM>%. Thus, in a "deuterium-enriched" compound, the abundance of deuterium at any of its relevant sites is more than <NUM>% and can range from more than <NUM>% to <NUM>%. Deuterium-enriched compounds may be obtained by exchanging hydrogen with deuterium or synthesizing the compound with deuterium-enriched starting materials.

The active compounds for use according to the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms.

Examples of pharmaceutically acceptable addition salts include the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the L-tartrate, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-<NUM>-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like. Such salts may be formed by procedures well known and described in the art.

Albanese et al. , (2013b) describes the results of a task force convened to critique existing dystonia rating scales and place them in clinical and clinimetric context.

The following abbreviations are used throughout this application:
ALT: alanine aminotransferase; ADL: Activities of Daily Living; AR: Autoregressive; AUC: area under the concentration-time curve; bid or b. : twice daily; BL = Baseline; CAB: cognitive assessment battery; CGI-C: Clinical Global Impression of Change; CGI-S: Clinical Global Impression of Severity; CI: confidence interval; CIBIC-Plus: Clinician's Interview-based Impression of Change plus Caregiver Input; CIBIS: Clinician's Interview-based Impression of Severity; CIOMS: Council for International Organizations of Medical Sciences; Cmax: maximum observed plasma drug concentration; CNS: central nervous system; CRF: case report form; CRO: contract research organization; CS: Compound Symmetry; C-SSRS: Columbia-Suicide Severity Rating Scale; CYP: cytochrome P450; DSM-IV TR: Diagnostic and Statistical Manual - Fourth Edition Text Revision; EM: extensive metabolizers; EU: European Union; FA: Functional Assessment; FAS: full analysis set; Freq: tapping frequency; GCP: Good Clinical Practice; GFV-C: grip force variability in the static phase; GGT: gamma-glutamyl transpeptidase; HART: Huntington's disease ACR16 Randomized Trial; HCG: human chorionic gonadotropin; HD: Huntington's disease; HD-QoL = Huntington's disease Quality of Life; HVLT-R: HAD-CAB Hopkins Verbal Learning Test-Revised; ICH: International Conference on Harmonisation; IEC: Independent Ethics Committee; IOI: inter onset interval; IPI: inter peak interval; IRB: Institutional Review Board; IRT: interactive response technology; IS: Independence Score; ITI: inter tap interval; ITT: intent-to-treat; LSO: local safety officer; MAD: multiple ascending dose; MedDRA: Medical Dictionary for Regulatory Activities; MermaiHD: Multinational European Multicentre ACR16 study in Huntington's Disease; ML: Maximum-Likelihood; mMS: Modified Motor Score; MoCA: Montreal cognitive assessment; MS: Multiple sclerosis; MTD: maximum tolerated dose; NMDA: N-methyl-D-aspartate; NOAEL: no observed adverse effect level; PBA-s: Problem Behaviors Assessment-Short form; PD: pharmacodynamic(s); PDS: Physical disability scale; PK: pharmacokinetic(s); PM: poor metabolizer; PPT: physical performance test; Qd: once daily; Q-Motor: Quantitative motor; QoL: Quality of life; QTcF: Fridericia-corrected QT interval; RBC: red blood cell; REML: Restricted Maximum-Likelihood; SAE: serious adverse event; SD: standard deviation; SDMT: symbol digit modalities test; SOC: system organ class; SOP: standard operating procedure; SUSAR: suspected unexpected serious adverse reaction; t½: half life; TC = telephone call; TD: tap duration; TF: tapping force; TFC: Total Functional Capacity; TMS: Total Motor Score; TMS Involuntary Movements = TMS for performance of Domestic Chores and Dystonia scores combined. TUG: timed up and go; UHDRS: Unified Huntington's Disease Rating Scale; ULN: upper limit of the normal range; US: United States; WBC: white blood cell; WHO: World Health Organization; WHO: Drug World Health Organization (WHO) drug dictionary; ΔHR: change from baseline in heart rate; ΔQTcF: change from baseline in QTcF; ΔΔHR: placebo-corrected change from baseline in heart rate; Placebo-Controlled Study-Huntington's Disease; ΔΔQTcF: placebo-corrected change from baseline in QTcF, wk: week; EQ5D-<NUM> European Quality of Life-<NUM> Dimensions (<NUM> levels).

Sixteen (<NUM>) clinical studies have been completed with pridopidine, including <NUM> studies in healthy subjects (of which <NUM> study also included patients with schizophrenia), <NUM> study in patients with Parkinson's disease, <NUM> studies in patients with schizophrenia (including the study mentioned above), and <NUM> studies in patients with HD (including <NUM> open-label extension study). In addition, a compassionate use program for pridopidine in patients with HD is ongoing in Europe, and an open-label, long term safety study is ongoing in the United States (US) and Canada. An overview of these studies are presented in International Publication No. <CIT>.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

The PRIDE-HD study assessed the efficacy of pridopidine <NUM> to <NUM> twice daily (bid) on motor impairment in patients with HD over at least <NUM> weeks of treatment using the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS). The study also assessed the effect of at least <NUM> weeks of treatment with pridopidine <NUM> bid to <NUM> bid on the Modified Physical Performance Test (mPPT). The study also assessed the effect of at least <NUM> weeks of treatment with pridopidine <NUM> bid to <NUM> bid on UHDRS measures for total function capacity (TFC) and cognitive assessment battery (CAB). The study also compared data from all patients to those obtained in HD subpopulations. The study also (i) evaluated the safety and tolerability of a range of pridopidine doses in patients with HD during at least <NUM> weeks of treatment, (ii) explored the pharmacokinetics (PK) of pridopidine in the study population and (iii) investigated the relationship between exposure to pridopidine and outcome measures (e.g., clinical efficacy and toxicity parameters).

This was a randomized, parallel-group, double blind, placebo controlled study that compared the efficacy and safety of pridopidine <NUM>, <NUM>, <NUM>, and <NUM> bid versus placebo in the treatment of motor impairment in HD.

The administration of pridopidine to patients is summarized in Table <NUM>. The study procedures and assessments are summarized in Table <NUM>. A detailed clinical procedure, including screening procedures and other procedures, is listed as Example <NUM> in U. Patent Application Publication No. <CIT> and International Publication No. <CIT>.

The primary efficacy variable and endpoint for this study was change from baseline in the UHDRS TMS (defined as the sum of all UHDRS motor domains ratings) at Week <NUM> or Week <NUM>. The primary measure of motor impairment is the UHDRS motor assessment section, which was administered by a trained examiner. The first part of the motor assessment consisted of five TMS subscores, provided below. The sum total of all the <NUM> items is referred to as the Total Motor Score (TMS). The secondary efficacy variable and endpoint was change from baseline in the mPPT at Week <NUM> or Week <NUM>. The TMS scale includes measurement of dystonia.

Other efficacy variables and endpoints for this study are as follows:.

Safety variables and endpoints include the following:.

Tolerability variables and endpoints include the following:.

The primary PK measure was determination of plasma concentration of pridopidine. Concentrations were also incorporated into a pridopidine population PK model and individual exposure for the study patients (Cmax and AUC) was calculated.

Pridopidine (as pridopidine hydrochloride) was provided as a white hard gelatin capsule, size <NUM> containing <NUM> pridopidine and a white hard gelatin capsule, size <NUM> containing <NUM> pridopidine. Placebo was presented as white hard gelatin capsules matching the <NUM> or <NUM> pridopidine capsules but containing no active ingredient, only the excipients (silicified microcrystalline cellulose and magnesium stearate).

The UHDRS comprises a broad assessment of features associated with HD (Huntington Study Group <NUM>). It is a research tool which has been developed to provide a uniform assessment of the clinical features and course of HD. The TMS component of UHDRS comprises <NUM> assessments from the <NUM> items of the UHDRS, with each assessment rated on a <NUM>-point scale from <NUM> (normal) to <NUM> (maximally abnormal).

The secondary efficacy variable and endpoint, the Modified Physical Performance Test (mPPT), quantifies the patient's performance in physical tasks (Brown <NUM>). It is a standardized <NUM>-item test that measures the patient's performance on functional tasks. Assistive devices are permitted for the tasks that require a standing position (items <NUM> to <NUM>). Both the speed and accuracy at which the patients complete the items were taken into account during scoring. The maximum score of the test is <NUM>, with higher scores indicating better performance.

The CIBIC-Plus (version ADCS-CGIC) was developed, validated, and is commonly used in studies of anti-dementia drugs in Alzheimer's disease (Joffres <NUM>). An independent rater evaluated the patient's overall disease severity prior to the initiation of pridopidine or placebo. This assessment, known as the CIBIS, rates the patient on a <NUM>-point Likert scale from extremely severe HD to no symptoms of HD.

The PDS was used during the study as a measure of disability. Patients were scored on a scale from <NUM> ("Fixed posture requiring total care - gastrotomy, catheterization") to <NUM> ("Normal; no disease evident") (Myers <NUM>).

The FA scale of the UHDRS assessed functionality in <NUM> tasks of daily living (e.g., "Could patient engage in gainful employment in his/her accustomed work?"). Each question was answered with 'yes' or 'no.

CGI-S was assessed at baseline and CGI-C was used at all subsequent time points to assess changes from baseline. The CGI-S scale was initially designed to assess treatment response in patients with mental disorders (Guy <NUM>) but is now used widely in a range of illnesses.

The TFC scale of the UHDRS is a standardized scale used to assess <NUM> functional domains associated with disability shown below (occupation, finances, domestic chores (e.g. laundry, washing dishes), activities of daily living, and care level). Total functional capacity score has a range of <NUM>-<NUM> and is a well-established endpoint for trials aiming disease progression. The Total functional capacity score has been developed and deployed by the Huntington Study Group (HSG, <NUM>) in multiple trials over <NUM> decades and is accepted by regulators.

Occupation: <NUM> = unable, <NUM> = marginal work only, <NUM> = reduced capacity for usual job, <NUM> = normal. Finances: <NUM> = unable, <NUM> = major assistance, <NUM> = slight assistance, <NUM> = normal.

Domestic Chores: <NUM> = unable, <NUM> = impaired, <NUM> = normal.

ADL: <NUM> = total care, <NUM> = gross tasks only, <NUM> = minimal impairment, <NUM> = normal.

Care level: <NUM> = fill time skill nursing, <NUM> = home or chronic care, <NUM> = home.

The independence scale of the UHDRS is a rating scale where the patient's degree of independence was given in percentage, from <NUM>% (tube fed, total bed care) to <NUM>% (no special care needed).

The HD-QoL is a standardized instrument for measuring health-related quality of life. (Hocaoglu <NUM>). It is a validated disease-specific measure designed for HD, and can provide a summary score of overall health-related quality of life, as well as scores on several discrete scales.

The hand movement score is defined as the sum of UHDRS domains finger taps, pronate-supinate hands and luria (fist-hand-palm test).

The gait and balance score is defined as the sum of UHDRS domains gait, tandem walking and retropulsion pull test.

The UHDRS-mMS is defined as the sum of following domains from UHDRS-TMS: dysarthria, tongue protrusion, finger taps, pronate-supinate hands, luria, rigidity, bradykinesia, gait, tandem walking, and retropulsion pull test.

In the UHDRS, maximal chorea was scored from <NUM> (absent) to <NUM> (marked/prolonged) on each of the following items: face, mouth, trunk, right upper extremity, left upper extremity, right lower extremity, and left lower extremity. Maximal chorea is the sum of all scores.

In the UHDRS, maximal dystonia was scored from <NUM> (absent) to <NUM> (marked/prolonged) on each of the following items: trunk, right upper extremity, left upper extremity, right lower extremity, and left lower extremity. Maximal dystonia is the sum of all scores.

The percentage of responders, defined as patients with UHDRS-TMS change from baseline ≤<NUM> at Week <NUM>.

The Multiple Sclerosis Walking Scale (MSWS-<NUM>) was adapted to become a generic measure of walking and mobility and renamed the Walk-<NUM>.

The EQ5D <NUM> level version (EQ5D-<NUM>) was introduced in <NUM> (EuroQol Group <NUM>). It essentially consists of the EQ5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ5D-<NUM> descriptive system comprises the following <NUM> dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression.

Motor deficits can be objectively assessed using different Q-Motor assessments. All Q-Motor assessments are based on the application of precalibrated and temperature controlled force transducers and <NUM>-dimensional position sensors with very high sensitivity and test-retest reliability across sessions and sites in a multicenter clinical study. Q-Motor measures thus aim to reduce the limited sensitivity of categorical clinical rating scales, the intra- and inter-rater variability, and placebo effects observed in scales such as UHDRS-TMS. In addition, Q-Motor assessments allow for the objective monitoring of unintended motor side-effects in clinical studies. Thus, Q-Motor is an objective, reliable, and sensitive measure of motor function that is free of rater bias and limits placebo effect influence. <FIG> shows the Q-motor tap measurements for a normal patient, a patient with mild defects and a patient with severe defects. In Track-HD, the largest natural history study of pre-manifest and early stage HD Q-motor tapping deficits correlated with clinical scores as well as regional brain atrophy (<FIG>, <FIG> and Bechtel <NUM>).

The patient places their hand on a hand rest with their index finger positioned above a force-transducer. Recordings start after practice runs. The patient is instructed to finger tap as fast as possible between <NUM> auditory cues. The beginning of a tap is defined as a rise of the force by <NUM> N above maximal baseline level. The tap ends when it drops to <NUM> N before the maximal baseline level is reached again. The duration and variability of tap durations (TD), inter onset intervals (IOI), inter peak intervals (IPI), and inter tap intervals (ITI) are the exploratory outcome measures for speeded tapping. In addition, variability of peak tapping forces (TF) is calculated as coefficient of variation, and the tapping frequency (Freq), i.e., the number of taps between the onsets of the first and the last tap divided by the time in between, is determined. Five trials of <NUM> seconds duration are performed with each hand.

This task assessed the regularity of hand taps performed when alternating between the palm and dorsal surface of the hand performing a repetitive pronation/supination movement. The force and duration of the hand taps are recorded similarly to the speeded tapping task. A tone cues the start and end of an assessment. Five trials of <NUM> seconds duration are performed with each hand.

An assessment of the ability to rotate the forearm and hand such that the palm is down (pronation) and to rotate the forearm and hand such that the palm is up (supination) on both sides of the body.

This task assessed the coordination of isometric grip forces in the precision grip between the thumb and index finger. Grip forces are assessed during grip initiation, object transport, and in a static holding phase. Patients are instructed to grasp and lift a device equipped with a force transducer and <NUM>-dimensional position sensor in the precision grip between thumb and index finger and hold it stable adjacent to a marker <NUM>-cm high. Grip forces and <NUM>-dimensional position and orientation of the object are recorded. Mean isometric grip forces and grip force variability in the static phase (expressed as coefficient of variation = standard deviation [SD]/mean × <NUM>) (GFV-C) are calculated during a <NUM>-second period starting <NUM> seconds after the first cueing tone. Five trials of <NUM> seconds duration are performed with each hand. Chorea is assessed calculating a "position-index" and "orientation-index". Start and end of assessment are signaled by a cueing tone.

The patient places a foot on the foot device such that the ball of the foot is positioned above a force-transducer. Recordings start after practice runs. The patient is instructed to tap with the foot as fast as possible between <NUM> auditory cues. The beginning of a tap is defined as a rise of the force by <NUM> N above maximal baseline level. The tap ends when it dropped to <NUM> N before the maximal baseline level is reached again. The duration and variability of TD, IOI, IPI, and ITI are the exploratory outcome measures for speeded tapping. In addition, variability of peak TF is calculated as coefficient of variation, and the tapping Freq, i.e., the number of taps between the onsets of the first and the last tap divided by the time in between, is determined. Five trials of <NUM> seconds duration are performed with each foot.

The TUG is a simple test used to assess a person's mobility and requires both static and dynamic balance. It uses the time that a person takes to rise from a chair, walk <NUM> meters, turn around, walk back to the chair, and sit down. During the test, the person is expected to wear their regular footwear and use any mobility aids that they would normally require. The TUG is used frequently in the elderly population, as it is easy to administer and can generally be completed by the majority of older adults. The test is quick, requires no special equipment or training, and is easily included as part of the routine medical examination (Podsiadlo <NUM>). The use of the TUG test in conjunction with UHDRS has been recommended for clinical studies of HD (Rao <NUM>).

The following six sections describe the tests that are part of the CAB brief.

The SDMT is a paper-and-pencil test of psychomotor speed and working memory.

Emotion recognition of facial expressions of emotions is examined using computerized presentations of photographs depicting <NUM> basic emotions or a neutral expression.

Visual attention and task switching are assessed using the Trail Making test, which consists of <NUM> circles on a standard sheet of paper. For Trail A, participants are required to connect, as quickly as possible, circles containing numbers in ascending numerical order. For Trail B, participants are to connect, as quickly as possible, circles containing numbers and letters, alternating between numbers and letters in ascending order (e.g., <NUM>, A, <NUM>, B, <NUM>, C, etc.).

The HVLT-R offers a brief assessment of verbal learning and memory (recognition and recall).

Psychomotor function is assessed in a Paced Tapping test. Participants tap on left and right mouse buttons, alternating between thumbs, at <NUM>. They first listen to a tone presented at the desired tapping rate, and then begin tapping to the tone. After <NUM> taps with the tone, the repetition of the tone is discontinued, and participants attempt to continue tapping at the same rate until the end of the trial (<NUM> taps later).

OTS is a spatial planning task which gives a measure of frontal lobe function. OTS is a variant of the Stockings of Cambridge task, and places greater demands on working memory as the participant has to visualize the solution.

Because of the prominence of psychiatric symptoms in HD, it is recommended that the PBA-s form be used in all HD studies with any need for behavioral assessment as a comprehensive screen for the most common psychiatric symptoms in HD. (Craufurd <NUM>, Kingma <NUM>).

In this Example, safety was assessed by qualified study staff by evaluating the following: reported AEs, clinical laboratory test results, vital signs measurements, ECG findings, physical and neurological examination findings (including body weight), and concomitant medication usage.

Clinical laboratory tests (serum chemistry including electrolytes, hematology and urinalysis) were performed as listed below.

The following serum chemistry tests were performed: calcium; phosphorus; sodium; magnesium; potassium; chloride; bicarbonate or carbon dioxide; glucose; blood urea nitrogen; creatinine; cholesterol; uric acid; ALT; AST (aspartate aminotransferase); lactate dehydrogenase; gamma-glutamyl transpeptidase (GGT); alkaline phosphatase; creatine phosphokinase (in case of elevated creatine phosphokinase, the MB fraction should be measured); total protein, albumin; total bilirubin; direct bilirubin; indirect bilirubin; and prolactin. The following hematology tests were performed: Hemoglobin; hematocrit; red blood cell (RBC) count; platelet count; white blood cell (WBC) count and differential count; absolute neutrophil count; absolute lymphocyte count; absolute eosinophil count; absolute monocytes count; absolute basophil count; and absolute atypical lymphocyte count. Urinalysis includes testing for the following: Protein; glucose; ketones; blood (hemoglobin); pH; specific gravity; leukocyte esterase; microscopic; bacteria; RBCs; WBCs; casts; and crystals.

Vital signs, including pulse, blood pressure, and body temperature were measured.

The primary PK measure is a determination of plasma concentration of pridopidine. Concentrations were also incorporated into a pridopidine population PK model and individual exposure for the study patients (Cmax and AUC) was calculated.

Blood samples (<NUM> each) were collected for the determination of plasma concentrations via venipuncture or indwelling catheter in the morning before study drug administration at the following visits:
Titration Period: day <NUM> (baseline) - prior and <NUM> to <NUM> hours post first dose and day <NUM> - <NUM> to <NUM> hours post afternoon dose. Full Treatment Dose Period: day <NUM> - pre afternoon dose and <NUM> to <NUM> hours post afternoon dose, day <NUM> - pre afternoon dose and <NUM> to <NUM> hours post afternoon dose, day <NUM> - <NUM> to <NUM> hours post afternoon dose, day <NUM> - pre afternoon dose and <NUM> to <NUM> hours post afternoon dose, day <NUM> - <NUM> to <NUM> hours post afternoon dose, day <NUM> - prior to morning dose, and follow-up visit.

Samples were analyzed using an appropriate validated method for pridopidine and its main metabolite TV-<NUM> (previously called ACR30). The lower limits of quantification for pridopidine and TV-<NUM> in plasma are approximately <NUM> to <NUM> ng/mL and <NUM> to <NUM> ng/mL, respectively.

A blood sample (<NUM>) was collected in <NUM> dipotassium ethylenediaminetetraacetic acid (K2EDTA) plastic tubes at the screening visit for genetic analyses. Analyses include CAG repeats, CYP2D6 status, and genetic long QT syndrome, or any other genetic analyses related to pridopidine response or HD.

The change from baseline in UHDRS-TMS was analyzed using a Repeated Measures model (SAS® MIXED procedure with REPEATED sub-command). The model includes the following fixed effects: categorical week in study by treatment interaction, center, neuroleptic use or no use, and baseline UHDRS-TMS score. The unstructured covariance matrix for repeated observations within patients was used. In case that the model does not converge, the Maximum-Likelihood (ML) estimation method is used instead of the default Restricted ML (REML). If the model still does not converge then a simpler covariance structures with less parameters is used, according to the following order: Heterogeneous Autoregressive(<NUM>) [ARH(<NUM>)], Heterogeneous Compound Symmetry (CSH), Autoregressive(<NUM>) [AR(<NUM>)], and Compound Symmetry (CS). The estimated means at the Week <NUM> visit of the change from baseline in UHDRS-TMS was compared between the active treatment arms) and the placebo arm.

A sensitivity analysis to evaluate if the observed effect in UHDRS-TMS is driven by the Chorea UHDRS-TMS sub-score, the Dystonia UHDRS-TMS sub-score, or the Involuntary Movements (Chorea + Dystonia) UHDRS-TMS sub-score was performed as follows:
Three variables were calculated: (<NUM>) The change from baseline to Week <NUM> and Week <NUM> in the sum of the UHDRS-TMS items except the Chorea items, (<NUM>) The change from baseline to Week <NUM> and Week <NUM> in the sum of the UHDRS-TMS items except the Dystonia items, and (<NUM>) The change from baseline to Week <NUM> and Week <NUM> in the sum of the UHDRS-TMS items except the Chorea and Dystonia items. These variables were analyzed in the same way as the primary efficacy endpoint except that the variable evaluation at baseline were included in the model instead of baseline UHDRS-TMS.

Plasma concentration data on pridopidine and the main metabolite TV-<NUM> are presented by descriptive statistics by dose of pridopidine and also by CYP2D6 metabolizer status. Concentrations are also incorporated into a pridopidine population PK model and individual exposure for the study patients (Cmax and AUC) are calculated.

Many clinicians and diagnosticians adopt the Shoulson and Fahn rating scale, based on TFC scores, to follow progression of HD. This rating scale groups total TFC scores into five stages of disease, with lower stages indicating more intact functioning. Table <NUM>, below, provides the TFC scores, average years from diagnosis and broad guidelines for typical care level for each stage of disease. (Johnson <NUM>.

The results of this example are shown in <FIG>.

Overview of preliminary analysis of functional, exploratory endpoints and safety:
Endpoints not dependent on rater bias were less prone to placebo effect, such as the Q-motor assessment. The signals detected suggest biological effects of pridopidine. Total Functional Capacity (TFC) showed trends favoring pridopidine after <NUM> weeks of treatment. There was no major safety findings despite high doses.

Expected deterioration of about <NUM> points were seen in the placebo group at <NUM> months. Historical data indicates that TFC deteriorates about <NUM> point per year in patients with Huntington's disease. TFC starts showing separation from placebo at week <NUM> to <NUM> and separation becomes a strong trend at week <NUM>. The TFC data supports a finding that pridopidine causes a delay of progression of functional decline.

Without wishing to be bound to this theory, the treatment effects shown in the figures were more pronounced when treating early patients (including stages <NUM> and <NUM>), especially early stages with BL TFC greater than or equal to <NUM>, and even more so in stage <NUM> (BL TFC =<NUM>-<NUM>). Without wishing to be bound to this theory this is particularly true for TFC finances and ADL, dystonia, involuntary movements (dystonia and chorea). A patient affected with HD with a baseline TFC score of <NUM>-<NUM> is considered to be a stage <NUM> HD patient.

The following items may account for the placebo effect seen in this example: Rater bias, a lack of hope in Huntington's disease, together with a high expectation for an effective treatment and a desire to get better from patients, overall positive data with pridopidine treatment causes high expectations, patients have an <NUM>% chance to receive active treatment, a high number of pills may cause expectancy, protocol changes during the study, and the number of assessments per visit.

The results shown in the figures, especially <FIG>, <FIG>, <FIG>and <FIG>, demonstrate that patients undergoing pridopidine therapy experienced an improved dystonia score in comparison to those patients receiving a placebo. For example, <FIG> show anti-dystonia effect especially in patients who have a degree of dystonia (GE <NUM>) at baseline with doses <NUM> and <NUM> pridopidine bid showing numerical improvement.

By carefully selecting the patients (e.g. assessing functional capacity at baseline) and selecting patients with a TFC of <NUM>-<NUM> at baseline, doses of pridopidine, in particular at <NUM> and <NUM> bid, show a treatment effect (<FIG> & <FIG>).

The dystonia treated in <FIG>, <FIG>, <FIG> and <FIG> is representative of treating dystonia as described in this application. The effects of pridopidine on non-HD dystonias is expected to be similar to its benefit on HD dystonia due to shared areas of direct pathological involvement (e.g. striatum) and/or impaired connectivity between these brain regions (striatum, cerebellum, etc.), plus the known complex effects of pridopidine on multiple targets in the brain, including the striatum and cerebellum.

The total dystonia treatment exemplified in this application is representative of treatment of, inter alia, the following types of dystonia: early onset generalized dystonia (DYT1 and non-DYT1 dystonias), early onset and late onset dystonias, focal, segmental, multifocal, hemi- or generalized dystonias, Musician's dystonias, Dopa-responsive dystonias, Myoclonus dystonias, Paroxysmal dystonias and dyskinesias, X-linked dystonia-parkinsonisms, Rapid-onset dystonia-parkinsonisms, Primary dystonias, Secondary dystonias (including Huntington's dystonia), and Psychogenic dystonias.

Motor effects were statistically significant in Huntington's disease stage <NUM> subpopulations. For example, statistically significant changes were seen in the HD Stage <NUM> patient subgroups for Total TMS, Involuntary movements (Dystonia, Chorea), Ambulation (TMS Gait and Balance, Time Up and Go, Walk-<NUM>).

In early HD there was a statistically significant effect on TMS at weeks <NUM> (<FIG>) and <NUM> (<FIG>) driven by a lower placebo effect. Involuntary Movements (chorea and dystonia) as measured by TMS improved in HD1 patients at <NUM> weeks (<FIG>). The effect persisted at <NUM> weeks as well (<FIG>).

Liang, et al. (<NUM>) mouse model for primary generalized dystonia.

Overt dystonic symptoms were observed in mice with either a conditional deletion of the complete torsin-1A (Torla) gene, or a three-nucleotide Torla deletion that is associated with DYT1 in humans.

Multiple cellular effects were observed in these mice, including mislocalization of associated proteins, alterations in protein turnover, and age-restricted, region-specific neurodegeneration.

Liang's model highlights how subtle and selective dystonia associated neurodegeneration can occur in specific cell populations during certain stages of CNS development, with no further neurodegeneration occurring thereafter.

There is evidence for striatal involvement and abnormal synaptic connectivity in the pathophysiology of most forms of primary and secondary dystonia. In patients with DYT-<NUM> dystonia, Positron Emission Tomography (PET) and Diffusion Tensor Imaging (DTI) MRI studies suggest abnormalities of basal ganglia, thalamic, cortical, and / or cerebellar regions (e.g. metabolism) or circuits.

Pridopidine has complex pharmacological effects on multiple targets found in the basal ganglia and cerebellum. Without wishing to be bound to theory, the potential synaptic actions of pridopidine may be consistent with a therapeutic effect in dystonia, including promoting synapse formation.

In clinical trials conducted in HD patients (HART, MermaiHD, and PRIDE-HD), those receiving pridopidine often had better outcomes on specific measures of dystonia. In PRIDE-HD, responder analysis in patients reporting some measure of dystonia further supports a benefit of pridopidine in dystonia.

Periodic (e.g., daily or twice daily) oral administration of pridopidine is effective in treating human patients afflicted with dystonia. Periodic (e.g., daily or twice daily) oral administration of pridopidine is effective to treat the subject suffering from dystonia. The administration of pridopidine is effective to reduce dystonia in afflicted patients.

A pridopidine composition as described herein is administered orally to a subject suffering from dystonia. The administration of the composition is effective to treat the subject suffering from dystonia. The administration of the composition is effective to reduce dystonia in afflicted patients.

To conduct a randomized, double-blind, placebo-controlled study to assess the change in the severity of dystonia (using the Burke-Fahn-Marsden Dystonia (BFMD) Rating Scale or the Unified Dystonia Rating Scale (UDRS)) in a population of patients with DYT1 and other primary genetic forms of dystonia after <NUM> weeks of treatment compared to baseline in patients on pridopidine versus a placebo.

This study compares a cohort that receives pridopidine <NUM> b. , and placebo b. for a period of <NUM> weeks. The study population consists of those with DYT1 and other primary genetic forms of dystonia, as confirmed by genetic testing. The study's other inclusion criteria are patients with a BFMD score greater than <NUM>, male or female patients, patients of any race or ethnicity, and patients with the ability to provide informed consent.

Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) Rating Scale evaluates nine body parts (eyes, mouth, speech, swallowing, neck, trunk, right arm, right leg, left arm, and left leg) by rating the severity factor and provoking factors for each part on a <NUM> point scale of <NUM> (no dystonia) to <NUM> (indicating the presence of dystonia at rest). The dystonia scores of the eyes, mouth and neck are assigned a weighting factor of <NUM>, while the other <NUM> parts are assigned a weighting factor of <NUM>. The score of each part is obtained by multiplying the provoking factor by the severity factor and the weighting factor, and then summing the scores of each part. The maximum score possible is <NUM>. A higher score indicates more severe dystonia.

The UDRS Rating Scale evaluates <NUM> body parts (eyes and upper face, lower face, jaw and tongue, larynx, neck, trunk, right shoulder/proximal arm, left shoulder/proximal arm, right distal arm/hand, left distal arm/hand, right proximal leg, left proximal leg, right distal leg/foot, and left distal leg/foot) by rating the severity and duration factors for each part. The severity factor for each part is rated using a <NUM>-point scale, ranging from <NUM> (no dystonia) to <NUM> (severe dystonia). The duration factor is rating on a <NUM> point scale ranging from <NUM> (at rest/action) to <NUM> (submaximal/maximal). The total score is the sum of each domain (part), with the maximum being <NUM>. A higher score indicates more severe dystonia.

The primary outcome is the change in the severity of dystonia (using the Burke-Fahn-Marsden Dystonia Rating Scale or the Unified Dystonia Rating Scale) after <NUM> weeks of treatment compared to baseline in patients on pridopidine vs. placebo.

The secondary outcomes are Clinical Global Impression (CGI), Patient Global Assessment, Visual Analogue Score for pain, Patient Evaluation of Global Response, Burke-Fahn-Marsden Disability Scale (BFMDS), Health Related quality of life (EQ-5D, SF-<NUM>), safety and tolerability of pridopidine including Beck Depression Inventory, cognitive impairment (e.g. Montreal Cognitive Assessment, Mattis Dementia Rating Scale, or Mini-Mental State Examination, and differences in number of treatment responders (at least <NUM>% improvement in BFMDRS).

The study does not enroll patients with segmental and focal dystonias. Other exclusion criteria include: patients with primary genetic complex forms of dystonia with clear syndromic features, patients with secondary dystonias, patients whose conditions are judged by their physician to be too severe to participate in the study, patients with active seizure disorder, patients with comorbidities such as Parkinson's disease, schizophrenia, moderate to severe depression, cognitive impairment, dementia, renal failure, or other severe comorbidities, patients who are pregnant, lactating, probably pregnant, and patients who want to become pregnant, patients who cannot agree to contraception, patients who have participated in other trials within <NUM> weeks before consent, patients who are presently participating in other clinical trials, patients with the inability to follow the study protocol, and patients who are judged by their physician to be a poor candidate for this study.

The standard of care therapy may include oral medications, injectable medications, deep brain stimulation or intrathecal baclofen.

Treatment with pridopidine as described in this example is found to improve the severity of dystonia as measured by the primary endpoint. Treatment with pridopidine as described in this example is also found to improve the secondary outcomes discussed in this example.

In the current pre-clinical study, <NUM> compounds (the test compound, pridopidine, and a positive control) are tested in <NUM> different mouse models known for testing dystonia: Bay K <NUM>-induced dystonia; Tottering mouse mutants (with induction by caffeine); and kainite-induced dystonia.

For each model, <NUM> doses of the test compound (plus dosage vehicle) are given, and <NUM> dose of the positive control (plus dosage vehicle). <NUM> mice will receive each dose. The tottering mouse mutants model is a crossover design and the tests in the Bay K <NUM>-induced dystonia and kainite-induced dystonia models are grouped independently.

Claim 1:
A pharmaceutical composition comprising pridopidine or a pharmaceutically acceptable salt thereof for use in treating dystonia by periodic administration to a human subject afflicted with dystonia, wherein the subject has a Unified Huntington's Disease Rating Scale Total Motor Score dystonia (UHDRS-TMS-dystonia) rating of ≥<NUM>, and wherein the pridopidine is administered at a dosage of <NUM> bid to <NUM> bid.