EA041256B1 - THE USE OF PRIDOPIDINE FOR THE TREATMENT OF FUNCTIONAL IMPAIRMENT - Google Patents

Description

This patent application claims the benefit of US Provisional Application No. 62/416685 filed November 2, 2016, US Provisional Application No. 62/411511 filed October 21, 2016, US Provisional Application No. 62/395263 filed September 15, 2016. , and U.S. Provisional Application No. 62/379175, filed August 24, 2016, the contents of which are hereby incorporated by reference in their entirety.

The invention refers to various publications by first author and year of publication. Full references to these publications are provided in the References section immediately before the claims. The disclosures of publications cited in the References section are incorporated herein by reference in their entirety for a more complete description of the state of the art at the date of the invention described herein.

Background of the Invention

Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disease with an autosomal dominant pattern of inheritance. The disease is associated with a triad of motor, behavioral and cognitive symptoms. Movement disorders are the defining feature of the disease, with chorea being the most obvious movement symptom. Although chorea is useful for diagnosis, it is a poor marker of disease severity. Disability and disease severity seem to correlate best with negative motor signs such as fine motor impairment, bradykinesia, and simple motor coordination skills, including speech difficulties, gait, and postural dysfunction (Mahant 2003).

Dopamine is rightfully considered an important neurotransmitter that modulates several aspects of brain function, including motor function (Nieoullon 2003). Impaired dopaminergic signaling is associated with a number of neurological and psychiatric conditions (Zhan 2011, Dunlop 2007), and there is considerable clinical and preclinical evidence suggesting that dopaminergic functions are also impaired in HD (Kung 2007, Huot 2007).

A number of drugs are prescribed to relieve the motor and emotional problems associated with HD; however, scientific evidence for the usefulness of various drugs in HD is lacking (Mestre 2009, Mestre 2009). Only tetrabenazine and deutetrabenazine, which reduce dopamine availability and transmission, are registered specifically for the treatment of patients with HD for the treatment of chorea. There are no registered drugs to treat the diverse symptoms of HD, resulting in an inevitable deterioration in functional ability throughout the course of the disease. Thus, there is a significant unmet medical need for the development of drugs to slow or reduce functional impairment in HD.

pridopidin.

Pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine) (formerly known as ACR16) is a drug under development for the treatment of Huntington's disease. Pridopidine has been shown to modulate locomotor activity by suppressing hyperactivity or enhancing hypoactivity. It is assumed that the neuroprotective properties of pridopidine are due to its high affinity for the sigma-1 receptor (S1R, binding IC ₅₀ ~ 100 nM), while the locomotor activity of pridopidine may be mediated mainly by its low affinity, antagonistic activity against dopamine D2 receptor (D2R) (binding IC ₅₀ ~ 10 µM) (Ponten 2010). Pridopidine exhibits low affinity binding to additional receptors in the micromolar range.

S1R is an endoplasmic reticulum (ER) chaperone protein that is involved in cell differentiation, neuroplasticity, neuroprotection, and cognitive function in the brain. Recently, transcriptomic analysis of the rat striatum has shown that pridopidine treatment upregulates the expression of BDNF, dopamine receptor 1 (D1R), glucocorticoid receptor (GR), and serine-threonine kinase protein kinase B (Akt)/phosphoinositide 3-kinase (PI3K) pathways, which are known to promote neuronal plasticity and survival and are impaired in HD. In addition, the gene expression profile for pridopidine showed an inverse pattern to the gene expression profile for HD disease in a Q175 knockdown (Q175 KI) mouse model of HD (Geva 2016). Pridopidine also enhances the secretion of the neuroprotective brain-derived neurotrophic factor (BDNF) in the neuroblastoma cell line in an S1R-dependent manner (Geva 2016).

Brief summary of the invention

The present invention provides a method for maintaining functional ability, improving functional ability, or reducing impairment of functional ability in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, so that the daily dose of pridopidine administered to the patient is 90225 mg, so as to maintain functionality, improve functionality or reduce deterioration in functional ability in a human patient. In some embodiments, the method includes a dose of 90 or 180 mg of pridopidine administered to the patient daily. In some embodiments, the method includes a dose of 90 mg of pridopidine administered to the patient daily. IN

- 1 041256 In some embodiments, the patient is a patient with Huntington's disease (HD).

The present invention provides a method of maintaining functional ability, improving functional ability, or reducing the rate of deterioration of functional ability in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidine administered to the patient is 90-225 mg, so that maintain functional ability, improve functional ability, or reduce the rate of deterioration of functional ability in a human patient. In some embodiments, the method includes a dose of 90 or 180 mg of pridopidine administered to the patient daily. In some embodiments, the method includes a dose of 90 mg of pridopidine administered to the patient daily. In some embodiments, the patient is an HD patient.

The invention further provides a method for slowing the clinical progression of HD, as measured by overall functional capacity in a human patient, comprising intermittent oral administration to a patient afflicted with HD of a pharmaceutical composition containing pridopidine such that the daily dose of pidopidine administered to the patient is 90-225 mg so that most slow the clinical progression of HD in a patient, as measured by overall functional ability. In some embodiments, the method includes a dose of 90 or 180 mg of pridopidine administered to the patient daily. In some embodiments, the method includes a dose of 90 mg of pridopidine administered to the patient daily. In some embodiments, a daily dose of 90 mg is administered to the patient as 45 mg twice daily.

In addition, a method is provided for reducing deterioration in functional capacity in a HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidine administered to the patient is 90-180 mg, to thereby reduce the deterioration in functional capacity in the patient. In some embodiments, deterioration in functional ability from baseline compared to placebo (HD subject not receiving pridopidine) is reduced by at least 10%, at least 15%, at least 20%, at least 25 %, at least 30%, at least 35% or at least 40%. In some embodiments, the method includes a dose of about 90 mg to about 180 mg of pridopidine administered daily to the patient. In some embodiments, the method includes a dose of 90 mg of pridopidine administered to the patient daily. In some embodiments of the method, the 90 mg dose is administered to the patient as 45 mg twice daily. In some embodiments of the method, pridopidine is administered orally. In some embodiments of the method, administration continues for at least 26 weeks, at least 52 weeks, about 78 weeks, or at least 78 weeks. In some embodiments of the method, the HD patient is an adult patient. An HD patient is classified as an early stage patient, for example, as a stage 1 or stage 2 (HD1 or HD2) patient. In some embodiments, the patient has a baseline TFC score of 7-13, or at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, 13, or 7-10, or 1113 In some embodiments, the functional ability of the patient is measured using the General Functional Ability (TFC) scale of the Unified Huntington's Disease Rating Scale (UHDRS), UHDRS-TFC, or TFC. In some embodiments of the method, the patient's baseline functional ability and one or more subsequent functional ability assessments are performed to determine any change in impairment of functional ability.

In addition, a method is provided to achieve a reduced change from baseline in UHDRS-TFC score in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the daily dose of pridopidin administered to the patient is 90-180 mg so that thereby affecting the change in UHDRS-TFC score in a patient compared to a subject with HD who did not receive pridopidine. In some embodiments, the method includes a dose of about 90 to about 180 mg of pridopidin administered to the patient daily. In some embodiments, the method includes a dose of 90 mg of pridopidine administered to the patient daily. In some embodiments of the method, administration continues for at least 26 weeks, or at least 52 weeks, or about 78 weeks, or at least 78 weeks. In some embodiments of the method, the HD patient is classified as a Stage 1 or Stage 2 HD patient based on the patient's UHDRS-TFC score. In some embodiments, the patient has a baseline TFC score of 7-13 or at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, 13, or 7-10 or 11- 13. In some embodiments of the method, the difference in change in UHDRS-TFC score from baseline compared to an HD subject not treated with pridopidine is reduced by at least 0.2 points over a period of 26 weeks, or by at least 0.3 points in for 52 weeks or 0.5 for 78 weeks. In some embodiments of the method, the difference in change in UHDRS-TFC score from baseline compared to an HD subject not treated with pridopidine is a decrease in the rate of TFC decline of at least 20%, at least 30%, at least at least 40% or at least 50% in 78 weeks.

In some embodiments of the methods disclosed herein, TFC includes one or more of maintaining employment, taking care of finances, taking care of household chores, requiring minimal attention

- 2 041256 mania and elementary self-care activities (ADL).

The invention further provides a method for achieving a reduced change from baseline in the Get Up and Go Time (TUG) test in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the dose is 90-180 mg . Pridopidin is administered to the patient on a daily basis to thereby reduce the change in the TUG test in the patient compared to an HD subject not receiving pridopidin.

The invention further provides a method of achieving a reduced change from baseline in a TUG test in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin such that the daily dose of pridopidin administered to the patient is 90-180 mg such that way to reduce the change in the TUG test in a patient compared to an HD subject not receiving pridopidine.

The invention further provides a method for achieving a reduced change from baseline in the Symbol to Digit Matching Test (SDMT) in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the daily dose of pridopidine administered to the patient is 90 -180 mg, thus reducing the change in the SDMT test in the patient compared to the HD subject not receiving pridopidine.

The invention further provides a method of achieving a reduced change from baseline in a Stroop verbal test in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, wherein the patient is dosed with 90-180 mg of pridopidine daily to thereby reduce the change in Stroop verbal test in a patient compared to a HD subject not receiving pridopidine.

The invention further provides a method for achieving a reduced change from baseline in the UHDRS: Independence (UHDRS-IS) score in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the daily dose of pridopidine administered to the patient is 90 -180 mg, thus reducing the change in UHDRS-IS in the patient compared to the HD subject not receiving pridopidine.

The invention further provides a method for achieving a reduced change from baseline in the Gait and Balance scale, as determined by the sum of the domains of the Total Movement Scale from UHDRS (UHDRS-TMS): gait, tandem walking, and retropulsion stability test in a human patient with HD, comprising intermittent oral administration to a patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-180 mg, thereby reducing the change in the patient's gait and balance score compared to an HD subject not receiving pridopidin.

The invention further provides a method for achieving a reduced change from baseline in the UHDRS-TMS subscale: Chorea in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the daily dose of pridopidine administered to the patient is 90-180 mg, thus reducing the change in the UHDRS-TMS subscale: Chorea in a patient compared to an HD subject not receiving pridopidine.

The present invention also provides a method of maintaining or improving the ability of a human patient to perform basic self-care activities, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidin administered to the patient is 90-225 mg, so that maintain or improve a person's ability to perform basic self-care activities.

The invention further provides a method for reducing or maintaining dystonia in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidin administered to the patient is 90-225 mg, to thereby reduce dystonia or maintain a constant level of dystonia in a human patient.

The invention also relates to a method for treating limb dystonia in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg, so as to treat limb dystonia in a human.

The invention further provides a method for improving or maintaining the gait and balance of a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidin administered to the patient is 90-225 mg, to thereby improve or support unchanged

- 3 041256 level of gait and balance in a human patient.

In addition, a method is provided for improving, maintaining at a constant level, or slowing down the deterioration of gait and balance in a human patient, including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90 mg in order to improve, maintain on unchanged level or slow the deterioration of gait and balance in a human patient.

The invention also relates to a method for improving or maintaining the autonomy of a human patient, comprising periodically oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidine administered to the patient is 90-225 mg, so as to improve or maintain the autonomy of the patient.

The invention also provides a method for improving, maintaining or slowing the deterioration of independence in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve, maintain on unchanged level or slow the deterioration of the patient's independence.

The invention also provides a method for improving or maintaining domains of cognitive function in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidine administered to the patient is 90-225 mg, to thereby improve or maintain domains of cognitive functions in a human patient.

In addition, a method is provided for improving, maintaining, or slowing down the deterioration of domains of cognitive functions in a human patient, including intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90 mg, to thereby improve, maintain level or slow the deterioration of domains of cognitive function in a human patient. Patient cognitive domains can also be the patient's cognitive activities in different domains.

Domains of cognition in a human patient can be measured, for example, using the Cognitive Ability Battery (CAB) analysis and/or the revised Hopkins Verbal Learning Test (HVLT-R). Cognitive function domains can also be measured using the route building test B (TMT-B). Cognitive domains can also be measured using the HD Cognitive Battery Analysis (HD-CAB), which includes 6 tests.

The invention also relates to a method for reducing the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg, so that thereby reduce the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient. In one embodiment of this method, the patient is afflicted with HD.

The severity of prolonged or intermittent muscle contractions associated with dystonia in humans can be measured, for example, on the scale UHDRS TMS: Dystonia.

In addition, a method is provided for improving or maintaining a motor ability at a constant level in a human patient, including periodically oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidine administered to the patient is 90-225 mg, so as to improve motor abilities in person.

Motor abilities can be measured, for example, on the UHDRS Total Movement Scale (TMS), the UHDRS TMS without chorea, or the UHDRS TMS without dystonia.

The invention also provides a method for reducing or maintaining a level of chorea in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the dose of pidopidin administered daily to the patient is 90-225 mg, in order to reduce or maintain the level of chorea. in a human patient.

The level of chorea can also be slowed down. Accordingly, the invention provides a method for reducing, maintaining or slowing the progression of chorea in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidin administered to the patient is 90 mg to thereby reduce, maintain on unchanged level or slow the increase in chorea in humans.

The chorea of a human patient can be measured by the UHDRS TMS scale: Chorea.

The invention further provides a method for improving or maintaining the behavior and/or psychiatric condition of a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, such that the daily dose of pridopidine administered to the patient is 90-225 mg, so that thereby improving or maintaining the behavior and/or psychiatric condition of the human patient.

The behavior and/or psychiatric condition of the human patient may be measured, for example, on a general Problem Behavior Rating scale. Behavior and/or psychiatric condition of the patient

- 4 041256 can also be measured using the problematic behavior score for depressed mood. The behavior and/or psychiatric condition of the human patient can also be measured using the Problem Behavior Assessment for Annoyance. The behavior and/or psychiatric condition of the human patient can also be measured by the Problem Behavior Assessment for lack of initiative or apathy. The behavior and/or psychiatric condition of a human patient can be measured, for example, using the Problem Behavior Assessment for Obsessive Compulsive Behavior. The behavior and/or psychiatric condition of the human patient can also be measured using the Problem Behavior Assessment for Disoriented Behavior.

Furthermore, a method is provided for improving or reducing the worsening of loss of initiative or apathy in a HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidine administered to the patient is 90-225 mg, to thereby improve or reduce the worsening. loss of initiative or apathy in the human patient.

The invention also provides a method for reducing or maintaining involuntary movements in a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidin administered to the patient is 90-225 mg, to thereby reduce or maintain on unchanged level of involuntary movements in a human patient.

The invention further provides a method for improving or maintaining the mobility of a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidin administered to the patient is 90-225 mg, to thereby improve or maintain at a constant level of patient mobility.

The present invention also relates to a method for improving or maintaining the ability of a human patient to perform physical work tasks, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, such that the daily dose of pridopidine administered to the patient is 90-225 mg, so that such improve or maintain at a constant level the ability of a human patient to perform tasks for the performance of physical work.

In some embodiments of the methods disclosed above, the patient is administered a dose of 90 or 180 mg of pridopidine daily. In some embodiments of the methods disclosed above, a dose of 90 mg of pridopidine is administered to the patient per day. In preferred embodiments of the methods disclosed above, a 90 mg daily dose of pridopidine administered to the patient is administered to the patient as 45 mg twice daily.

In some embodiments, the patient is administered 45 mg of pridopidine daily for about one to two weeks and 45 mg of pridopidine twice daily thereafter. In some embodiments of the methods disclosed above, administration continues for at least 12 weeks, at least 26 weeks, more than 26 weeks, at least 52 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 described above, the HD patient is an early stage HD patient and has a baseline TFC score of at least 7, at least 8, at least 9, at least 10, at least least 12, 13 or 7-10 or 11-13.

In some embodiments of the methods disclosed above, a HD patient has been diagnosed as having at least 36 CAG repeats in the huntingtin gene. In some embodiments, the HD patient has been diagnosed as having at least 44 repeats in the huntingtin gene. In some embodiments of the methods disclosed above, the HD patient is an adult patient and is at least 18 years old or at least 21 years old. In some embodiments of the methods disclosed above, the HD patient is an early stage HD patient. In some embodiments, the patient is an HD stage 1 (HD1) patient or an HD stage 2 (HD2) patient. In some embodiments, the patient is an HD 1 patient and is experiencing one or more symptoms of HD. In some embodiments, the HD patient is not an asymptomatic HD patient.

This document provides a pharmaceutical composition containing pridopidin for use in reducing functional impairment in a human patient, wherein the pharmaceutical composition is to be administered orally to the patient intermittently such that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, the functional ability is a general functional ability. In some embodiments, the daily dose is 90 mg of pridopidine. In some embodiments, the daily dose is 45 mg twice daily.

This document provides a pharmaceutical composition containing pridopidin for use in maintaining functional capacity in a human patient, where the pharmaceutical composition is to be periodically administered orally to the patient, so that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, functionality includes elementary self-service activities (ADL).

- 5 041256

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament that maintains functional ability in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, functionality includes ADL.

This document provides a pharmaceutical composition containing pridopidin for use in slowing the clinical progression of HD, as measured by overall functional ability in a human patient, where the pharmaceutical composition is to be administered orally to the patient intermittently such that the daily dose of pridopidin administered to the patient is 90-225 mg. In many embodiments, (a) the pharmaceutical composition is administered for more than 26 weeks, or (b) the titration dose in an amount different from the intended dose is administered for some period of time at the beginning of the periodic administration, or (c) the human patient is afflicted with an early stage of the disease Huntington.

In some embodiments of the pharmaceutical compositions and uses, the TFC includes one or more of employment maintenance, financial care, household chores requiring minimal attention, and basic self-care activities (ADL).

The present invention relates to the use of an amount of pridopidine in the manufacture of a medicament for slowing the clinical progression of HD as measured by overall functional ability in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in maintaining the ability of a human patient to perform basic self-care activities, where the pharmaceutical composition should be periodically administered to the patient orally, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

This document proposes the use of an amount of pridopidine in the manufacture of a medicament for use while maintaining the ability of a human patient to perform basic self-care activities, where the medicament is formulated for intermittent oral administration to the patient so that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in reducing dystonia or maintaining a constant level of dystonia in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, dystonia includes limb dystonia.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament intended to reduce dystonia or maintain a constant level of dystonia in a human patient, where the medicament is formulated for intermittent oral administration to the patient so that the daily dose of pridopidine administered to the patient is 90-225 mg. In some embodiments, dystonia includes limb dystonia.

This document provides a pharmaceutical composition containing pridopidin for use in the treatment of dystonia of the extremities in a human patient, where the pharmaceutical composition should be periodically administered to the patient orally so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament for use in the treatment of dystonia of the extremities in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining the same level of gait and balance in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, the administration slows the deterioration of gait and balance in the patient.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament to improve or maintain the same level of gait and balance in a human patient, where the drug is formulated for intermittent oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90-225 mg. In some embodiments, the administration slows down deterioration in the patient's gait and balance.

Provided herein is a pharmaceutical composition containing pridopidin for use in improving, maintaining or retarding deterioration in gait and balance in a human patient, wherein the pharmaceutical composition is to be administered orally to the patient intermittently such that the daily dose of pridopidine administered to the patient is 90 mg. IN

- 6 041256 some embodiments, the introduction slows down the deterioration of the patient's gait and balance.

Provided herein is the use of an amount of pridopidine in the manufacture of a medicament to improve, maintain, or retard deterioration in gait and balance in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90 mg. In some embodiments, the administration slows down deterioration in the patient's gait and balance.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining the independence of a human patient, where the pharmaceutical composition is to be periodically administered orally to the patient so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament intended to improve or maintain the autonomy of a human patient, the medicament being formulated for intermittent oral administration to a patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving, maintaining or slowing the deterioration of the independence of a human patient, and the pharmaceutical composition should be periodically administered to the patient orally, so that the dose of pridopidine administered daily to the patient is 90 mg.

The present document proposes the use of an amount of pridopidine in the formulation of a medicament to improve or maintain or slow the deterioration of patient independence when the medicament is formulated for intermittent oral administration to a patient such that the daily dose of pridopidine administered to the patient is 90 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining domains of cognition in a human patient, where the pharmaceutical composition is to be periodically administered orally to the patient so that the daily dose of pridopidin administered to the patient is 90-225 mg.

Provided herein is the use of a certain amount of pridopidine in the manufacture of a medicament for use in improving or maintaining domains of cognition in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90 mg.

Provided herein is a pharmaceutical composition containing pridopidin for use in improving, maintaining, or slowing the deterioration of domains of cognitive function in a human patient, where the pharmaceutical composition is to be administered orally to the patient intermittently, such that the daily dose of pridopidine administered to the patient is 90 mg.

Provided herein is the use of an amount of pridopidine in the manufacture of a medicament for use in improving, maintaining, or retarding deterioration of domains of cognition in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in reducing the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidine administered to the patient is 90 -225 mg.

This document proposes the use of some amount of pridopidine in the manufacture of a medicament to reduce the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient, where the drug is formulated for intermittent oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90- 225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining a constant level of motor ability in a human patient, where the pharmaceutical composition should be periodically administered to the patient orally, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in improving or maintaining a constant level of motor ability in a human patient, where the drug is formulated for periodic oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90-225 mg .

This document provides a pharmaceutical composition containing pridopidin for

- 7 041256 application in reducing or maintaining the level of chorea in a human patient, where the pharmaceutical composition must be periodically administered orally to the patient, so that the dose of pridopidine administered daily to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in reducing or maintaining the level of chorea in a human patient, where the drug is formulated for intermittent oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in reducing or maintaining a constant level or slowing the increase in chorea in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidine administered to the patient is 90 mg.

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament intended to reduce or maintain or slow the increase in chorea in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient so that the daily dose of pridopidine administered to the patient is 90 mg .

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining the behavior and/or psychiatric state of a human patient, where the pharmaceutical composition is to be administered orally to the patient periodically, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

Provided herein is the use of an amount of pridopidine in the manufacture of a medicament for use in improving or maintaining the behavior and/or psychiatric condition of a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90 -225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in reducing or maintaining the involuntary movements of a human patient, and the pharmaceutical composition should be periodically administered to the patient orally so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in reducing or maintaining the involuntary movements of a human patient, where the medicament is formulated for intermittent oral administration to the patient so that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining a constant level of mobility of a human patient, and the pharmaceutical composition should be periodically administered to the patient orally so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine for the manufacture of a medicament intended to improve or maintain a constant level of mobility of a human patient, and the drug is intended for periodic oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining the ability of a human patient to perform physical work tasks, while the pharmaceutical composition should be periodically administered to the patient orally, so that the daily dose of pridopidine administered to the patient is 90 -225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in improving or maintaining a constant level of the ability of a human patient to perform physical work tasks, while the drug is designed for periodic oral administration to a patient so that the dose of pridopidine administered daily to the patient is 90-225 mg.

The methods, compositions and uses disclosed herein are applicable to, for example, a human patient afflicted with Huntington's disease. In some embodiments of the compositions and uses of the methods, the human patient is afflicted with HD and has a baseline TMS score that is in the least severe quarter of the general population of patients afflicted with Huntington's disease; or the human patient is affected by HD and has a baseline TMS score that is in the two least severe quarters of the general population of patients affected by Huntington's disease; or the human patient is affected by HD and has a baseline TMS score that is in the three least severe quarters of the general population of patients affected by Huntington's disease; or a human patient is afflicted with HD and has a baseline TMS score that is in the three least

- 8,041,256 desired quarters of the total HD patient population, or baseline TFC score greater than or equal to 9; or the human patient is affected by HD and has a baseline TMS score that is in the three least severe quarters of the general HD patient population, or a baseline TFC score that is greater than or equal to 9 or has less than 44 CAG repeats in the huntingtin gene; or the human patient is afflicted with HD and has a baseline TMS score that is in the two least severe quarters of the general HD patient population; or the human patient is afflicted with HD and has a baseline TFC score greater than or equal to 7; or the human patient is afflicted with HD and has a baseline TFC score of 11-13; or the human patient is affected by HD and has a baseline TFC score greater than or equal to 9 or greater than 44 CAG repeats in the huntingtin gene; or the human patient suffers from HD and has a baseline TMS score that is three of the least severe quarters of the total population of patients suffering from HD, or has less than 44 CAG repeats in the huntingtin gene; or a human patient is afflicted with HD and has a baseline TFC score that is greater than or equal to 9, or a baseline TMS score that is in the three least severe quarters of the general HD patient population.

In some embodiments of the methods, compositions, and uses disclosed herein, pridopidine, or a pharmaceutically acceptable salt thereof, is pridopidine hydrochloride.

A pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof, e.g. pridopidine hydrochloride, should be periodically administered orally to a patient so that the daily dose of pridopidine administered to the patient is 90-225 mg.

In some embodiments of the compositions and uses disclosed above, the patient should be administered a dose of 90 or 180 mg of pridopidine daily. In some embodiments of the methods disclosed above, the patient should be administered a dose of 90 mg of pridopidine daily. In preferred embodiments of the methods disclosed above, the 90 mg dose of pridopidine to be administered to the patient on a daily basis is administered to the patient as 45 mg twice daily.

In some embodiments, the patient is administered 45 mg of pridopidine once a day (once a day) for about one to two weeks and 45 mg twice a day thereafter. In some embodiments of the methods disclosed above, administration continues for at least 12 weeks, at least 26 weeks, at least 52 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 is a Stage 1 or 2 HD patient and has a baseline TFC score of at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, 13 or 7-10 or 11-13. In some embodiments of the methods disclosed above, the HD patient has been diagnosed as having at least 36 CAG repeats in the huntingtin gene. In some embodiments of the methods disclosed above, the HD patient is 21 years of age or older.

In some embodiments of the methods, compositions and uses described above, the HD patient is an HD1 or HD2 patient and is not an asymptomatic HD patient.

Brief description of several types of figures

In the following figure summaries and corresponding figures, efficacy was assessed over a 52-week period using repeated measures mixed model (MMRM) analyzes compared to baseline (before pridopidine administration at week 0) on the UHDRSTMS, UHDRS-Behavior, UHDRS-Cognitive functions, TFC, UHDRS-Functional Assessment, UHDRS-Independence, Modified Physical Performance Test (mPPT), individual TMS subscales, HD-CAB analysis of cognitive batteries, Short Form Problem Behavior Assessments (PBA-s), and other outcomes .

Fig. 1. The concentration of pridopidine in the patient's blood (ng/ml; mean (± sd) measured values). Pre means before a dose and Post means after a dose. V2 means visit 2, V3 means visit 3, etc. Wk2 means the second week, Wk3 means the third week, and so on.

Fig. 2. Concentration of pridopidine in the patient's blood (ng/ml). Post-dose (C _max ) (± sd) at steady state.

For FIG. 1 and 2, a % coefficient of variation (CV) of about 40% for the measured values is considered adequate for these conditions [1-2 h post-dose, patient population, infrequent sampling]. Variability is expected to decrease when true sampling times are taken into account.

Fig. 3. General assessment of motor activity (TMS) - change from baseline (baseline, BL) with the introduction of pridopidine. A dose of 90 mg twice daily (circles) showed the greatest treatment effect. A decrease in TMS indicates an improvement. Tab. 1 below shows P values corresponding to FIG. 3.

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Table 1

A week 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily 4 0.0304 0.0004 <0001 <0001 8 <0001 <0001 <0001 <0001 12 0.0002 0.0003 <0001 0.0002 16 <0001 <0001 <0001 <0001 20 <0001 <0001 <0001 <0001 26 0.0013 0.0024 <0001 0.0063

Fig. 4. Total Movement Scale (TMS) - change from baseline placebo PRIDE-HD versus historical placebo in the HART and MermaiHD clinical trials. A lower number indicates an improvement. At week 26, the difference is about 6.5 TMS units.

Fig. 5a and 5b. Change from baseline in TMS. Fig. 5a: Using historical placebo in the HART and MermaiHD clinical trials, TMS results (change from baseline) are significant for both pridopidine 45 mg and pridopidine 90 mg. A lower number indicates an improvement. Fig. 5b: Change from baseline in full UHDRS-TMS analysis plotted over time. PRIDE-HD replicates the previous data in TMS changes from baseline because the changes from baseline were similar to those in HART and MermaiHD. In this graph, a decrease in TMS change from baseline indicates an improvement. Dark line with diamonds represents placebo, line with open circles represents 45 mg twice daily, gray line with triangles represents 67.5 mg twice daily, gray line with diamonds represents 90 mg twice daily, line with squares represents 112 .5 mg twice a day. A dose of 90 mg twice daily showed the greatest treatment effect.

Fig. 6a, 6b and 6c. Complete dystonia at 12 weeks (6a); at 20 weeks (6b); and at 26 weeks (6c); groups of patients were administered different doses of pridopidine. The y-axis is the change in dystonia from baseline. All data refer to adjusted mean±SE of dystonic change in the full assay set. A lower number indicates an improvement.

In FIG. 6d-6h show data relating to various aspects of dystonia.

Fig. 6d. Comparison of Patients with Baseline (BL) Dystonia Score >4 at 52 Weeks Post-Dose of Placebo, 45 mg pridopidine twice daily, 67.5 mg pridopidine twice daily, 90 mg pridopidine twice daily, or 112.5 mg pridopidine twice a day. Within the full assay set, there were no clinically significant changes from baseline for patients at week 26 or week 52 in the dystonia score across all placebo and active treatment groups (not shown). Patients with a baseline total dystonia score greater than or equal to 4 assessed at week 52 had a targeted clinical improvement in dystonia across all treatment groups, with the largest reductions seen in the 45, 67.5, and 90 mg twice daily treatment groups. The table below shows the change from baseline on the UHDRS scale: Dystonia over time.

A week 4 8 12 16 20 26 52 placebo n= 115 90 111 38 37 83 33 Pridop n= 109 82 102 25 24 81 21 Δ to placebo -0.35 -0.24 -0.96 -0.35 -1.09 -1.01 -1.54 p-value 0.3414 0.5783 0.0232 0.5515 0.0722 0.0326 0.0571

Fig. 6e-6f. Black bars refer to responders: subjects with or without improvement on the UHDRS scale: Dystonia. The gray columns refer to non-responders: subjects that showed deterioration on the UHDRS scale: Dystonia. The number at the base of each column refers to the number of features. Improvement or absence from: Percentage of subjects with UHDRS TMS: Dystonia (>0) treated with either placebo or 45 mg twice daily who were Responders or Non-Responders. Of those patients with baseline (BL) dystonia score >4 who completed 52 weeks of treatment with either placebo or pridopidine 45 mg twice daily, the percentage was classified based on change in UHDRS TMS: Dystonia from BL to 52 weeks per responder ( improvement or no change, eg change >0) or non-responders (deterioration, change <0).

Fig. 6f. Of patients with baseline (BL) dystonia score >4 who completed 52 weeks of treatment with placebo or 45 mg pridopidine twice daily, the percentage was classified based on change in UHDRS TMS: Dystonia from BL to 52 weeks per responder (improvement, eg change >1) or non-responders (deterioration or no change <1). The results of the responder analysis by dystonia points also confirm this trend of improvement, showing that a greater percentage of patients were categorized as responders within the dystonia points in the 45 mg twice daily treatment group compared to the placebo group (14 patients [77.8% ] and 18 patients [60.0%] respectively) and chorea+dystonia points in the 45 mg twice daily treatment group compared to the placebo group (14 patients [77.8%] and 20 patients [66.7%] respectively).

- 10 041256 venno) (not shown).

Fig. 6g. Graph of change in UHDRS score: Dystonia versus time for subjects enrolled in the MermaiHD, HART, and Pride-HD trials with baseline (BL) dystonia (>4) who received either placebo or pridopidine 45 mg twice daily. At week 26, patients treated with pridopidine 45 mg twice daily had a statistically significant improvement in dystonia scores compared with patients treated with placebo. The trend towards this improvement continued at week 52.

Fig. 6h. Of PRIDE-HD patients with a baseline (BL) dystonia score >4 who completed 52 weeks of treatment with placebo or pridopidine 45 mg twice daily, the percentage was classified based on change in UHDRS: Extremity dystonia from BL to 52 weeks per responder (improvement e.g. change >1) or non-responders (deterioration or no change <1).

A statistically significant greater percentage of patients were categorized as responders for the UHDRS item: Extremity Dystonia in the pridopidine 45 mg twice daily group compared to the placebo group (77.2% and 36.7%, respectively).

Fig. 7a. Change in limb dystonia (UHDRS limb dystonia) at week 12; Fig. 7b. Finger pressing and pronation/supination (P/S) of the arms at 20 weeks; Fig. 7s. Finger pressing and P/S hands at 26 weeks. Finger pressing and pronation/supination (P/S) of the hands is a combination of finger pressing (the ability to press with the fingers of both hands, while 15 repetitions in 5 seconds is considered normal) with pronation/supination (the ability to rotate the forearm and hand so that the palm is down (pronation), and the ability to rotate the forearm and arm so that the palm is up (supination) on both sides of the body). Hand pronation/supination is also known as Q-Motor: Pro-Sup-Frequency-MN-Hand (Hz). All data show adjusted mean+SE changes in dystonia in the full assay set for FIG. 7a-7c. The tables below present the data and p-values corresponding to the figures. N refers to the number of patients. Wk26 refers to the corresponding score at week 26. Wk52 refers to the relevant score at 52 weeks. And placebo refers to the difference in scores compared to placebo, specifically the mean change from baseline in the placebo group compared to the mean change from baseline in the respective group. ALL applies to patients treated with pridopidine, regardless of disease stage. The y-axes change from the original level for the characteristic shown in the above table. The x-axis is the dose, where P means placebo, 45 means 45 mg twice daily, 67.5 means 67.5 mg twice daily, 90 means 90 mg twice daily, and 112.5 means 112.5 mg twice a day. In the figures, the improvement occurs in the direction from the bottom of the graph to the top of the graph.

For example, in FIG. 8b shows the mean difference in UHDRS TMS scores for this group of patients (i.e. patients with a TFC score of 11-13 at baseline, i.e. HD1) between the score at baseline and the score after 26 weeks of pridopidine (at week 26) . In this FIG. the 90 mg twice daily dose shows the greatest improvement as its data point is the highest data point in the figure showing an improvement of approximately 8 points from baseline (i.e. UHDRS TMS score of -8 at week 26 vs. baseline). The table below the description of figure 8b shows that there were 11 patients in the 90 mg twice daily group (row N) and the mean UHDRS TMS score was 39.1 at baseline (row Baseline). Table below, descriptions of FIG. 8b also shows that the change in the 90 mg twice daily group from baseline (about -8, shown in the figure, not shown in the table) is 6.15 points better (-6.15) than the change in group placebo versus placebo (approximately - 2, shown in the figure, not shown in the table) (row A to placebo). In addition, in the table below the description in FIG. 8b shows a p-value of 0.0361 for the 90 mg twice daily group (row p-value). HD1 refers to an early stage HD patient with a baseline TFC score of 11-13. HD2 refers to an early stage HD patient with a baseline TFC score of 7-10.

Fig. 8a. Change from baseline UHDRS TMS score, 26 weeks, ALL. The table below and Fig. 8a do not show significant improvement in UHDRS TMS in all patients treated with pridopidine at 26 weeks compared to placebo. The improvement is confirmed by a more negative UHDRS TMS score.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 46.9 44.5 46.9 47 46.7 Δ relative to placebo 1.42 1.71 0.67 2.1 p-value 0.3199 0.2235 0.6282 0.1337

Fig. 8b. Change from baseline UHDRS TMS score, 26 weeks, stage 1, BL TFC 1113. (UHDRS TMS score at week 26 in pridopidine-treated HD1 patients with baseline total functional ability (BL TFC) score of 11 to 13). HD patients with a baseline TFC score of 11-13 are generally considered to be HD patients in the first stage (stage 1). In the table below and in Fig. 8b shows a trend towards improvement in UHDRS TMS in HD1 patients treated with pridopidine through

- 11,041,256 weeks compared to placebo.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 37.3 35.4 36.4 39.1 38.7 Δ relatively placebo -4.47 -3 -6.15 -4.79 p-value 0.0976 0.2505 0.0361 0.0676

Fig. 8s. Change from Baseline UHDRS TMS Score, Week 52, ALL. The table below and Fig. 8c show no significant improvement in UHDRS TMS in all patients treated with pridopidine at 52 weeks compared to placebo.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 46.9 44.5 46.9 47 46.7 Δ to placebo 0.59 2.55 1.78 2.71 p-value 0.7468 0.1591 0.3144 0.137

Fig. 8d. Change from baseline UHDRS TMS score, 52 weeks, stage 1, BL TFC 1113. In the table below and in FIG. 8d shows a trend towards improvement in UHDRS TMS in HD1 patients treated with pridopidine after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 37.3 35.4 36.4 39.1 38.7 Wk52 Δ to placebo -5.32 -0.84 -7.1 -0.92 p-value 0.1065 0.7918 0.047 0.7765

Fig. 8e. Change from baseline UHDRS TMS score: Gait and balance, 52 weeks. The table below and Fig. 8e show no significant improvement in UHDRS TMS: gait and balance in all patients treated with pridopidine after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.8 4.1 4.1 4 3.8 Δ to placebo -0.09 -0.05 -0.01 0.04 p-value 0.7404 0.8532 0.9747 0.8923

Fig. 8f. Change from baseline UHDRS TMS score. Gait and balance, 52 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 8f shows an improvement trend in UHDRS TMS: Gait and balance in HD1 patients treated with pridopidine at 52 weeks, with static significance for patients treated with pridopidine 45 mg twice daily.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2.3 2.8 2.6 2.6 2.4 Δ to placebo -0.94 -0.53 -0.49 -0.4 p-value 0.0445 0.2294 0.3056 0.3797

Fig. 8g. Change from baseline UHDRS TMS: Chorea, 26 weeks, ALL. The table below and Fig. 8g show no significant improvement in UHDRS TMS: Chorea in all patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline I,4 10.9 AND AND 2 10.9 Δ to placebo 0.92 0.81 0.36 1.05 p-value 0.1083 0.1501 0.5185 0.0609

Fig. 8h. Change from baseline UHDRS TMS: Chorea, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 8h shows a trend towards improvement in UHDRS TMS: Chorea in HD1 patients treated with pridopidine at 26 weeks, with statistical significance for patients treated with pridopidine 90 mg twice daily.

45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 17 17 AND 18 Wk26 Δ to placebo -1.4 -2.07 -2.52 -1.08 p-value 0.1805 0.0438 0.0271 0.2932

Fig. 8i. Change from baseline UHDRS TMS score: Dystonia, 26 weeks, ALL. In the table below and in Fig. 8i shows a trend towards improvement in UHDRS TMS: Dystonia in all patients treated with pridopidine at 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 4.1 3.6 4.1 4.9 4.5 Δ to placebo -0.06 -0.34 -0.33 -0.29 p-value 0.8711 0.3778 0.3845 0.4507

Fig. 8j. Change from baseline UHDRS TMS score: Dystonia, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 8j shows an improvement trend in UHDRS TMS: Dystonia in HD1 patients treated with pridopidine at 26 weeks, with patient significance.

mg twice a day

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2.8 2.1 2.2 3.2 2.4 Δ to placebo -0.99 -0.89 -1.56 -0.53 p-value 0.1569 0.1882 0.0396 0.4303

Fig. 8k. Change From Baseline UHDRS TMS Score: Dystonia, Week 52 In the table below and in FIG. 8k shows a trend towards improvement in UHDRS TMS: Dystonia in all patients treated with pridopidine after 52 weeks. ___________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 4.1 3.6 4.1 4.9 4.5 Δ to placebo -0.39 -0.35 -0.27 -0.24 p-value 0.4358 0.4795 0.5858 0.6382

Fig. 8l. Change from baseline for UHDRS TMS: Dystonia, 52 weeks, stage 1, BL TFC 11-13 In the table below and in FIG. 8l shows trend towards improvement in UHDRS TMS: Dystonia in HD1 patients treated with pridopidine at 52 weeks and significance for patients treated with pridopidine 45 mg twice daily.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2.8 2.1 2.2 3.2 2.4 Δ to placebo -1.65 -0.1 -1.46 -0.46 p-value 0.0243 0.8848 0.0575 0.5228

Fig. 8m. Change from baseline UHDRS TMS score: involuntary movements, 26 weeks, ALL. In the table below and in Fig. 8m showed no significant improvement in UHDRS TMS: Involuntary movements in all patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 15.6 14.4 15.1 16 15.4 Δ to placebo 0.89 0.48 0.01 0.76 p-value 0.2594 0.5328 0.9873 0.3268

Fig. 8n. Change from baseline UHDRS TMS score: involuntary movements, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 8n shows significant improvement in UHDRS TMS involuntary movements at 26 weeks in HD1 patients treated with pridopidine 45 mg twice daily, 67.5 mg twice daily and 90 mg twice daily pridopidine.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline I,5 12 12.2 12.9 13.2 Δ to placebo -2.49 -3.07 -4 -1.64 p-value 0.0469 0.0117 0.0033 0.1731

Fig. 8o. Change from baseline UHDRS TMS score: involuntary movements, 52 weeks. The table below and Fig. 8o show no significant improvement in UHDRS TMS involuntary movements in all patients treated with pridopidine after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 15.6 14.4 15.1 16 15.4 Δ to placebo 0.02 0.8 -0.26 0.57 p-value 0.9867 0.4196 0.7893 0.5648

Fig. 8p. Change from baseline UHDRS TMS score: involuntary movements, 52 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 8p shows a trend towards improvement in UHDRS TMS: Involuntary movements in HD1 patients treated with pridopidine at 52 weeks, specifically in patients treated with 45 mg twice daily and 90 mg twice daily.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline I,5 12 12.2 12.9 13.2 Δ to placebo -2.73 -0.2 -3.8 0.8 p-value 0.1487 0.9111 0.0643 0.6751

Fig. 8q. Change from baseline UHDRS TMS score: no chorea, 52 weeks. The table below and Fig. 8q show no significant improvement in UHDRS TMS: no chorea, in all patients treated with pridopidine at 52 weeks._________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 35.5 33.6 35.9 35.8 35.8 Δ to placebo 0.05 1.31 1.67 1.94 p-value 0.9693 0.3495 0.2234 0.1704

Fig. 8r. Change from Baseline UHDRS TMS Score: No Chorea, 52 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 8r shows a trend towards improvement in UHDRS TMS: no Chorea in HD1 patients treated with pridopidine at 52 weeks, especially in patients treated with 45 mg twice daily and 90 mg twice daily.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 28.6 25.5 26.4 29.4 27.8 Δ to placebo -4.09 -0.18 -4.92 -1.59 p-value 0.083 0.9358 0.0505 0.4924

Fig. 8s. Change from baseline UHDRS TMS score: no dystonia, 26 weeks, ALL. The table below and Fig. 8 s show no significant improvement in UHDRS TMS: no dystonia, in all patients treated with pridopidine at 26 weeks. __________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 42.7 40.9 42.8 42.1 42.2 Δ to placebo 1.39 1.97 1.2 2.4 p-value 0.2733 0.1137 0.3314 0.0539

Fig. 8t. Change from baseline UHDRS TMS score: no dystonia, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 8t shows a trend towards improvement in UHDRS TMS: no dystonia in HD1 patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 34.6 33.4 34.1 35.9 36.3 Δ to placebo -3.6 -2.2 -4.35 -4.31 p-value 0.1594 0.376 0.1167 0.0842

Fig. 9a. Change from Baseline UHDRS Total Functional Score, 26 weeks, ALL. The table below and Fig. 9a show no significant improvement in UHDRS TFC in all patients treated with pridopidine after 26 weeks. The improvement is confirmed by a higher TFC score.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 18.6 19 18.6 18.8 19.1 Δ to placebo 0.02 0.09 -0.41 -0.1 p-value 0.9511 0.8211 0.277 0.7979

Fig. 9b. Change from Baseline UHDRS Overall Functional Ability Score, 26 weeks, Stage 1, BL TFC 11-13. The table below and Fig. 9b show a trend towards improvement in UHDRS TFC in HD1 patients treated with pridopidine at 52 weeks, especially in patients treated with 45 mg twice daily.________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 22.8 23.9 23 23.1 22.9 Δ to placebo 1.23 1.08 0.87 1.33 p-value 0.0516 0.0696 0.1899 0.0273

Fig. 9s. Change From Baseline UHDRS Score: Independence Scale, 26 weeks, ALL. In the table below and in Fig. 9c shows a significant improvement in UHDRS IS in all patients treated with pridopidine 45 mg after 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 76.4 76.1 74.6 76.3 75.6 Δ to placebo 1.79 oh, s 0.78 1.41 p-value 0.0328 0.7124 0.341 0.0887

Fig. 9d. Change from Baseline UHDRS Score: Independence Scale, 26 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. Figure 9d shows improvement in UHDRS IS in HD1 patients treated with 45 mg twice daily at 26 weeks.________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 83.8 84.1 81.5 84.1 83.1 Δ to placebo 4.94 2.27 1.73 2.38 p-value 0.001 0.1126 0.2738 0.0958

Fig. 9e. Change From Baseline UHDRS Score: Independence Scale, 52 weeks, ALL. The table below and Fig. 9e show no significant improvement in UHDRS IS in all treated patients at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 76.4 76.1 74.6 76.3 75.6 Δ to placebo 0.86 0.25 -0.07 0.18 p-value 0.5082 0.8431 0.9558 0.8871

Fig. 9f. Change from Baseline UHDRS Score: Independence Scale, 52 weeks, Stage 1, BL TFC 11-13. The table below and Fig. 9f show a trend towards improvement in UHDRS IS in HD1 patients treated with 45 mg twice daily at 52 weeks.____________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 83.8 84.1 81.5 84.1 83.1 Δ to placebo 3.05 0.91 1D6 -1.61 p-value 0.1289 0.6415 0.5899 0.4193

Fig. 9g. Housework at 52 weeks, early HD (TFC>7). The table below shows the data and p-values corresponding to FIG. 9g. Significant improvement in TFC: Housework was observed in HD1 and HD2 patients taking 45 mg twice daily for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 1.4 1.5 1.4 1.4 1.4 Δ to placebo 0.24 0.09 0.16 0.04 p-value 0.0196 0.3829 0.1155 0.7145

Fig. 9h. Level of care at 52 weeks, early HD (TFC>7). The table below shows the data and p-values corresponding to FIG. 9h. Significant improvement in TFC: The level of care was observed in patients with HD1 and HD2 who took 45 mg twice a day and 90 mg twice a day of pridopidine for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 2 1.9 2 2 2 Δ to placebo 0.12 0.09 0.08 0.04 p-value 0.0044 0.0319 0.0411 0.403

Fig. 10a. Change from Baseline UHDRS Score: Total Functional Ability, 26 weeks, ALL. In the table below and in Fig. 10a shows a trend towards improvement in UHDRS TFC in all patients treated with pridopidine after 26 weeks._________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 7.9 8.1 7.8 7.8 8 Δ to placebo 0.34 0.21 0.33 0.42 p-value 0.1474 0.3639 0.1465 0.0676

Fig. 10b. Change from baseline UHDRS score: Full functional capacity, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 10b shows improvement in UHDRS IS in HD1 patients treated with pridopidine 45 mg twice daily and 90 mg twice daily for 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 11.8 I,5 I,5 I,7 11.8 Δ to placebo 1.65 0.84 1.43 1.75 p-value 0.004 0.1245 0.0191 0.0019

Fig. 10s. Baseline change in UHDRS: full functional capacity, 52 weeks. In the table below and in Fig. 10c shows the reduction in functional impairment as measured by the TFC scale in all patients treated with 45 mg twice daily for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 7.9 8.1 7.8 7.8 8 Δ to placebo 0.87 oh and 0.19 0.24 p-value 0.0032 0.7042 0.5099 0.4061

Fig. 10d. UHDRS Baseline Change: Total Functional Capacity, 52 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 10d shows a statistically significant reduction in functional impairment as measured by TFC in a HD1 patient treated with pridopidine 45 mg twice daily for 52 weeks._________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline I,8 I,5 I,5 I,7 I,8 Δ to placebo 1.89 -0.03 0.99 1.06 p-value 0.0059 0.9588 0.1678 0.1154

Fig. 10th. Change from baseline UHDRS score: overall functional ability, 52 weeks, stage 2, BL TFC 7-10. In the table below and in Fig. 10e shows a statistically significant reduction in functional impairment as measured by TFC in HD2 patients treated with 45 mg twice daily for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 8.3 8.2 8.4 8.5 8.2 Δ to placebo 0.94 0.64 0.51 0.03 p-value 0.009 0.0924 0.1448 0.9331

Fig. 11a. Change From Baseline UHDRS TFC Score: Finance and ADL, 26 weeks,

ALL. In the table below and in Fig. 11a shows a trend towards improvement in ADL and Finance as measured as part of the UHDRS TFC scale in all patients treated with pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 4 4.1 3.9 4 4 Δ to placebo 0.22 0.16 0.31 0.38 p-value 0.1782 0.3184 0.0543 0.0168

Fig. 11b. Change From Baseline UHDRS TFC Score: Finance & ADL 26 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 11b shows a statistically significant improvement in ADL and Finance as measured as part of the UHDRS TFC scale in HD1 patients treated with all doses of pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 5.8 5.7 5.8 5.9 5.9 Δ to placebo 0.92 0.65 0.97 1.12 p-value 0.0012 0.0168 0.0017 <0001

Fig. 11s. Change from Baseline UHDRS TFC Score: Finance and ADL, 26 weeks, Stage 2, BL TFC 7-10. In the table below and in Fig. 11c shows the statistically significant improvement in ADL and Finance as measured as part of the TFC scale in HD2 patients treated with the highest dose of pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 4.4 4.3 4.4 4.5 4.2 Δ to placebo 0.33 0.26 oh, s 0.46 p-value 0.1492 0.2634 0.1674 0.0459

Fig. 11d. Change from Baseline UHDRS TFC Score: Finance and ADL, 52 weeks, ALL. In the table below and in Fig. 11d shows the statistically significant improvement in ADL and Finance as measured as part of the UHDRS TFC scale in all patients treated with 45 mg two

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 4 4.1 3.9 4 4 Δ to placebo 0.46 OD 0.17 0.1 p-value 0.0164 0.5831 0.3558 0.6018

Fig. 11th. Change From Baseline UHDRS TFC Score: Finance & ADL 52 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 11e shows a statistically significant improvement in ADL and Finance as measured as part of the TFC scale in HD1 patients treated with 45 mg twice daily for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 5.8 5.7 5.8 5.9 5.9 Δ to placebo 0.77 -0.18 0.4 0.64 p-value 0.0277 0.5997 0.2805 0.0697

Fig. 11f. Change from Baseline UHDRS TFC Score: Finance and ADL, 26 weeks, Stage 2 BL TFC 7-10. In the table below and in Fig. 11f shows a statistically significant improvement in ADL and Finance as measured as part of the TFC scale in HD2 patients treated with 45-90 mg twice daily for 26 weeks. ____________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 4.4 4.3 4.4 4.5 4.2 Δ to placebo 0.7 0.54 0.56 0.18 p-value 0.0045 0.0407 0.0199 0.4962

Fig. 12a. Change from Baseline UHDRS TFC Score: Finance, 26 weeks, ALL. In the table below and in Fig. 12a showed no significant improvement in UHDRS TFC: finances in all patients treated with pridopidine after 26 weeks.__________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 1.6 1.8 1.7 1.7 1.7 Δ to placebo 0.1 0.05 0.15 0.21 p-value 0.3629 0.6131 0.1389 0.0449

Fig. 12b. Change from Baseline UHDRS TFC Score: Finance, 26 weeks, Stage 1 BL TFC 11-13. In the table below and in Fig. 12b shows a statistically significant improvement in

UHDRS TFC: Finance in HD1 patients receiving >67.5 mg twice daily for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2.8 2.9 2.8 2.9 2.9 Δ to placebo 0.25 0.31 0.43 0.44 p-value 0.1183 0.0494 0.0162 0.0062

Fig. 12s. Change from Baseline UHDRS TFC Score: Finance 52 weeks. In the table below and in Fig. 12c shows a statistically significant improvement in TFC:Fin in HD1 patients treated with 45 mg twice daily for 52 weeks. __________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 1.6 1.8 1.7 1.7 1.7 Δ to placebo 0.31 0.05 0.16 0.05 p-value 0.0143 0.6644 0.1976 0.7059

Fig. 12d. Change from Baseline UHDRS TFC Score: Finance Week 52, Stage 2, BL TFC 7-10. In the table below and in Fig. 12b shows a statistically significant improvement in UHDRS TFC:Finance in HD2 patients treated with 45 and 90 mg twice daily for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 1.8 1.9 1.9 1.9 1.8 Δ to placebo 0.39 0.23 0.4 0.01 p-value 0.0336 0.24 0.0248 0.9559

Fig. 13a. Change from baseline UHDRS TFC score: Housework, 26 weeks,

ALL. In the table below and in Fig. 13a showed no significant improvement in UHDRS TFC: Housework in all patients treated with pridopidine after 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 1.2 1.3 1.3 1.2 1.2 Δ to placebo -0.01 0.02 0 0.06 p-value 0.9015 0.8331 0.977 0.438

Fig. 13b. Change from baseline UHDRS TFC score: Housework 26 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 13b shows a trend towards improvement in TFC: Homework in HD1 patients treated with pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2 1.8 1.9 1.7 1.9 Δ to placebo 0.34 0.21 0.34 0.47 p-value 0.0589 0.2169 0.0872 0.0079

Fig. 13s. Change from baseline UHDRS TFC score: Housework 52 weeks ALL. In the table below and in Fig. 13c shows no significant improvement in UHDRS TFC: Housework in all patients over 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 59 56 59 62 67 Baseline 1.3 1.3 1.3 1.2 1.2 Δ to placebo 0.23 -0.03 0.05 0.04 p-value 0.0647 0.7825 0.6869 0.7093

Fig. 13 d. Change from baseline UHDRS TFC score: Housework, 52 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 13d shows a statistically significant improvement in TFC: Housework in HD1 patients treated with 45 mg twice daily for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2 1.8 1.9 1.7 1.9 Δ to placebo 0.49 0.05 0.1 0.23 p-value 0.0161 0.7793 0.6442 0.2463

Fig. 14a. Change from baseline UHDRS TFC score: ADL, 26 weeks, ALL. The table below and Fig. 14a show no significant improvement in TFC ADL in all patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.4 2.3 2.2 2.3 2.3 Δ to placebo 0.12 0.09 0.14 0.17 p-value 0.205 0.3427 0.1296 0.0773

Fig. 14b. Change from Baseline UHDRS TFC Score: ADL, 26 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 14b shows a statistically significant improvement in UHDRS TFC: ADL in HD1 patients treated with 45 mg twice daily, 90 mg twice daily, and

112.5 mg twice a day for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 eleven 18 Baseline 2.9 2.8 2.9 3 3 Δ to placebo 0.65 0.34 0.58 0.7 p-value 0.0011 0.0715 0.0062 0.0003

Fig. 14s. Change from baseline UHDRS TFC score: ADL, 52 weeks, ALL. The table below and Fig. 14c show no significant improvement in UHDRS TFC:ADL in all patients treated with pridopidine after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.4 2.3 2.2 2.3 2.3 Δ to placebo 0.14 0.03 -0.01 0.03 p-value 0.2216 0.7943 0.9318 0.7868

Fig. 14d. Change from Baseline UHDRS TFC Score: ADL, 52 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 14d shows a statistically significant improvement in UHDRS TFC: ADL in HD1 patients treated with 45 mg twice daily or 112.5 mg twice daily for 52 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2.9 2.8 2.9 3 3 Δ to placebo 0.62 0.21 0.42 0.46 p-value 0.0044 0.3054 0.0646 0.0345

Fig. 14th. Change from baseline UHDRS TFC score: ADL, 52 weeks, stage 2 BL TFC 7-10. In the table below and in Fig. 14e shows a statistically significant improvement in UHDRS TFC: ADL in HD2 patients treated with 45 mg , twice daily for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 2.6 2.5 2.5 2.5 2.4 Δ to placebo 0.27 0.31 0.16 0.15 p-value 0.0356 0.0244 0.1894 0.2776

Fig. 15a. Change from Baseline UHDRS TFC Score: Level of Care, 52 weeks, ALL. In the table below and in Fig. 15a showed no significant improvement in UHDRS TFC: care level in all patients treated with pridopidine after 52 weeks. _________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 59 56 59 62 67 Baseline 1.9 1.9 1.9 1.9 1.9 Δ to placebo 0.09 0 -0.08 -0.03 p-value 0.1153 0.9365 0.1509 0.5713

Fig. 15b. Change from Baseline UHDRS TFC Score: Level of Care, 52 weeks, Stage 2, BL TFC 7-10. In the table below and in Fig. 15b shows a statistically significant improvement in UHDRS TFC: care rate in HD2 patients treated with 45 mg twice daily for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 1.9 1.9 2 2 2 Δ to placebo 0.13 0.12 0.1 0.03 p-value 0.0156 0.0395 0.0585 0.6168

Fig. 16a. Change From Baseline HD-QoL Score, Participant Total Score, 26 weeks, ALL. The table below and Fig. 16a show no significant improvement in HD-QoL in all patients treated with pridopidine after 26 weeks._________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 68.1 67.3 76.5 73.3 69.9 Δ to placebo 1.91 8.7 6.95 -1.36 p-value 0.6775 0.0572 0.1251 0.7663

Fig. 16b. Baseline change in HD-QoL, Participant Total Score 26 weeks, Stage 2, BL TFC 7-10. In the table below and in Fig. 16b shows a significant improvement in HD-QoL in HD2 patients treated with 67.5 mg twice daily treated with dvidopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 62.5 64.3 82.8 74.3 78 Δ to placebo 3.22 16.33 10.64 4.29 p-value 0.5601 0.0054 0.0566 0.4577

Fig. 17a. Change from Baseline PBA Score Overall Scale 26 weeks, ALL, complete analytic set. In the table below and in Fig. 17a shows the change in baseline PVA General scale in patients treated with pridopidine for 52 weeks._____

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 12 10.9 13.8 AND 2 I,8 Δκ placebo -0.46 -1.83 0.51 -1.85 p-value 0.7838 0.2748 0.7567 0.2659

Fig. 17b. Change from baseline PBA score General scale, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 17b shows a trend towards improvement in the PVA Overall Scale in patients with HD1 treated with pridopidine for 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 8.8 8.1 10.2 4 7.7 Δ to placebo -4.83 -9.22 -4.74 -7.08 p-value 0.319 0.0533 0.3721 0.1351

Fig. 17s. Baseline change in PVA: Depressive mood, severity x frequency, 26 weeks, ALL. The table below and Fig. 17c show no significant improvement in PVA: Depressed mood in all patients treated with pridopidine at 26 weeks.________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 1.5 1.8 1.9 1.2 1.3 Δ to placebo -0.29 -0.65 -0.34 -0.52 p-value 0.4015 0.0583 0.3174 0.1237

Fig. 17d. Change from baseline PBA score: Depressive mood, severity x frequency, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 17d showed no significant improvement in PVA: Depressed mood in HD1 patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 1.9 1.3 2.2 0.8 1.1 Δ to placebo -0.63 -2.01 -0.84 -1.43 p-value 0.5782 0.0704 0.4957 0.1942

Fig. 17th. Change in PVA from baseline on the global scale, 52 weeks, complete assay set. In the table below and in Fig. 17e shows the trend towards improvement in the PVA Overall Scale in patients treated with pridopidine 45 mg twice daily.

N 81 75 79 81 81 Baseline 12 10.9 13.8 AND 2 I,8 Δ to placebo -3.98 -0.63 -0.38 oh, s p-value 0.0603 0.7602 0.851 0.8845

Fig. 17f. Change from baseline PBA score total score, 52 weeks, full assay set BL TFC>7. In the table below and in Fig. 17f shows a trend towards improvement in PVA Overall Scale in HD1 and HD2 patients treated with pridopidine 45 mg twice daily at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline I,4 Yu,1 14.4 10.9 10.4 Δ to placebo -2.74 0.61 0.9 1.4 p-value 0.1911 0.7785 0.6653 0.5171

Fig. 17g. Change from baseline PVA score: Irritability, Severity x Frequency, 52 weeks, ALL. The table below and Fig. 17g show significant improvement in PVA: Irritability in most (except 67.5 mg twice daily) patients treated with pridopidine after 52 weeks. _________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2 1.6 1.7 1.4 1.5 Δ to placebo -1.03 -0.63 -1.01 -0.84 p-value 0.0126 0.1176 0.0108 0.0419

Fig. 17h. Change from Baseline PBA Score Irritability, Severity x Frequency, 52 weeks, Stages 3-5, BL TFC 0-6. In the table below and in Fig. 17 hours shows a significant improvement in PVA: Irritability in HD1 patients treated with pridopidine with a baseline TFC level of 0-6 at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 1.3 0.9 0.9 1.3 1.6 Δ to placebo -2.42 -1.78 -1.79 -1.71 p-value 0.0165 0.0429 0.0422 0.0542

Fig. 17i. Change from baseline PVA score: Lack of initiative (apathy), Severity x Frequency, 26 weeks, ALL. The table below and Fig. 17i show no significant improvement in PVA: Apathy, in all patients treated with pridopidine, after 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.6 2.5 3.1 2.9 3 Δ to placebo -0.87 -0.53 -0.2 -0.26 p-value 0.1235 0.3437 0.7198 0.6445

Fig. 17j. Change from baseline PVA score: Lack of initiative (apathy), Severity x Frequency, 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 17j shows a trend towards improvement in PVA: Apathy in HD1 patients treated with pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 1.2 1 1.3 0.4 1.5 Δ to placebo -1.85 -1.51 -1.46 -2.62 p-value 0.0703 0.1267 0.1822 0.0089

Fig. 17k. Change from baseline PVA score: Lack of initiative (apathy), Severity x Frequency, 52 weeks, full analytic set. In the table below and in Fig. 17k shows a trend towards improvement in PVA: Apathy in patients with BL stage 1 treated with pridopidine for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily placebo N 81 75 79 81 81 Baseline 2.6 2.5 3.1 2.9 3 Δ to placebo -1.27 0.26 -0.12 -0.04 p-value 0.0704 0.7052 0.8599 0.9523

Fig. 171 Change in PVA from Baseline in PVA: Lack of Initiative (Apathy), Severity x Frequency, 52 weeks, 1 BL TFC > 7. In the table below and in FIG. 171 shows an improvement trend in PVA: Apathy in HD1 and HD2 patients treated with pridopidine for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily placebo N 62 59 54 56 58 Baseline 2.5 2 3 2.7 2.8 Δ to placebo -1.39 -0.29 -0.02 0.26 p-value 0.0608 0.703 0.9734 0.7346

Fig. 17sh. Change From Baseline PVA Score: Obsessive-Compulsive, Severity x Frequency, 26 weeks, ALL. The table below and Fig. 17m show no significant improvement in PVA O-C in all patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 1.2 1.1 1.3 1.1 1 Δ to placebo 0.1 -0.45 -0.12 -0.63 p-value 0.8081 0.2512 0.7541 0.1061

Fig. 17p. Change from Baseline PVA Score: Obsessive-Compulsive, Severity x Frequency, 26 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 17p shows a statistically significant improvement in PVA O-C in patients with HD1 treated with pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 0 1 0.4 0.1 0.1 Δ to placebo -2.11 -2.03 -1.71 -1.73 p-value 0.0035 0.0035 0.0251 0.0114

Fig. 17j. Change from Baseline PVA Score: Obsessive-Compulsive, Severity x Frequency, 52 weeks, ALL. In the table below and in Fig. 17j showed no significant improvement in PVA O-C in all patients treated with pridopidine after 52 weeks.______

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 1.2 1.1 1.3 1.1 1 Δ to placebo -0.24 -0.28 -0.13 -0.12 p-value 0.5733 0.5068 0.7508 0.7789

Fig. 17r. Change from Baseline PVA Score: Obsessive-Compulsive, Severity x Frequency, 52 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 17p shows a statistically significant improvement in PVA O-C in patients with HD1 who received pridopidine for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 0 1 0.4 OD OD Δ to placebo -2.73 -3.24 -2.47 -2.73 p-value 0.007 0.0011 0.021 0.005

Fig. 17q. Change from baseline PVA score: Disoriented Behavior, Severity x Frequency, 26 weeks, ALL. In the table below and in Fig. 17q showed no significant improvement in PVA: Confused Behavior in all patients treated with pridopidine after weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 0.6 0.4 0.8 0.6 0.6 Δ to placebo -0.2 -0.28 -0.09 -0.08 p-value 0.2864 0.1357 0.607 0.6771

Fig. 17r. Change from Baseline PVA Score: Confused Behavior, Severity x Frequency, 26 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 17r shows a significant improvement in PVA: Confused Behavior in HD1 patients treated with pridopidine 45 mg twice daily or 112.5 mg twice daily.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 0.1 0 0.3 0 0.3 Δ to placebo -0.19 -0.16 -0.16 -0.18 p-value 0.0381 0.0615 0.093 0.0357

Fig. 18a. Change From Baseline in Stand Up and Walk Time Test (s), 26 weeks, ALL. The table below and Fig. Figure 18a shows no significant improvement in the Time to Get Up and Walk test in all patients treated with pridopidine after 26 weeks.________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 12.1 12.1 10.4 10.3 I,6 Δ to placebo -2.16 -0.09 -1.54 -2.33 p-value 0.1765 0.9571 0.3255 0.1456

Fig. 18b. Change from baseline in the Get up and walk time test (c), 26 weeks, stage 1, BL TFC 11-13. In the table below and in Fig. 18b shows a trend towards improvement in the Stand and Walk time test in HD1 patients treated with pridopidine at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 9.7 8.6 8.7 9.6 9.4 Δ to placebo -6.98 -5.59 -5.87 -7.24 p-value 0.0612 0.1259 0.1498 0.0482

Fig. 18s. Change from Baseline in the Get Up and Walk Time Test (s) at Week 52. In the table below and in FIG. 18c shows no statistically significant improvement in the Get Up and Walk time test in all patients treated with pridopidine at 52 weeks. .

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 12.1 12.1 10.4 10.3 I,6 Δ to placebo -1.49 -0.74 0.22 -0.47 p-value 0.0899 0.4022 0.7918 0.595

Fig. 18d. Change from baseline on the Get Up and Walk Time Test (s), 52 weeks, Stage 1, BL TFC 11-13. In the table below and in Fig. 18d shows the trend of improvement in the Stand and Walk time test in HD1 patients treated with pridopidine at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 9.7 8.6 8.7 9.6 9.4 Δ to placebo -5.26 -4.65 -4.02 -5.13 p-value 0.0627 0.0921 0.1859 0.0652

Fig. 19a. Change From Baseline Walk-12 Total Scale, 26 weeks, ALL. The table below and Fig. 19a show no significant improvement in Walk-12 TS in all patients treated with pridopidine after 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 31.5 32.1 32.8 29.7 29.7 Δ to placebo -2.45 0.13 1.7 -4.71 p-value 0.3359 0.9604 0.4931 0.0622

Fig. 19b. Change From Baseline Walk-12 Overall Scale, 26 weeks, Stage 1 BL TFC 11-13. In the table below and in Fig. 19b shows a statistically significant improvement in Walk-12 TS in HD1 patients treated with pridopidine after 26 weeks. _________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 21.2 6.3 12.3 17.7 13 Δ to placebo -9.63 -7.45 -10.88 -9.38 p-value 0.0241 0.054 0.0116 0.0173

Fig. 19s. Change from baseline Walk-12 Total scale 26 weeks, stage 3-5 BL TFC 0-6. The table below and Fig. 19c show no significant improvement in Walk-12 TS in late stage patients treated with pridopidine (BL TFC 0-6) at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 56.6 55.4 48.3 39.6 45.9 Δ to placebo -1.97 -4.7 -3.18 -14.22 p-value 0.7524 0.4242 0.5934 0.0151

Fig. 19d. Change From Baseline Walk-12 Total Scale, 52 weeks, ALL. The table below and Fig. 19d show no statistically significant improvement in Walk-12 TS in patients treated with pridopidine after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 31.5 32.1 32.8 29.7 29.7 Δ to placebo 1.62 3.01 2.53 0.56 p-value 0.6486 0.3891 0.4587 0.8738

Fig. 19th. Change From Baseline Walk-12 Overall Scale 52 weeks, Stage 1 BL TFC 11-13. The table below and Fig. 19e show a statistically significant improvement in Walk-12 TS in HD1 patients treated with pridopidine 90 mg twice daily after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 21.2 6.3 12.3 17.7 13 Δ to placebo -5.86 -8.57 -13.6 -4.13 p-value 0.3018 0.1032 0.0193 0.4534

Fig. 20a. Change from Baseline UHDRS Score: Independence Scale, 26 weeks, BL TFC<7. The table below and Fig. 20a show no significant improvement in UHDRS IS in pridopidine-treated patients with BL TFC less than 7, at 26 weeks.____

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 65.5 63.8 64.8 68.2 66.3 Δ to placebo 0.3 -0.44 0.2 1.65 p-value 0.8796 0.8027 0.9116 0.3578

Fig. 20b. Change From Baseline UHDRS Score: Independence Scale, 26 weeks,

BL TFC>7. In the table below and in Fig. 20b shows a statistically significant improvement in UHDRS IS in HD1 and HD2 patients treated with pridopidine 45 mg twice daily at 26 weeks.

45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 59 54 56 58 Wk26 Δ to placebo 2.22 0.99 1.48 1.51 p-value 0.0128 0.2755 0.0949 0.0919

Fig. 20s. Change from Baseline UHDRS Score: Independence Scale, 52 weeks, BL TFC<7. In the table below and in Fig. 20c shows no significant improvement in UHDRS IS in pridopidine-treated HD1 patients with a baseline TFC of less than 7 through. 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 65.5 63.8 64.8 68.2 66.3 Δ to placebo -1.85 -3.46 -5.25 -0.52 p-value 0.5799 0.2415 0.0779 0.8613

Fig. 20d. Change From Baseline UHDRS Score: Independence Scale, 52 weeks,

- 23 041256

BL TFC>7. In the table below and in Fig. 20d shows a statistically significant improvement in UHDRS IS in HD1 and HD2 patients treated with pridopidine 90 mg twice daily at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 79.8 79.4 79.2 79.9 79.3 Δ to placebo 1.99 2.22 2.79 0.44 p-value 0.1047 0.0788 0.0228 0.7301

Fig. 21a-21p, 22a-22b, 23a-23b, 24a-24b are graphs comparing characteristics of patients with HD at an early stage (TFC>7, HD1 and HD2) or at a late stage (TFC<7).

Fig. 21a. Change from baseline UHDRS score: overall functional ability, 26 weeks, BL TFC<7. The table below and Fig. 21a show no significant improvement in UHDRS TFC in late stage patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 8.9 9.2 9.4 9.1 9.3 Δ to placebo 0.56 0.33 0.61 0.67 p-value 0.0359 0.215 0.0199 0.0125

Fig. 21b. Change from baseline UHDRS score: overall functional ability, 26 weeks, BL TFC>7. In the table below and in Fig. 21b shows a statistically significant improvement in UHDRS TFC in HD1 and HD2 patients treated with pridopidine 45 mg twice daily and greater than 90 mg twice daily and above, at 26 weeks. ____________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 8.9 9.2 9.4 9.1 9.3 Wk26 Δ to placebo 0.56 0.33 0.61 0.67 p-value 0.0359 0.215 0.0199 0.0125

Fig. 21s. Change from Baseline UHDRS TFC Score: Finance and ADL, 26 weeks, BL TFC<7. In the table below and in Fig. 21c showed no significant improvement in UHDRS TFC:Finance and ADL in advanced patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 2 2 1.9 2.2 2.3 Δ to placebo -0.34 -0.06 0.28 0.03 p-value 0.3239 0.8408 0.3747 0.9361

Fig. 21d. Change from Baseline UHDRS TFC Score: Finance and ADL, 26 weeks, BL TFC>7. In the table below and in Fig. 21d shows a statistically significant improvement in UHDRS:Finance and ADL in HD1 and HD2 patients treated with pridopidine 45 mg twice daily and 90 mg twice daily or more after 26 weeks. .____________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 4.6 4.7 4.9 4.8 4.7 Δ to placebo 0.46 0.32 0.47 0.62 p-value 0.0114 0.0817 0.0093 0.0007

Fig. 21st. Change from Baseline UHDRS TFC Score: Finance, 26 weeks, BL TFC<7. In the table below and in Fig. 21e did not show a significant improvement in UHDRS TFC:Finance in patients with advanced stage treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 0.5 0.5 0.5 0.7 0.7 Δ to placebo -0.19 -0.1 0.05 0.03 p-value 0.3508 0.5934 0.774 0.8925

Fig. 21f. Change from Baseline UHDRS TFC Score: Finance 26 weeks, BL TFC>7. In the table below and in Fig. 21f shows a statistically significant improvement in UHDRS TFC:Finance in HD1 and HD2 patients treated with pridopidine 90 mg twice daily and above at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 2 2.2 2.2 2.1 2.2 Δ to placebo 0.2 0.16 0.27 0.33 p-value 0.0853 0.1865 0.0236 0.0061

Fig. 21g. Change from baseline UHDRS TFC score: ADL, 26 weeks, BL TFC<7.

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The table below and Fig. 21g show no significant improvement in UHDRS TFC: ADL in late stage patients treated with pridopidine at 26 weeks.___________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 1.5 1.5 1.4 1.5 1.7 Δ to placebo -0.19 -0.04 0.18 -0.04 p-value 0.3596 0.8518 0.3507 0.8438

Fig. 21h. Change from baseline UHDRS TFC score: ADL, 26 weeks, BL TFC>7. In the table below and in Fig. 21h shows a statistically significant improvement in UHDRS TFC: ADL in HD1 and HD2 patients treated with pridopidine 45 mg twice daily and 90 mg twice daily and above after 26 weeks. __________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 2.6 2.6 2.6 2.6 2.6 Δ to placebo 0.24 0.16 0.19 0.27 p-value 0.0176 0.1132 0.0526 0.0076

Fig. 21i. Change from baseline UHDRS score: overall functional ability, 52 weeks, BL TFC<7. In the table below and in Fig. 21i showed no significant improvement in UHDRS IS in pridopidine-treated advanced patients after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 4.5 4.1 4.5 4.9 4.7 Δ to placebo 0.07 -0.5 -0.64 0.1 p-value 0.9108 0.3933 0.2828 0.8605

Fig. 21j. Change in UHDRS: overall functional ability, 52 weeks, BL TFC>7. In the table below and in Fig. 21j shows the slowdown in functional decline measured by UHDRS TFC in HD1 and HD2 patients treated with pridopidine 45 mg twice daily and 90 mg twice daily after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 8.9 9.2 9.4 9.1 9.3 Wk52 Δ to placebo 1.16 0.36 0.71 0.27 p-value 0.0003 0.2704 0.0239 0.4144

Fig. 21k: Change from Baseline UHDRS TFC Score: Finance & ADL, 52 weeks, BL TFC<7. In the table below and in Fig. 21k showed no significant improvement in UHDRS TFC: ADL finance in late stage patients treated with pridopidine at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 2 2 1.9 2.2 2.3 Δ to placebo 0.01 -0.25 -0.29 -0.22 p-value 0.9863 0.497 0.4368 0.5626

Fig. 21l: Change from baseline UHDRS TFC score: Finance and ADL, 52 weeks, BL TFC>7. In the table below and in Fig. 21l shows a statistically significant improvement in UHDRS TFC: ADL finance in HD1 and HD2 patients treated with pridopidine 45 mg twice daily and 90 mg twice daily at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 4.6 4.7 4.9 4.8 4.7 Δ to placebo 0.72 0.27 0.53 0.36 p-value 0.0004 0.1926 0.0088 0.0841

Fig. 21m. Change from Baseline UHDRS TFC Score: Finance Week 52, BL TFC<7. In the table below and in Fig. 21m shows no significant improvement in UHDRS TFC: finances in pridopidine-treated, advanced stage patients at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 0.5 0.5 0.5 0.7 0.7 Δ to placebo 0.29 0.07 0.02 0.04 p-value 0.2468 0.7631 0.9318 0.8543

Fig. 21n. Change from Baseline UHDRS TFC Score: Finance, 52 weeks, BL TFC>7. In the table below and in Fig. 21n shows a statistically significant improvement in UHDRS IS in HD1 and HD2 patients treated with pridopidine 45 mg twice daily and 90 mg twice daily through

- 25 041256 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 2 2.2 2.2 2.1 2.2 Δ to placebo 0.35 0.07 0.31 0.12 p-value 0.0171 0.6373 0.0332 0.4466

Fig. 21j. Change from baseline UHDRS TFC score: ADL, 52 weeks, BL TFC<7. The table below and Fig. 21j show no significant improvement in UHDRS TFC:ADL in late stage patients.

weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 1.5 1.5 1.4 1.5 1.7 Δ to placebo -0.33 -0.4 -0.39 -0.32 p-value 0.178 0.0671 0.073 0.1393

Fig. 21r. Change from baseline UHDRS TFC score: ADL, 52 weeks, BL TFC>7. In the table below and in Fig. 21p shows a statistically significant improvement in UHDRS TFC: ADL in HD1 and HD2 patients treated with pridopidine 45 mg twice daily after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 2.6 2.6 2.6 2.6 2.6 Wk52 Δ to placebo 0.35 0.22 0.21 0.23 p-value 0.0019 0.0598 0.0545 0.0493

Fig. 22a. Change from baseline PBA score Irritability, Severity x Frequency, 52 weeks, BL TFC<7. In the table below and in Fig. 22a shows a statistically significant improvement in PBA irritability in late stage patients treated with pridopidine after 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 1.3 0.9 0.9 1.3 1.6 Δ to placebo -2.42 -1.78 -1.79 -1.71 p-value 0.0165 0.0429 0.0422 0.0542

Fig. 22b. Change from baseline PBA score Irritability, Severity x Frequency, 52 weeks, BL TFC>7. In the table below and in Fig. 22b shows a statistically significant improvement in PVA: Irritability in HD1 and HD2 patients treated with pridopidine 90 mg twice daily after 52 weeks. __________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 2.1 1.8 2.1 1.4 1.4 Wk52 Δ to placebo -0.59 -0.33 -0.95 -0.6 p-value 0.1789 0.466 0.0311 0.1927

Fig. 23a. Change from baseline on Stand and Walk time test (c) 26 weeks, BL TFC<7. In the table below and in Fig. 23a showed no significant improvement in the Time to Get Up and Walk test in advanced stage patients treated with pridopidine at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 18.9 13.8 I,9 I,5 16.2 Δ to placebo 0.5 6.24 1.23 -0.99 p-value 0.9181 0.1715 0.7846 0.8295

Fig. 23b. Change from baseline on Stand and Walk time test (c) 26 weeks, BL TFC>7. In the table below and in Fig. 23b shows a statistically significant improvement in PVA: Irritability in HD1 and HD2 patients treated with pridopidine 112.5 mg twice daily at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 10 I,7 9.7 9.8 9.8 Δ to placebo -2.09 -2.41 -2.37 -2.84 p-value 0.1397 0.0933 0.0896 0.0478

Fig. 24a. Change From Baseline HD-QoL Score, Participant Total Score, 26 weeks, BL TFC<7. The table below and Fig. 24a show no significant improvement in HD-QoL TS in late stage patients treated with pridopidine after 26 weeks.

- 26 041256

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 94.7 113.1 86.3 83 79.5 Δ to placebo 4.87 1 2.61 -4.33 p-value 0.6958 0.9304 0.817 0.7016

Fig. 24b. Change from Baseline HD-QoL Score, Participant Total Score, 26 weeks, BL TFC>7. In the table below and in Fig. 24b shows a statistically significant improvement in PVA: Irritability in HD1 and HD2 patients treated with pridopidine 67.5 mg twice daily after 26 weeks. _________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 61.2 55.1 73.5 68.8 67.3 Δ to placebo 0.51 10.63 5.17 -0.99 p-value 0.9144 0.0284 0.2834 0.8365

Fig. 25a-25e show histograms of changes in UHDRS TMS: Finger Press scores in the 26 and 52 week patient groups.

Fig. 25a. Change from baseline UHDRS TMS score: Finger pressure, ALL, 26 weeks. The table below lists the p-values corresponding to FIG. 25 a. In the table below and in Fig. 25a showed no significant improvement in UHDRS TMS: Finger pressing in all patients treated with pridopidine after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.8 3.5 4.1 3.7 3.9 Δ to placebo -o,z -0.07 -0.07 -0.12 p-value 0.1466 0.7306 0.7114 0.5475

Fig. 25b. Change from Baseline UHDRS TMS Score: Finger Press: Patients at week 26 with Baseline Total Functional Capacity (BL TFC) >9 and CAG repeat count >44. The table below shows the p-values corresponding to FIG. 25b. In the table below and in Fig. 25b shows a statistically significant improvement in UHDRS TMS: Finger pressing in patients taking 45 mg twice daily and receiving 112.5 mg twice daily in patients with BL TFC greater than or equal to 9 and the number of CAG repeats in the htt gene greater than 44 at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 13 15 19 22 AND Baseline 2.6 2.7 3.3 3 3.6 Δ to placebo -0.86 -0.34 -0.52 -1.07 p-value 0.0499 0.4255 0.1972 0.0424

Fig. 25s. Change from baseline UHDRS TMS score: Fingertip: 26 weeks, patients with BL TFC>9, CAG repeats <44, and patients who present the three least severe quarters of TMS (BL TMS 1st 3 Qs). The table below lists the p-values corresponding to FIG. 25s. In the table below and in Fig. 25 s shows a statistically significant improvement in UHDRS TMS: Finger pressing in patients who took 45 mg twice a day and received 112.5 mg twice a day, in patients with BL TFC greater than or equal to 9 and the number of CAG repeats in the htt gene less than 44, after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 13 15 19 21 10 Baseline 2.6 2.7 3.3 3 3.5 Δ to placebo -0.87 -0.36 -0.54 -1.05 p-value 0.05 0.41 0.1888 0.0537

Fig. 25d. Change from baseline UHDRS TMS score: Finger pressure: Patients who completed 52 weeks of treatment: UHDRS TMS score: Finger pressure at 26 weeks. The table below lists the p-values corresponding to FIG. 25d. In the table below and in Fig. 25d shows a statistically significant improvement in UHDRS TMS: Finger Press in patients treated with pridopidine 45 mg twice daily who completed 52 weeks at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 52 43 44 53 44 Baseline 3.8 3.2 4 3.5 3.8 Δ to placebo -0.59 -0.13 -0.01 -0.21 p-value 0.0182 0.5881 0.9554 0.3833

Fig. 25th. Change from baseline UHDRS TMS score: Finger pressure: Patients who completed 52 weeks of treatment: UHDRS TMS score: Finger pressure at 52 weeks. The table below lists the p-values corresponding to FIG. 25th. The table below and Fig. 25e show no significant improvement in UHDRS TMS: Finger pressure in ALL patients treated with pridopidine at 52 weeks. __________________________________________________

With placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 52 43 44 53 44 Baseline 3.8 3.2 4 3.5 3.8 Δ to placebo -0.31 0.13 0.08 0.1 p-value 0.2091 0.6027 0.7179 0.6835

Fig. 26a. Change from baseline UHDRS TMS score: Finger tapping+pronation-supination of hands: patients who completed 52 weeks of treatment - score at week 26. The table below lists the p-values corresponding to FIG. 26a. In the table below and in Fig. 26a shows a statistically significant improvement in UHDRS TMS: Finger tapping+pronation/supination of hands in 45 mg twice daily pridopidine treated patients who completed 52 weeks at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 52 43 44 53 44 Baseline 7.1 6.1 7 6.5 7 Δ to placebo -0.79 0.02 0.02 -0.23 p-value 0.0294 0.9443 0.9412 0.5268

Fig. 26b. Change from baseline UHDRS TMS score: Finger tapping+pronation-supination of hands: patients who completed 52 weeks of treatment score at week 52. The table below lists the p-values corresponding to FIG. 26b. In the table below and in Fig. 26b showed no significant improvement in UHDRS TMS: Finger tapping+pronation-supination of hands in patients treated with pridopidine at week 26.________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 52 43 44 53 44 Baseline 7.1 6.1 7 6.5 7 Δ to placebo -0.37 0.68 0.48 0.28 p-value 0.3801 0.1066 0.2337 0.4978

Fig. 27a. Change from baseline UHDRS TMS score: Gait and Balance: Gait and balance scores at week 26 for patients with BL TFC>7. The table below shows the p-values corresponding to FIGS. 27a. In the table below and in Fig. 27a shows a statistically significant improvement in UHDRS TMS: Gait and balance in HD1 and HD2 patients treated with pridopidine 90 mg twice daily after 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 3.2 3.7 3.4 3.5 3.1 Δ to placebo -0.48 -0.37 -0.62 -0.49 p-value 0.0563 0.1442 0.013 0.0518

Fig. 27b. Change from baseline UHDRS TMS score: Gait and balance: Gait and balance score at week 52 for patients with BL TFC>7. The table below lists the p-values corresponding to FIG. 27b. The table below and Fig. 27b show no significant improvement in UHDRS TMS: Gait and Balance in HD1 and HD2 patients treated with pridopidine at 52 weeks. _________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 3.2 3.7 3.4 3.5 3.1 Δ to placebo -0.41 -0.43 -0.28 -0.09 p-value 0.1811 0.1691 0.365 0.7719

In FIG. 28a-28d are histograms showing change from baseline in UHDRS TMS: Dystonia scores in patient groups at 26 and 52 weeks.

Fig. 28a. Change from baseline UHDRS TMS score: Dystonia, ALL: UHDRS TMS: Dystonia at week 26 in all patients. The table below lists the p-values corresponding to FIG. 28 a. No significant improvement is observed.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 4.1 3.6 4.1 4.9 4.5 Δ to placebo -0.06 -0.34 -0.33 -0.29 p-value 0.8711 0.3778 0.3845 0.4507

Fig. 28b. Change from baseline UHDRS TMS score: Dystonia: UHDRS TMS: Dystonia for patients with BL TFC>9 and CAG repeat count <44 at week 26. Table

- 28 041256 p-values corresponding to FIG. 28b. Patients with baseline TFC greater than or equal to 9 show statistically significant improvement in UHDRS TMS scores: Dystonia at 45 mg twice daily, 67.5 twice daily, and 90 mg twice daily for pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 13 15 19 22 AND Baseline 3.8 1.7 2.8 3.4 1.9 Δ to placebo -1.54 -1.58 -1.72 -1.4 p-value 0.0313 0.0191 0.0078 0.0847

Fig. 28s. Change from Baseline UHDRS TMS Score: Dystonia: UHDRS TMS Score: Dystonia for patients with <44 CAG repeats and BL TMS 1x3 Q at 26 weeks. The table below lists the p-values corresponding to FIG. 28s. Patients with baseline TMS who represent three less severe quarters of TMS and have fewer than 44 CAG repeats in their htt gene show a statistically significant improvement in UHDRS TMS scores: Dystonia at 45 mg twice daily, 67.5 twice daily day and 90 mg twice a day of pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 29 29 32 37 22 Baseline 3 2.6 2.6 2.9 2.6 Δ to placebo -1.04 -1.15 -1 -0.62 p-value 0.0437 0.0235 0.0399 0.2655

Fig. 28d. Change from Baseline UHDRS TMS Score: Dystonia: UHDRS TMS Scores: Dystonia for patients with BL TFC>9 and CAG repeat count <44 and BL TMS 1x3 Qs at 26 weeks. The table below lists the p-values corresponding to FIG. 28d. Patients with baseline TFC greater than or equal to 9, baseline TMS representing the three least severe quarters of TMS, and fewer than 44 CAG repeats in their htt genes show statistically significant improvement in UHDRS TMS scores: Dystonia at 45 mg twice daily 67, 5 mg twice a day and 90 mg twice a day of pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 13 15 19 21 10 Baseline 3.8 1.7 2.8 3.1 2.1 Δ to placebo -1.53 -1.6 -1.64 -1.29 p-value 0.0349 0.02 0.0132 0.1276

Fig. 29a, 29b and 29c are bar graphs showing changes from baseline Gait and balance at week 12 (29a); 20 weeks (29b); and 26 weeks (29c). The y-axis is the change in UHDRS TMS score: Gait and balance.

Fig. 30 is a graph showing change from baseline in UHDRS TFC score over 26 weeks when treated with pridopidine and placebo. Data for 112.5 mg twice daily is shown on the top line of this graph, and data for placebo is shown on the bottom line of this graph. The difference in p-value of pridopidine 112.5 mg twice daily from placebo was 0.1498 at week 4, 0.6065 at week 12, 0.3238 at week 20, and 0.0676 at week 26. An increase in change in UHDRS TFC is indicative of a delay/reduction in deterioration in functional ability.

In FIG. 31a-31n are bar graphs or line charts showing changes from baseline in UHDRS TFC scores in the 26 and 52 week patient groups.

Fig. 31a and 31b show the change from baseline in UHDRS TFC scores over time. Y-axes represent changes in TFC score, X-axes represent pridopidine treatment time in weeks. In FIG. 31a shows the trend in the full assay set at 52 weeks. Fig. 31b shows trends in patients with BL TFC>7 (n=54-62).

Fig. 31s. Change from Baseline UHDRS Score: Overall Functional Capacity for BL Patients with <44 CAG Repeat Count at Week 26. The table below lists the p values corresponding to FIG. 31s.______________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 37 37 38 42 29 Baseline 7.4 7.9 8.5 8.3 7.9 Δ to placebo 0.6 0.43 0.79 0.38 p-value 0.056 0.1707 0.0102 0.2643

Fig. 31d. Change from Baseline UHDRS Score: Total Functional Capacity for Patients with BL TFC>9 or CAG Repeat <44 at Week 26. The table below lists the p-values corresponding to FIG. 31 d.

- 29 041256

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 56 56 53 52 49 Baseline 8.5 8.8 8.9 8.7 9.1 Δ to placebo 0.56 0.18 0.67 0.38 p-value 0.0321 0.5069 0.0117 0.1665

Fig. 31st. Change from Baseline UHDRS Score: Total Functional Ability for BL Patients with <44 CAG Repeat Counts and 1 x 3 Qs BL TMS at Week 26. The table below lists the p-values corresponding to FIG. 31st. ______________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 29 29 32 37 22 Baseline 8 8.7 9 8.6 8.6 Δ to placebo 0.73 0.47 0.71 0.48 p-value 0.0469 0.1952 0.0405 0.2324

Fig. 31f. Change from Baseline UHDRS Score: Overall Functional Capacity for BL patients with <44 CAG repeats or 1 x 3 Qs BL TMS at week 26 (baseline TMS in first 3 quartiles). The table below lists the p-values corresponding to FIG. 31f.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 69 65 66 66 68 Baseline 8.1 8.4 8.3 8.3 8.5 Δ to placebo 0.36 0.18 0.52 0.51 p-value 0.1493 0.4727 0.0349 0.0379

Fig. 31g. Change from baseline in UHDRS: overall functional ability for patients with mean BL TFC or CAG repeat count <44 at week 26, or 1 x 3 Qs BL TMS at week 26. The table below lists the p-values corresponding to FIG. 31g.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 71 67 66 66 69 Baseline 8.2 8.5 8.3 8.3 8.5 Δ to placebo 0.36 0.21 0.55 0.53 p-value 0.1423 0.3863 0.0244 0.0289

Fig. 31h. Change from baseline UHDRS score: total functional ability for patients with BL TFC>9 or 1 x 3 Qs BL TMS at 26 weeks. The table below lists the p-values corresponding to FIG. 31h._____________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N thirty 32 34 31 29 Baseline 10.3 10.5 10.4 10.3 10.9 Δ to placebo 0.69 0.01 0.54 0.6 p-value 0.0601 0.9741 0.1371 0.1136

Fig. 32. Graph showing change from baseline in TFC scores: finances and ADL at 26 weeks for treatment with pridopidine and placebo. Data for 112.5 mg twice daily is shown on the top line of this graph, and data for placebo is shown on the bottom line of this graph. The difference in p-value for pridopidine 112.5 mg twice daily compared with placebo was 0.4382 at week 4, 0.6636 at week 12, 0.4437 at week 20, and 0.0125 at week 26. An increase in changes in TFC: finance and ADL indicates a decrease in impairment of functional capacity.

Fig. 33a, 33b and 33c. change from baseline in TFC scores in HD patients treated with pridopidine. Doses at week 12 (FIG. 33a), week 20 (FIG. 33b), and week 26 (FIG. 33c). The adjusted score means +SE changes in TFC for the complete analysis set.

Fig. 34a, 34b and 34c. change from baseline in TFC scores: finances and ADL in HD patients treated with pridopidine. Doses at week 12 (34a), week 20 (34b) and week 26 (34c). The adjusted score means +SE changes in TFC: Finance and ADL for the full analysis set.

Fig. 35a-35s are bar graphs showing changes from baseline UHDRS TFC: Finance and UHDRS TFC: Finance and ADL scores in 26- and 52-week patient groups according to quartiles.

Fig. 35a. Change from Baseline UHDRS TFC Score: Finance for 1st Q TMS Patients (First Least Severe Quarter of TMS) at Week 26. The table below shows the p-values corresponding to FIGS. 35 a. Significant improvement in TFC: Financials in patients with the first least severe quarter of TMS treated with pridopidine 45 mg twice daily for 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 21 24 20 25 15 Baseline 2.2 2.1 2.3 2.2 2.6 Δ to placebo 0.38 0.27 0.26 0.63 p-value 0.0347 0.1556 0.1336 0.0038

Fig. 35b. Change from baseline UHDRS TFC score: finances for 1st Q TMS patients at 52 weeks. The table below lists the p-values corresponding to FIG. 35b. An improvement trend in TFC:Finance was observed in patients with the first least severe quarter of TMS treated with 45 mg for 52 weeks.

twice in

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 21 24 20 25 15 Baseline 2.2 2.1 2.3 2.2 2.6 Δ to placebo 0.43 0.25 0.21 0.32 p-value 0.0673 0.3084 0.3653 0.2369

Fig. 35s. Change from baseline UHDRS TFC score: finances for patients with 1x 2Qs TMS (first two least severe quarters of TMS) at week 26. The table below lists the p values corresponding to FIG. 35s. An improvement trend in TFC:Finance was observed in patients in the first two least severe quarters of TMS treated with pridopidine 45 mg twice daily for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 42 44 39 40 43 Baseline 2 2.1 2.2 2.1 2.1 Δ to placebo 0.33 0.04 0.14 -0.06 p-value 0.0566 0.8406 0.4275 0.7529

Fig. 35d. Change from baseline UHDRS TFC score: finances for patients with 1x 2Qs TMS at 52 weeks. The table below lists the p-values corresponding to FIG. 35d. Significant improvement in TFC:Finance was observed in patients in the first two least severe quarters of TMS treated with pridopidine 45 mg twice daily, for 52 weeks. __________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 42 44 39 40 43 Baseline 2 2.1 2.2 2.1 2.1 Δ to placebo 0.29 0.15 0.23 0.2 p-value 0.0299 0.2941 0.0994 0.1432

Fig. 35th. Change from baseline UHDRS TFC score: finances for patients with 1x 3Qs TMS at week 26. The table below lists the p-values corresponding to FIG. 35 e. Trend to improve TFC: finances in patients in the first three least severe quarters of TMS treated with pridopidine 45 mg twice daily for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 58 59 62 58 62 Baseline 1.8 2 1.9 1.9 2 Δ to placebo 0.12 0.03 0.22 0.26 p-value 0.315 0.8115 0.0665 0.0323

Fig. 35f. Change from Baseline UHDRS TFC Score: Finance for TMS Patients 1x 3Qs at Week 52. The table below lists the p-values corresponding to FIG. 35f. Significant improvement in TFC:Finance was observed in patients in the first three least severe quarters of TMS treated with pridopidine 45 mg twice daily for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 58 59 62 58 62 Baseline 1.8 2 1.9 1.9 2 Δ to placebo 0.39 0.01 0.17 0.05 p-value 0.0072 0.97 0.2295 0.7396

Fig. 35 g. Change from baseline UHDRS TFC score: finances and ADL for patients with BL TFC>9 at 26 weeks. The table below lists the p-values corresponding to FIG. 35g. Significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily and 90 mg twice daily and had a baseline TFC level greater than or equal to 9 for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 32 34 34 32 31 Baseline 5.2 5.1 5.4 5.4 5.4 Δ to placebo 0.53 0.23 0.51 0.57 p-value 0.0143 0.2874 0.0197 0.0109

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Fig. 35h. Change from baseline UHDRS TFC score: finances and ADL for BL patients with >44 CAG repeat count at week 26. The table below lists the p-values corresponding to FIG. 35h. A significant improvement in TFC: finances and ADL was observed in patients taking pridopidine 45 mg twice daily and 90 mg twice daily and having more than 44 CAG repeats in their htt gene for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 37 37 38 42 29 Baseline 3.7 4.1 4.2 4.2 4.1 Δ to placebo 0.55 0.21 0.67 0.47 p-value 0.017 0.3497 0.0026 0.0597

Fig. 35i. Change from Baseline UHDRS TFC Score: Finance and ADL for Patients with BL TFC >9 and CAG Repeat >44 at Week 26. The table below shows the p-values corresponding to FIG. 35i. Significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily and 90 mg twice daily and had a baseline TFC level greater than or equal to 9 and greater than 44 CAG repeats in their htt gene during 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 13 15 19 22 AND Baseline 5.1 5.2 5.5 5.4 5.5 Δ to placebo 0.74 0.57 0.83 1.02 p-value 0.0296 0.083 0.0089 0.0094

Fig. 35j. Change from Baseline UHDRS TFC Score: Finance and ADL for Patients with BL TFC >9 or CAG Repeat >44, at Week 26. The table below shows the p-values corresponding to FIGS. 35j. Significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily and pridopidine 90 mg twice daily with baseline TFC greater than or equal to 9 or greater than 44 CAG repeats in their htt gene, within 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 56 56 53 52 49 Baseline 4.2 4.5 4.5 4.5 4.7 Δ to placebo 0.5 0.08 0.52 0.4 p-value 0.0055 0.6381 0.0039 0.0317

Fig. 35k. Change from Baseline UHDRS TFC Score: Finance and ADL for Patients with <44 CAG Repeat Counts and BL 1x3 Qs TMS at Week 26. The table below lists the p values corresponding to FIG. 35k. Significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily and 90 mg twice daily, in the first 3 quarters of baseline TMS and having fewer than 44 CAG repeats in their htt gene, for 26 weeks .

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 29 29 32 37 22 Baseline 4.1 4.6 4.5 4.4 4.6 Δ to placebo 0.59 0.18 0.6 0.57 p-value 0.0236 0.4782 0.0145 0.0478

Fig. 35l. Change from baseline UHDRS TFC score: finances and ADL for patients with BL TFC>9 and CAG repeat count <44 and -x 3 Qs BL TMS 1 at 26 weeks. The table below lists the p-values corresponding to FIG. 35l. Significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily and 90 mg twice daily, having a baseline TFC level greater than or equal to 9 and less than 44 CAG repeats in their htt gene, for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 13 15 19 21 10 Baseline 5.1 5.2 5.5 5.3 5.5 Δ to placebo 0.74 0.57 0.81 1.08 p-value 0.0315 0.0848 0.0118 0.009

Fig. 35m. Change from Baseline UHDRS TFC Score: Finance and ADL for Patients with BL TFC>9 and 1x3 Qs BL TMS at Week 26. The table below lists the p-values corresponding to FIG. 35m. Significant improvement in TFC: finances and ADL was observed in patients taking pridopidine 45 mg twice daily and 90 mg twice daily and having a baseline TFC level greater than or equal to 9 or less than 44 CAG repeats in their htt gene, or relating to the first three quarters of baseline TMS, within 26 weeks.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N thirty 32 34 31 29 Baseline 5.1 5.1 5.4 5.4 5.5 Δ to placebo 0.53 0.18 0.45 0.54 p-value 0.018 0.4039 0.0455 0.0193

Fig. 35n. Change from baseline UHDRS TFC score: finances and ADL for TMS patients 1st Q, at 26 weeks. The table below lists the p-values corresponding to FIG. 35n. Significant improvement in TFC:Finance and ADL was observed in patients treated with pridopidine 45 mg twice daily and 90 mg twice daily during the first three quarters of baseline TMS for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 21 24 20 25 15 Baseline 4.9 4.8 5 4.8 5.3 Δ to placebo 0.63 0.5 0.63 1.1 p-value 0.038 0.1136 0.0342 0.0024

Fig. 35o. Change from Baseline UHDRS TFC Score: Finance and ADL for TMS 1st Q Patients at Week 52. The table below lists the p-values corresponding to FIG. 35o. A significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily, relating to the first quarter of baseline TMS, c. within 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 21 24 20 25 15 Baseline 4.9 4.8 5 4.8 5.3 Δ to placebo 0.71 0.61 0.57 0.74 p-value 0.0319 0.0744 0.0762 0.0534

Fig. 35r. Change from Baseline UHDRS TFC Score: Finance and ADL for TMS Patients 1-2 Q at Week 26. The table below lists the p-values corresponding to FIG. 35r. Significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily, related to the first two quarters of baseline TMS, for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 42 44 39 40 43 Baseline 4.5 4.7 4.8 4.6 4.7 Δ to placebo 0.48 0.1 0.26 0.19 p-value 0.045 0.6867 0.3021 0.4543

Fig. 35q. Change from Baseline UHDRS TFC Score: Finance and ADL for 1st 2 Qs TMS Patients at Week 52. The table below lists the p-values corresponding to FIG. 35q. A significant improvement in TFC: finances and ADL was observed in patients taking 45 mg twice a day and 90 mg twice a day, related to the first two quarters of TMS, for 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 42 44 39 40 43 Baseline 4.5 4.7 4.8 4.6 4.7 Δ to placebo 0.47 0.25 0.47 0.44 p-value 0.0294 0.255 0.0326 0.0433

Fig. 35r. Change from Baseline UHDRS TFC Score: Finance and ADL for TMS Patients 1-3 Qs at Week 26. The table below lists the p-values corresponding to FIG. 35r. No significant improvement in TFC:Finance and ADL was observed in patients treated with pridopidine in the first three quarters of TMS for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 58 59 62 58 62 Baseline 4.3 4.5 4.3 4.4 4.5 Δ to placebo 0.18 0.04 0.35 0.41 p-value 0.3393 0.8205 0.0555 0.0253

Fig. 35s. Change from Baseline UHDRS TFC Score: Finance and ADL for 1st 3 Qs TMS Patients at Week 52. The table below lists the p-values corresponding to FIG. 35s. Significant improvement in TFC: finances and ADL was observed in patients treated with pridopidine 45 mg twice daily during the first three quarters of TMS for 52 weeks._____

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 58 59 62 58 62 Baseline 4.3 4.5 4.3 4.4 4.5 Δ to placebo 0.52 -0.03 0.21 0.09 p-value 0.0122 0.8661 0.3033 0.6679

Fig. 36a and 36b. General Information on Finger Pressing (quantitative measurements of motor activity when pressed). In FIG. 36a shows a drawing of an object's hand with a key. In FIG. 36b shows normal and aberrant depression measurements.

Fig. 37a and 37b. Quantification of motor activity (Q-motor) by finger tapping test: a well-validated objective measure. (Bechtel 2010).

Fig. 38. Quantitative assessment of motor activity (Q-motor) with a finger tapping test: Speed-Frequency. Pridopidine 90 mg twice daily showed consistent improvement from baseline. Data for 90 mg twice daily is shown on the top line of this graph, and data for placebo is shown on the bottom line of this graph. The difference in p value between 90 mg twice daily and placebo was 0.0259 at week 4, 0.0365 at week 12, and 0.0056 at week 26. Increasing the tapping speed indicates an improvement. The y-axis unit is frequency (Hz).

Fig. 39a and 39b. Velocity and intervals between clicks (IOI) for quantitative assessment of motor activity (Q-motor) in a finger tapping test. Pridopidine 90 mg twice daily showed consistent and significant improvement from baseline for 90 mg twice daily. The data for pridopidine 90 mg is shown in the bottom line of this graph, and the data for placebo is shown in the top line of this graph. The difference in p-value of pridopridin 90 mg twice daily with placebo was 0.0342 at week 4, 0.0368 at week 12, and 0.0162 at week 26. Reducing the interval between clicks indicates an improvement. The unit of the Y-axis in FIG. 39a is the frequency (Hz). In FIG. 39b shows the change from baseline in Tap-Speed-Inter-Onset-interval-MN-Hand-L (sec) versus time (week) for the full analysis set.

Fig. 39s. Improvement in objective pharmacodynamic parameters of motor activity control: change from baseline Q-Motor: Tap-Speed-Inter-Onset-interval-MNHand (c), 52 weeks FAS. The table below shows the data and p-values corresponding to FIG. 39s. An improvement trend was noted in patients receiving 45 mg twice daily.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 0.4065 0.4154 0.4608 0.4029 0.4366 Δ to placebo -0.0402 0.0152 -0.0064 -0.017 p-value 0.1956 0.6063 0.8258 0.5689

Fig. 39d. Improvement in objective pharmacodynamic measures of motor control: change from baseline Q-Motor: Tap-Speed-Inter-Onset-interval-MNHand (c), 52 weeks in HD1 and HD2 patients treated with pridopidine. The table below shows the data and s-values corresponding to FIG. 39d. An improvement trend was noted in all treatment groups. _________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 0.3725 0.3605 0.3983 0.3789 0.4056 Δ to placebo -0.0351 -0.0464 -0.0291 -0.022 p-value 0.1347 0.0449 0.2039 0.3509

Fig. 39th. Improvement in objective pharmacodynamic parameters of motor activity control, change from baseline Q-Motor: Pro-Sup-Frequency-MN-Hand (Hz), 52 weeks FAS. The table below shows the data and p-values corresponding to FIG. 39th. An improvement trend was noted in patients treated with 45 mg twice daily.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 1.6686 1.7789 1.7255 1.7505 1.7251 Wk52 Δ to placebo 0.0599 -0.0124 -0.0087 0.0127 p-value 0.3122 0.8278 0.8763 0.8261

Fig. 39f. Improvement in objective pharmacodynamic parameters of motor control, change from baseline Q-Motor: Pro-Sup-Frequency-MN-Hand (Hz), 52 weeks in patients with HD1 and HD2 treated with pridopidine. The table below shows the data and p-values corresponding to FIG. 39f. An improvement trend was noted in patients treated with 45 mg twice daily.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 1.77 1.8513 1.8928 1.8658 1,841 Wk52 Δ to placebo 0.1195 0.0548 0.0575 0.08 p-value 0.0692 0.3996 0.3709 0.229

Fig. 40a. Change from baseline in the Hopkins Cognitive Battery Analysis Scale: Revised Hopkins Verbal Learning Test (CAB HVLT-R) for patients at week 26. The table below lists the p-values corresponding to FIG. 40a. In patients treated with pridopidine, no significant improvement in CAB HVLT-R score was observed over 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 19.3 19.5 20.3 19.4 19.1 Δ to placebo -0.53 0.15 -0.73 -0.47 p-value 0.5837 0.8758 0.4384 0.6217

Fig. 40b. Change from Baseline in Cognitive Battery Analysis: Revised Hopkins Verbal Learning Test (CAB HVLT-R) for Patients at Week 52. The table below lists the p-values corresponding to FIG. 40b. A trend toward improvement in the CAB HVLT-R score was observed in patients treated with 45 mg twice daily while on pridopidine.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 19.3 19.5 20.3 19.4 19.1 Δ to placebo -2.21 -2.74 -1.07 -2.19 p-value 0.0517 0.0148 0.3265 0.0562

Fig. 41a. Change from baseline in the Cognitive Battery Analysis Scale (CAB): Pathway Test for Patients at Week 26. The table below lists the p values corresponding to FIG. 41a. Significant improvement in CAB score: No route building test was observed in patients treated with pridopidine for 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline -184.7 -181.6 -182.2 -185 -178.9 Δ to placebo -0.95 -3.03 -6.64 2.97 p-value 0.8773 0.6211 0.2713 0.6283

Fig. 41b. Change From Baseline in the Cognitive Battery Analysis Scale (CAB): Pathway Test for Patients at Week 52. The table below lists the p values corresponding to FIG. 41b. A trend towards improvement in CAB score: A route building test was observed in patients who took pridopidine for 52 weeks._________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline -184.7 -181.6 -182.2 -185 -178.9 Δ to placebo -13.56 -7.54 -12.48 2.01 p-value 0.0773 0.3266 0.0913 0.7951

Fig. 41s. Change from baseline on the Cognitive Battery Analysis Scale (CAB): tapping at a given pace at a frequency of 3 Hz, after 26 weeks. The table below shows the data and p-values corresponding to FIG. 41s.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 5.935 6.035 5.027 4.943 5.572 Δ to placebo 0.4736 -0.041 0.1975 0.9515 p-value 0.4081 0.9441 0.7276 0.0937

Fig. 41d. Change from baseline on the Cognitive Battery Analysis Scale (CAB): tapping at a given pace at a frequency of 3 Hz, after 52 weeks. The table below shows the data and p-values corresponding to FIG. 41d.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 5.935 6.035 5.027 4.943 5.572 Δ to placebo 1.3234 0.3701 0.2659 0.1523 p-value 0.0402 0.5681 0.6681 0.8152

Fig. 42. The annual rate of deterioration (y-axis) in TFC is higher in the early stages of the disease (Marder 2000).

Fig. 43a. Mean change from baseline TFC in placebo groups (1) open-label add-on trial of pridopidin (ACR16) in symptomatic treatment of Huntington's disease (OPEN-HART) (n=50), (2) Coenzyme Q10 AND remacemide: Evaluation in HD (CARE- HD) (n=80) (Kieburtz 2001) and (3) coenzyme Q10 in Huntington's disease (HD) (2CARE) (n=213): TFC score change from baseline (unmatched cohorts). The circle beyond the 12-month points reflects the ~1 point difference observed in the rate of decline in functional capacity in OPEN-HART patients treated with pridopidine.

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Fig. 43b. Change from baseline TFC score plotted against time at week 52 in subjects with HD1 and HD2 treated with pridopidine (n=54-62) in the PRIDE-HD study. The dark line with a diamond represents the placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily. The y-axis represents the change from baseline in TFC scores, the x-axis represents the treatment time in weeks.

Fig. 44a-44c are graphs that demonstrate multiple outcome measures related to ambulation showing trends in favor of pridopidine in the early stages of HD (stage 1-2 patients). The data for TMS showed a strong placebo effect. A trend towards improvement in TMS was observed after 52 weeks.

Fig. 44a. UHDRS TMS: Gait: Early HD at 52 weeks. The table below shows the data and p-values corresponding to FIG. 44a. _____________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 0.9 1.1 1 1.1 1 Wk52 Δ to placebo -0.21 -0.17 -0.17 -0.06 p-value 0.0855 0.168 0.1521 0.628

Fig. 44b. Time test Get up and go (s). HD1 and HD2 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 44b.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 10 I,7 9.7 9.8 9.8 Wk52 Δ to placebo -1.61 -1.64 -1.46 -0.96 p-value 0.1348 0.1369 0.171 0.3827

Fig. 44s. Walk-12 improved in HD1 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 44s.______________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 eleven 18 Baseline 21.2 6.3 12.3 17.7 13 Δ to placebo -5.86 -8.57 -13.6 -4.13 p-value 0.3018 0.1032 0.0193 0.4534

Fig. 44d and 44e. HD, 26 and 52 weeks, respectively. HD1 patients treated with pridopidine, Involuntary movements: total maximal chorea (TMS).

The table below shows the data and p-values corresponding to FIG. 44d.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 12 17 17 AND 18 Δ to placebo -1.4 -2.07 -2.52 -1.08 p-value 0.1805 0.0438 0.0271 0.2932

The table below shows the data and p-values corresponding to FIG. 44th.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 eleven 18 Baseline 12 17 17 eleven 18 Δ to placebo -0.93 -0.13 -2.43 0.88 p-value 0.5315 0.931 0.1313 0.5622

Fig. 45a-45b. Fig. 45. Change from baseline TMS score plotted against time in the full TMS analysis set plotted against time in PRIDE-HD. The data replicate previous TMS changes from baseline as changes from baseline were similar to HART and MermaiHD. A decrease in TMS change from baseline indicates an improvement. The y-axis represents the change from baseline in TMS from baseline, the x-axis represents treatment time in weeks. Fig. 45b. Change from baseline TMS plotted against time for HD1 patients. The dark diamond line indicates placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily. 45 mg twice daily shows improvement in TMS score at 52 weeks. The y-axis represents the change from baseline in TMS from baseline, the x-axis represents treatment time in weeks.

In FIG. 46a-46v and 47a-47y show Modified Physical Performance Test (MPPT) data related to locomotion. The table below each graph contains data and p

-36041256 values corresponding to the graph.

Fig. 46a. Change from Baseline TPPT Total Score, Full Assay Set from Treatment Week 4 to Week 52. ptRT quantifies a patient's performance on physical and functional tasks using a standardized 9-item test. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily. The introduction of 45 mg twice a day shows an improvement in the score ptRRT after 52 weeks. The y-axis represents the change from baseline in ptRT from baseline, the x-axis represents treatment time in weeks.

Fig. 46b. Total TPPT score - change from baseline, full analytical set, 26 weeks. The table below shows the data and p-values corresponding to FIG. 46b.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 25.5 24.9 26.1 25.7 25.7 Δ to placebo 0.04 -0.07 -0.01 0.29 p-value 0.9462 0.8968 0.9853 0.6063

Fig. 46s. Total TPPT score - change from baseline, full analytical set, 52 weeks. The table below shows the data and p-values corresponding to FIG. 46s.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 25.5 24.9 26.1 25.7 25.7 Δ to placebo 0.46 0.17 -0.33 -0.47 p-value 0.5541 0.8284 0.661 0.5482

Fig. 46d. Total TPRT score - change from baseline in pridopidine-treated patients with baseline TFC<7, 26 weeks. The table below shows the data and values corresponding to Fig. 46d._________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 21.5 21.4 23.3 23.1 21.3 Δ to placebo 0.9 -0.85 -0.73 -0.33 p-value 0.5266 0.5247 0.5786 0.802

Fig. 46th. Total ptRT score - change from baseline in HD1 and HD2 patients treated with pridopidine at 26 weeks. The table below shows the data and p-values corresponding to FIG. 46e._____________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 26.6 25.9 27.4 26.9 27.5 Δ to placebo -0.24 0.59 0.46 0.79 p-value 0.6903 0.3296 0.4429 0.1889

Fig. 46f. Total TPRT score - change from baseline in HD1 patients treated with pridopidine with baseline TFC<7, 52 weeks. The table below shows the data and p-values corresponding to FIG. 46f._____________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 21.5 21.4 23.3 23.1 21.3 Δ to placebo 1.57 -1.37 -2.73 -0.49 p-value 0.4267 0.4515 0.1288 0.7822

Fig. 46g. Total ptRT score - change from baseline in HD1 and HD2 patients treated with pridopidine, 52 weeks. The table below shows the data and p-values corresponding to FIG. 46g._______________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 26.6 25.9 27.4 26.9 27.5 Δ to placebo 0.15 1.04 0.88 -0.26 p-value 0.8564 0.2087 0.2728 0.7532

Fig. 46h. Change from baseline in total TPRT score in HD1 patients treated with pridopidine at 26 weeks. The table below shows the data and p-values corresponding to FIG. 46h.

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placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 28.1 30.1 28.7 27.8 30.2 Δ to placebo -1.31 -0.2 0.81 0.03 p-value 0.2537 0.8574 0.5048 0.9789

Fig. 46i. Change from baseline in total sPRT score in HD2 patients treated with pridopidine at 26 weeks. The table below shows the data and p-values corresponding to FIG. 46i.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 26.3 24.1 26.8 26.7 26.3 Δ to placebo -0.07 0.68 0.35 0.85 p-value 0.9231 0.3603 0.6191 0.242

Fig. 46j. Change from baseline in total sPPT score in HD patients treated with pridopidine, BL, stages 3-5 (TFC 0-6) at 26 weeks. The table below shows the data and p-values corresponding to FIG. 46j.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 21.5 21.4 23.3 23.1 21.3 Δ to placebo 0.9 -0.85 -0.73 -0.33 p-value 0.5266 0.5247 0.5786 0.802

Fig. 46k. Change from baseline in total sPRT score in HD1 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 46k.____________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 28.1 30.1 28.7 27.8 30.2 Δ to placebo 0.76 0.45 1.11 0.08 p-value 0.5292 0.7013 0.388 0.9456

Fig. 461. Change from baseline in total sPRT score in HD2 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 461._________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 26.3 24.1 26.8 26.7 26.3 Δ to placebo -0.39 1 0.71 -0.65 p-value 0.7028 0.3539 0.4672 0.5427

Fig. 46m. Change from baseline in total sPPT score in HD patients treated with pridopidine, BL, stage 3-5, at 52 weeks. The table below shows the data and values corresponding to FIG. 46m._____________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 21.5 21.4 23.3 23.1 21.3 Δ to placebo 1.57 -1.37 -2.73 -0.49 p-value 0.4267 0.4515 0.1288 0.7822

Fig. 46p. Graph showing change from baseline in sPPT scores: Standing static balance, full assay set from week 4 to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 46o. TPPT scores: Standing static balance, full analytical set at 26 weeks. The table below shows the data and p-values corresponding to FIG. 46o._________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.1 2.9 2.9 3.1 3 Δ to placebo 0.07 -0.2 -0.1 0.05 p-value 0.6768 0.2154 0.5123 0.7294

Fig. 46r. TPPT scores: Standing static balance, full analytical set at 52 weeks. The table below shows the data and p-values corresponding to FIG. 46r.

-38041256

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.1 2.9 2.9 3.1 3 Δ to placebo -0.15 -0.19 -0.14 -0.12 p-value 0.4019 0.3018 0.435 0.5024

Fig. 46q. graph showing change from baseline in TPPT scores: Standing up from a chair, full assay set from week 4 of treatment to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 46g. SPPT scores: Getting up from a chair, complete analytical set at 26 weeks. The table below shows the data and p-values corresponding to FIG. 46y.________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.5 2.6 2.8 2.8 2.6 Δ to placebo 0.05 0.01 0.01 0.12 p-value 0.7238 0.9436 0.9222 0.3883

Fig. 46s. TPPT scores: Standing up from a chair, complete analytical set at 52 weeks. The table below shows the data and p-values corresponding to FIG. 46s. ___________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.5 2.6 2.8 2.8 2.6 Δ to placebo -0.05 -0.1 -0.31 -0.12 p-value 0.7501 0.5267 0.0414 0.4515

Fig. 46t. Graph showing change from baseline in TPPT scores: pick up and put book on shelf, full assay set from week 4 treatment to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 46i. Change from baseline in TPPT scores: pick up and put book on shelf, complete analysis set at week 26._____________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.6 2.4 2.6 2.6 2.7 Δ to placebo 0.14 0.1 0.04 0.14 p-value 0.2277 0.3649 0.6982 0.2057

Fig. 46v. Change from baseline in TPPT scores: pick up and put the book on the shelf, complete analysis set at 52 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.6 2.4 2.6 2.6 2.7 Δ to placebo 0.25 0.17 0.22 0.12 p-value 0.0755 0.224 0.1116 0.3956

Fig. 47a. Graph showing Change from baseline in TPPT: Put on and take off jacket, full assay set from week 4 treatment to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 47b. Change from baseline in TPPT scores: Put on and take off jacket, complete assay set at 26 weeks.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.2 2.1 2.3 2.3 2.2 Δ to placebo -0.22 0.17 -0.01 -0.03 p-value 0.1319 0.2355 0.9331 0.8307

Fig. 47s. Change from baseline in TPPT scores: Put on and take off jacket, complete assay kit at 52 weeks.

-39041256

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.2 2.1 2.3 2.3 2.2 Δ to placebo 0.2 0.21 0.08 -0.18 p-value 0.2306 0.1943 0.615 0.2614

Fig. 47d. Graph showing change from baseline in TPPT: Pick up pennies from the floor, complete assay set from treatment week 4 to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 47th. Change from baseline in TPPT scores: Pick up pennies off the floor, complete assay set at 26 weeks. The table below shows the data and p-values corresponding to FIG. 47e.________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.6 2.7 2.8 2.6 2.7 Δ to placebo -0.13 0.14 0.1 0.07 p-value 0.2702 0.2404 0.3764 0.5559

Fig. 47f. Change from baseline in TPPT scores: Pick up a penny off the floor, complete assay set at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47f.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.6 2.7 2.8 2.6 2.7 Δ to placebo 0.04 0.09 0.14 0.07 p-value 0.7523 0.5148 0.3007 0.5939

Fig. 47g. Graph showing change from baseline in TPPT: 360 degree rotation, complete assay set from week 4 to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 47h. Change from baseline TPPT scores: 360-degree rotation, complete analytical set at 26 weeks. The table below shows the data and p-values corresponding to FIG. 47h.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.2 3.2 3.1 3 3.1 Δ to placebo 0.12 -0.06 0.12 0.2 p-value 0.557 0.7586 0.5746 0.3518

Fig. 47i. Change from baseline TPPT scores: 360-degree rotation, full analytic set at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47i.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.2 3.2 3.1 3 3.1 Δ to placebo -0.12 -0.1 0.04 -0.08 p-value 0.636 0.6733 0.8805 0.7413

Fig. 47j. Graph showing change from baseline in TPPT scores: Walking 50 feet, full assay set from treatment week 4 to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 47k. Change from baseline in TPPT scores: Walking 50 feet, full analytic set at 26 weeks. The table below shows the data and p-values corresponding to FIG. 47k. _________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline h, h 3.2 h, h 3.4 h, h Δ to placebo -0.02 0 -0.1 -0.17 p-value 0.8367 0.9738 0.3331 0.0945

Fig. 471. Change from baseline in TPPT scores: Walk 50 feet, full

-40041256 analytical kit at 52 weeks. The table below shows the data and p-values corresponding to FIG. 471. __________________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.3 3.2 3.3 3.4 3.3 Δ to placebo -0.03 0.15 -0.23 -0.15 p-value 0.8302 0.3032 0.1087 0.3004

Fig. 47m. Graph showing change from baseline in TPPT scores: Climbing one flight of stairs, full analysis set from week 4 of treatment to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 47p. Change from baseline in TPPT scores: Climbing one flight of stairs, full analytic set at 26 weeks. The table below shows the data and values corresponding to Fig. 47p.____________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.6 2.6 2.7 2.6 2.8 Δ to placebo 0.08 0.11 0.15 0.16 p-value 0.5139 0.3671 0.2061 0.1912

Fig. 47o. Change from baseline in TPPT scores: Climbing one flight of stairs, full analytic set at 52 weeks. The table below shows the data and values corresponding to FIG. 47o.____________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 2.6 2.6 2.7 2.6 2.8 Δ to placebo 0.26 0.13 0.08 oh and p-value 0.0896 0.4116 0.6043 0.4606

Fig. 47r. Change from baseline in TPPT scores: Climbing one flight of stairs in pridopidine-treated advanced HD patients with BL TFC<7 at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47 rubles _______

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 2.5 2.5 2.4 2.3 2.5 Δ to placebo 0.19 -o,z -0.26 -0.15 p-value 0.5914 0.3609 0.4198 0.6539

Fig. 47q. Change from baseline in TPRT scores: Climbing one flight of stairs in HD1 and HD2 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47g. __________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 2.7 2.6 2.8 2.7 2.9 Δ to placebo 0.27 oh, s 0.22 0.23 p-value 0.1076 0.0769 0.1955 0.1771

Fig. 47g. Change from baseline in TPRT scores: Climbing one flight of stairs in HD1 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47g. ____________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 12 17 17 AND 18 Baseline 2.7 3.2 2.7 2.9 3.2 Δ to placebo -0.02 0.01 -0.06 0.18 p-value 0.9539 0.9627 0.86 0.5277

Fig. 47s. Change from baseline in TPRT scores: Climbing one flight of stairs in HD2 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47s.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 50 42 37 45 40 Baseline 2.7 2.3 2.9 2.7 2.8 Δ to placebo 0.35 0.34 0.28 0.23 p-value 0.0958 0.1189 0.1482 0.2731

Fig. 47t. Change From Baseline in TPPT Scores: Climbing One Flight of Stairs in Pridopidine-Treated Late HD Patients with BL TFC 0-6 at Week 52 The table below shows the data and p-values corresponding to FIG. 47t.

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 2.5 2.5 2.4 2.3 2.5 Δ to placebo 0.19 -o,z -0.26 -0.15 p-value 0.5914 0.3609 0.4198 0.6539

Fig. 47u. Graph showing change from baseline in mPPT scores: Climbing stairs (up and down) provides a complete assay set from week 4 of treatment to week 52. The dark diamond line represents placebo; open circle line represents 45 mg twice daily, triangle line represents 67.5 mg twice daily, gray diamond line represents 90 mg twice daily, square line represents 112.5 mg twice daily.

Fig. 47v. Change from baseline in mPPT scores: Climbing stairs (up and down), full analytic set at 26 weeks. The table below shows the data and p-values corresponding to FIG. 47v._______________________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.4 3.5 3.6 3.6 3.7 Δ to placebo -0.03 -0.14 -0.08 -0.08 p-value 0.8134 0.195 0.464 0.4872

Fig. 47w. Change from baseline in mPPT scores: Climbing stairs (up and down), complete analysis set at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47w.__________________________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 81 75 79 81 81 Baseline 3.4 3.5 3.6 3.6 3.7 Δ to placebo 0.17 0.04 -0.04 0.1 p-value 0.3209 0.8251 0.8282 0.5759

Fig. 47x. Change from baseline in mPPT scores: Climbing stairs (up and down) in patients with advanced HD with BL TFC<7 at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47x.__________________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 19 16 25 25 23 Baseline 3.2 3.1 3.4 3.5 3.1 Δ to placebo 0.72 0.16 -0.36 0.31 p-value 0.0915 0.6827 0.3305 0.4235

Fig. 47y. Change from baseline in mPPT scores: Climbing stairs (up and down) in HD1 and HD2 patients treated with pridopidine at 52 weeks. The table below shows the data and p-values corresponding to FIG. 47y.___________________________

placebo 45 mg twice a day 67.5 mg twice daily 90 mg twice a day 112.5 mg twice daily N 62 59 54 56 58 Baseline 3.5 3.6 3.7 3.6 3.9 Δ to placebo -0.01 0.01 0.1 0.07 p-value 0.9572 0.9614 0.5816 0.7161

Detailed description of the invention

The present invention provides a method of maintaining functional ability, improving functional ability, or reducing deterioration in functional ability in a human patient in need thereof, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pidopidin or a pharmaceutically acceptable salt thereof, so that the daily dose of pidopidin administered to the patient is 90-225 mg, so as to maintain functional ability, improve functional ability, or reduce deterioration in functional ability in a human patient. In an embodiment, the method includes maintaining functional ability, improving functional ability, or reducing impairment of functional ability.

The present invention provides a method of maintaining functional ability, improving functional ability, reducing the rate of deterioration of functional ability, or slowing down the rate of deterioration of functional ability in a human patient in need thereof, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pidopidine or a pharmaceutically acceptable salt thereof, so that the daily dose of pridopidine administered to the patient was 90-225 mg, so as to maintain functional capacity, improve functional capacity, reduce the rate of deterioration of functional capacity, or slow down the rate of functional deterioration in a human patient. In an embodiment, the method includes maintaining functional ability, improving functional ability, or reducing the rate of deterioration in functional ability.

In an embodiment, the method includes maintaining functional ability. In another embodiment, the method includes improving functional ability. In some embodiments, functional ability is maintained or improved for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 3 years, or at least 5 years.

In another embodiment, functional ability is total functional ability (TFC) as measured by UHDRS-TFC and the human patient has an improvement of one (1) or more points in UHDRS TFC. In some embodiments, the human patient has an improvement of one (1) or more points in UHDRS TFC after 52 weeks of pridopidine administration. In another embodiment, the rate of decline in functional ability is less than one (1) point as measured by UHDRS TFC after 52 weeks of pridopidine administration.

In one embodiment, the method includes reducing the deterioration in functional ability. In another embodiment, the method comprises reducing functional impairment and (a) the pharmaceutical composition is administered for more than 26 weeks, or (b) the human patient is afflicted with HD at an early stage. In one embodiment, the method includes reducing the rate of deterioration in functional ability. In another embodiment, the method comprises reducing the rate of deterioration in functional ability and (a) the pharmaceutical composition is administered for more than 26 weeks or (b) the human patient is afflicted with early HD. In some embodiments, the method includes reducing the deterioration in functional ability. In some embodiments, the deterioration in functional ability is reduced or the rate of deterioration in functional ability is slowed down by at least 20%, at least 30%, at least 40%, at least 50%, or at least 80%. In another embodiment, the rate of deterioration in functional ability decreases over at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 3 years, or at least 5 years. In another embodiment, the rate of decline in functional ability slows down, functional ability decreases for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 3 years, or at least 5 years.

In one embodiment, the functional capability is total functional capability (TFC). Overall functional ability can be measured using UHDRS-TFC. Overall functional ability can also be measured using the UHDRS Functional Assessment Scale (UHDRS-FAS). In one embodiment, functionality is maintained for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

In one embodiment, the human patient has no functional impairment. In other embodiments, the human patient has had no deterioration in functional ability for at least 52 weeks.

The invention further provides a method for slowing the clinical progression of HD in a human patient, comprising intermittent oral administration to a patient suffering from HD of a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof, such that the daily dose of pidopidine administered to the patient is 90-225 mg, so that most slow the clinical progression of HD in a patient.

In one embodiment, the clinical progression of HD is measured by overall functional ability. In one embodiment, the clinical progression of HD is slowed down by at least 20%, at least 30%, at least 50%, at least 80%, or 20% to 90%. In another embodiment, the clinical progression of HD is retarded for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, at least 3 years, or at least 5 years. In a further embodiment, overall functional ability is measured by UHDRS-TFC.

The present invention also provides a method for reducing impairment of functional capacity, as measured by total UHDRS functional capacity, in a human patient in need thereof, comprising intermittent oral administration to the human patient of a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof, such that the daily dose of pridopidine administered to the patient is 90 -225 mg, so as to reduce the deterioration in functional capacity in a human patient, where the human patient is affected by HD and has a baseline TFC score of 11-13.

In one embodiment, deterioration in functional ability is measured using UHDRSTFC. In another embodiment, the method includes reducing the deterioration in functional ability in

- 43 041256 for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, at least 78 weeks, at least 3 years, or at least 5 years.

The invention also provides a method of maintaining, improving, or reducing the rate of deterioration in a human patient's ability to perform basic self-care activities, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition comprising pidopidine, or a pharmaceutically acceptable salt thereof, such that the daily dose pridopidine administered to the patient was 90-225 mg, thus maintaining, improving or reducing the rate of deterioration of the person's ability to perform basic self-care activities.

The present invention also provides a method of maintaining, improving, or reducing the rate of deterioration in a human patient's ability to perform basic self-care activities, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, or a pharmaceutically acceptable salt thereof, such that the daily dose administered the patient was pridopidine 90-225 mg, thus maintaining, improving or reducing the rate of deterioration of the person's ability to perform basic self-care activities.

In one embodiment, the ability of the human patient to perform basic self-care activities is maintained, improved, or the rate of deterioration decreases over a period of at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In one embodiment, the ability of the human patient to perform basic self-care activities is maintained, improved, or the rate of deterioration is reduced for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In another embodiment, the method includes maintaining the patient's ability to perform basic self-care activities. In one embodiment, the ability to perform elementary self-service actions is measured by the Basic Self-Service Action Domain (ADL) of the TFC.

The invention also provides a method of maintaining, improving, or reducing deterioration in a human patient's ability to manage finances, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, or a pharmaceutically acceptable salt thereof, such that the daily dose of pridopidine administered to the patient is 90-225 mg to thus maintain, improve or reduce the rate of deterioration of a person's ability to manage finances.

The invention also provides a method of maintaining, improving, or reducing the rate of deterioration of a human patient's ability to manage finances, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof, such as that the patient is administered a dose of 90- Pridopidine 225 mg daily to thus maintain, improve or reduce the rate of deterioration in the patient's ability to manage finances.

In another embodiment, the administration further supports, improves, or reduces deterioration in the human patient's ability to manage finances. In one embodiment, the patient's ability to manage finances is maintained, improved, or worsened for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In another embodiment, the administration further supports, improves, or reduces the rate of deterioration of the human patient's ability to manage finances. In one embodiment, the patient's ability to manage finances is maintained, improved, or the rate of deterioration is reduced for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In one embodiment, the method includes maintaining the patient's ability to manage finances. In another embodiment, the method includes improving the patient's ability to manage finances. In some embodiments, the ability to manage finances is measured by the Financial Management Domain of the TFC.

In one embodiment, the administration further maintains, improves, or reduces the rate of deterioration of the human patient's ability to perform household chores. In another embodiment, the administration further supports, improves, or reduces deterioration in the human patient's ability to perform housework.

The invention also provides a method of maintaining, improving or reducing the impairment of a person's ability to perform household chores, comprising intermittent oral administration to a person in need, therefore, of a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof, so that the daily dose of pridopidine administered to the patient is 90-225 mg so as to maintain, improve or reduce the impairment of a person's ability to perform household chores.

The invention also provides a method for maintaining, improving, or reducing the rate of deterioration in a human patient's ability to perform household chores, comprising intermittent pen

- 44 041256 oral administration to a human patient in need thereof of a pharmaceutical composition, i.e. a pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof, such that the patient is administered a dose of 90-225 mg of pridopidine daily, in order thereby to maintain, improve or reduce the rate of deterioration the patient's ability to do household chores.

In one embodiment, the ability to do household chores is measured by the Household Domain of the UHDRS TFC. In another embodiment, a person's ability to perform household chores is maintained or improved for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In another embodiment, the method includes maintaining the patient's ability to perform household chores. In one embodiment, the method includes improving the patient's ability to perform household chores. In another embodiment, the ability of the human patient to perform housework is maintained or improved, or the rate of deterioration decreases for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. . In a further embodiment, the ability of the human patient to perform household chores is maintained or improved, or the decline decreases for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

In one embodiment, the administration further maintains, improves, or reduces the rate of deterioration in the level of care of the human patient. In another embodiment, the administration further maintains, improves, or reduces deterioration in the level of care of the human patient.

The invention also provides a method of maintaining, improving or reducing deterioration in the level of care of a human patient, comprising intermittent oral administration to a human patient in need of it, a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg, so that thus maintaining, improving or reducing deterioration in the patient's level of care.

The invention also provides a method of maintaining, improving or reducing the rate of deterioration in the level of care of a human patient, including periodic oral administration to a human patient in need of it, a pharmaceutical composition containing pridopidine, so that the daily dose of pidopidine administered to the patient is 90-225 mg, so as to maintain, improve or reduce the rate of deterioration in the level of care of the human patient.

In an embodiment, the care level is measured by the Care Level Domain of the TFC. In another embodiment, the level of care of the human patient is maintained, improved, or the rate of deterioration decreases for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In another embodiment, the level of care of the human patient is maintained, improved, or worsened for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In another embodiment, the method includes maintaining the level of care of a human patient.

In one embodiment, the patient is dosed with 135-225 mg of pridopidine daily. In another embodiment, the patient is dosed with 180-225 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily, the patient is dosed with 135 mg of pridopidine daily, the patient is dosed with 180 mg of pridopidine daily, or the patient is dosed with 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 135 mg of pridopidine daily, the patient is dosed with 180 mg of pridopidine daily, or the patient is dosed with 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 180 mg of pridopidine daily, or the patient is dosed with 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily, the patient is dosed with 135 mg of pridopidine daily, or the patient is dosed with 180 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily in unit doses of 45 mg twice daily. In another embodiment, the patient is dosed with 135 mg of pridopidine daily. In another embodiment, a dose of 135 mg of pridopidine is administered to the patient daily in unit doses of 67.5 mg twice daily. In another embodiment, the patient is dosed with 180 mg of pridopidine daily. In another embodiment, a dose of 180 mg of pridopidine is administered to the patient daily in unit doses of 90 mg twice daily. In another embodiment, the patient is dosed with 225 mg of pridopidine daily. In another embodiment, a dose of 225 mg of pridopidine is administered to the patient daily in unit doses of 112.5 mg twice daily.

The invention further provides a method for reducing dystonia or maintaining a level of dystonia in a human patient in need thereof, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the patient is administered a dose of 90-225 mg of pridopidine. daily, so as to reduce dystonia or maintain the level of dystonia in a human patient.

In one embodiment, dystonia is measured on the UHDRS TMS scale: Dystonia. In another embodiment, the level of dystonia in the human patient is reduced or maintained for at least

- 45,041,256 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

In some embodiments, the dystonia is limb dystonia.

The invention also provides a method for treating limb dystonia in a human patient in need thereof, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidin administered to the patient is 90-225 mg, so as to thereby treat limb dystonia. in a person. In many embodiments, (a) the pharmaceutical composition is administered for more than 26 weeks, or (b) a titration dose in an amount other than the intended dose is administered over a period of time at the start of the intermittent administration, or (c) the human patient is suffering from early HD.

In one embodiment, the patient is dosed with 135-225 mg of pridopidine daily. In another embodiment, a dose of 135 mg of pridopidine is administered to the patient daily, a dose of 135 mg of pridopidine is administered to the patient daily, a dose of 180 mg of pridopidine is administered to the patient daily, or a dose of 225 mg of pridopidine is administered to the patient daily. In another embodiment, the patient is dosed with 135 mg of pridopidine daily, the patient is dosed with 180 mg of pridopidine daily, or the patient is dosed with 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 180 mg of pridopidine daily, or the patient is dosed with 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 180 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily.

In another embodiment, the pharmaceutical composition is administered for at least 12 weeks, at least 20 weeks, at least 26 weeks, more than 26 weeks, at least 52 weeks, at least 54 weeks, at least 78 weeks, at least 104 weeks or more. In another embodiment, treating limb dystonia includes preventing slowing, decreasing amplitude, or worsening of the ability to perform a finger tapping test in a human patient and/or preventing slowing or irregular performance of a pronation-supination hand test in a human patient.

The invention also provides a method for preventing slowdown, decrease in amplitude, or deterioration in the ability to perform a finger tapping test in a human patient and/or to prevent slowdown or irregular performance of the hand pronation-supination test in a human HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition comprising pridopidine, so that the daily dose of pridopidine administered to the patient is 90-225 mg, so as to prevent slowing down, decrease in amplitude or impaired ability to perform a finger tapping test in a human patient and / or prevent slowing down or irregular performance of the test person.

In another embodiment, treating limb dystonia includes preventing a human patient from impaired ability to perform a finger tapping test and/or preventing slow or irregular performance of a Q-Motor: Pro-Sup-Frequency-MN-Hand (Hz) test. In another embodiment, the treatment results in improved quantification of motor activity (Q-motor) in a finger tapping test. In another embodiment, the treatment comprises improving the Inter-Pulse Interval (IOI) to quantify motor activity (Q-motor) in a finger tapping test.

The invention further provides a method for improving or maintaining gait and balance in a human patient, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, such that the daily dose of pridopidine administered to the patient is 90-225 mg to thereby improve or maintain the patient's gait and balance.

In one embodiment, the patient is dosed with 90 mg, 135 mg, 180 mg, or 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily. In another embodiment, the patient is dosed with 180 mg of pridopidine daily. In another embodiment, the patient is dosed with 135 mg or 180 mg of pridopidine daily.

Further provided is a method for improving, maintaining, or reducing impairment of gait and balance in a human patient, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition such that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve , maintain or reduce deterioration in gait and balance in a human patient.

Also provided is a method for improving, maintaining or slowing the deterioration of gait and balance of a human patient, comprising intermittent oral administration to a patient in need of it, a pharmaceutical composition, so that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve, maintain or slow down the deterioration gait and balance in a human patient.

In one embodiment, a person's gait and balance are measured on the UHDRS scale: gait and balance. In some embodiments, the human patient's gait and balance are improved or maintained or deterioration is reduced over at least 12 weeks, at least 20

- 46,041,256 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

In one embodiment, a person's gait and balance are measured on the UHDRS scale: gait and balance. In some embodiments, the human patient's gait and balance are improved or maintained or deterioration slowed for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

The invention also relates to a method for improving or maintaining the independence of a human patient, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, so that the daily dose of pidopidine administered to the patient is 90-225 mg, thereby improving or maintaining independence. patient.

In one embodiment, the patient is dosed with 90 mg, 135 mg, 180 mg, or 225 mg of pridopidine daily. In another embodiment, the patient is administered a dose of pridopidine 90 mg daily. In another embodiment, the patient is administered a dose of pridopidine 225 mg daily.

The invention also provides a method for improving, maintaining, or reducing impairment of a human patient's independence, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition such that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve, maintain, or reduce impairment. patient independence.

The invention also provides a method for improving, maintaining, or slowing the deterioration of a human patient's independence, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition such that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve, maintain, or to slow down the deterioration of the independence of the human patient.

In one embodiment, the independence of the human patient is measured on the scale UHDRS: Independence. In some embodiments, the independence of the human patient is improved or maintained, or deterioration is retarded for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In one embodiment, the independence of the human patient is improved or maintained, or deterioration is reduced for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

The invention also provides a method for improving or maintaining domains of cognitive function in a human patient, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, such that the daily dose of pridopidine administered to the patient is 90-225 mg, so that most improve or maintain domains of the human patient's cognitive functions. Patient cognitive domains can also be the patient's cognitive activities in different domains.

In one embodiment, the patient is dosed with 90-180 mg of pridopidine daily. In another embodiment, the patient is dosed with pridopidine 90 mg, 135 mg, or 180 mg daily. In another embodiment, the patient is dosed with 90 or 180 mg of pridopidine daily.

In addition, a method is provided for improving, maintaining or reducing the deterioration of domains of cognitive functions in a human patient, including periodic oral administration to a patient in need of it, a pharmaceutical composition, so that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve, maintain or reduce deterioration in domains of cognitive function in a human patient. Cognitive domains can be understood as the patient's cognitive activities in different domains.

In addition, a method is provided for improving, maintaining or slowing the deterioration of domains of cognitive functions in a human patient, including periodic oral administration to a patient in need of it, a pharmaceutical composition, so that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve, maintain or slow the deterioration of domains of cognitive function in a human patient. Cognitive domains can be understood as the patient's cognitive activities in different domains.

The domains of a patient's cognitive function can be measured, for example, using the analysis of cognitive batteries (CAB). Cognitive domains in a human patient can also be measured using the revised Hopkins Verbal Learning Test (HVLT-R). Cognitive domains in a human patient can be further measured using the paced tapping test, the Montreal Cognitive Assessment Scale (MoCA), or the character-number matching test (SDMT). Cognitive domains in a human patient can be further measured using the Route Building Test B (TMT-B). In one embodiment, domains of cognition in the human patient are maintained or improved, or deterioration is retarded for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In some embodiments, slowing the deterioration of domains of the human patient's cognitive functions includes slowing the rate of deterioration

- 47 041256 cognitive abilities. In one embodiment, domains of cognition in the human patient are maintained or improved or deterioration is reduced for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

The invention also relates to a method for reducing the severity of prolonged or periodic muscle contractions associated with dystonia in a human patient in need thereof, including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg, to thereby reduce the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient. In many embodiments, (a) the pharmaceutical composition is administered for more than 26 weeks, or (b) a titration dose in an amount other than the intended dose is administered over a period of time at the start of the intermittent administration, and/or (c) the human patient is afflicted with early HD .

The severity of prolonged or intermittent muscle contractions associated with dystonia in humans can be measured, for example, on the scale UHDRS TMS: Dystonia.

In addition, a method is provided for improving or maintaining a constant level of motor ability in a human patient in need thereof, including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg, so that thus maintaining or improving the motor abilities of the human patient.

Motor abilities can be measured, for example, by the UHDRS TMS scale, the UHDRS TMS scale: Without chorea, or the UHDRS TMS scale: Without dystonia.

In one embodiment, the patient is dosed with 90 mg, 135 mg, 180 mg, or 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily. In another embodiment, the patient is dosed with 180 mg of pridopidine daily. In another embodiment, motor ability is maintained or improved for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, at least 78 weeks.

The invention also relates to a method for reducing or maintaining a constant level of chorea in a human patient in need thereof, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg, to thereby reduce or maintain the level of chorea in a human patient.

In one embodiment, the patient is dosed with 90 mg, 135 mg, 180 mg, or 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily. In another embodiment, the patient is dosed with 135 mg or 180 mg of pridopidine daily. The level of chorea can also be reduced.

The invention also relates to a method for reducing, maintaining or reducing the severity of chorea in a human patient in need thereof, including periodic oral administration to the patient of a pharmaceutical composition, so that the daily dose of pridopidine administered to the patient is 90 mg, so as to reduce, maintain or reduce the severity of chorea in a human patient.

The invention also relates to a method for reducing, maintaining or reducing the severity of chorea in a human patient in need thereof, including periodic oral administration to the patient of a pharmaceutical composition, so that the dose of pridopidine administered daily to the patient is 90 mg, so as to reduce, maintain or reduce the severity of chorea in a human patient.

In one embodiment, the chorea in the human patient improves or is maintained or decreases in severity for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In one embodiment, the chorea in the human patient improves or is maintained or decreases in severity for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. The chorea of a human patient can be measured by the UHDRS TMS scale: Chorea.

The invention further provides a method for improving, maintaining, attenuating, or reducing deterioration in the behavior and/or psychiatric state of a human patient, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, such that the dose of daily administered the patient was pridopidine 90-225 mg, thereby improving, maintaining, attenuating or reducing the deterioration in the behavior and / or psychiatric state of the patient.

In one embodiment, the method includes maintaining a constant level of behavior and/or psychiatric state of the patient. In another embodiment, the method includes improving behavior and/or psi

- 48 041256 chiatric condition of the patient. In another embodiment, the behavior and/or psychiatric condition of the human patient is improved, maintained, or deterioration is attenuated or reduced for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

The behavior and/or psychiatric condition of the patient may be measured by a total Problem Behavior Assessment (PBA) score. A patient's behavior and/or psychiatric status can also be measured using a short form of the Problem Behavior Assessment (PBA-s). The patient's behavior and/or psychiatric status may also be measured using the Problem Behavior Assessment for Depressed Mood. The behavior and/or psychiatric condition of the human patient can also be measured using the Problem Behavior Assessment for Annoyance. The behavior and/or psychiatric condition of the human patient can also be measured by the Problem Behavior Assessment for lack of initiative or apathy. The patient's behavior and/or psychiatric status can also be measured using the Apathy sub-item of the Problem Behavior Assessment summary form. The patient's behavior and/or psychiatric condition can also be measured using the Apathy Evaluation Scale (AES). A patient's behavior and/or psychiatric status can be measured using the Problematic Behavior Assessment for Obsessive-Compulsive Behavior. The patient's behavior and/or psychiatric status can also be measured using the Problem Behavior Assessment for Disorientated Behavior. In some embodiments, the behavior and/or psychiatric condition of the human patient is measured using the Apathy sub-item of the Short Form Problem Behavior Assessment or the Short Form Problem Behavior Assessment (PBA-s).

The invention also provides a method for reducing or maintaining the involuntary movements of a human patient, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, such that the daily dose of pidopidine administered to the patient is 90-225 mg, so that thereby reducing or maintaining at a constant level the involuntary movements of the human patient.

In one embodiment, the involuntary movements of the human patient are reduced or maintained at a constant level for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. The patient's involuntary movements can be measured on the UHDRS scale TMS: Involuntary movements.

The invention further provides a method for improving or maintaining the mobility of a human patient, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine, such that the daily dose of pidopidine administered to the patient is 90-225 mg, so that thereby improving or maintaining the patient's mobility.

In one embodiment, the mobility of the human patient is improved or maintained for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. The patient's mobility can be measured with the Stand Up and Walk Time Test. Patient mobility can also be measured using the Walk-12: Total Score. The mobility of the human patient can be further measured by the patient's ability to walk.

The present invention also provides a method for improving or maintaining the ability of a human patient to perform physical work tasks, comprising intermittent oral administration to a human patient in need thereof of a pharmaceutical composition containing pridopidine such that the daily dose of pridopidine administered to the patient is 90-225 mg to thereby improve or maintain the patient's ability to perform physical work tasks.

In one embodiment, the ability of the human patient to perform physical work tasks is improved or maintained for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In one embodiment, the ability of a human patient to perform physical work tasks is measured using a modified physical performance test (mPPT).

In another embodiment, the ability of the human patient to perform physical work tasks is measured using the mPPT test: Climbing Stairs. In another embodiment, the ability of the human patient to perform physical work tasks is measured using a total mPPT score. In another embodiment, the ability of the human patient to perform physical work tasks is measured using the mPPT test: Static Standing Balance. In another embodiment, the ability of the human patient to perform physical work tasks is measured using the mPPT test: Getting up from a chair. In another embodiment, the ability of a human patient to perform physical work tasks is measured using the mPPT: pick up and put a book on a shelf test. In another embodiment, the ability of the human patient to perform physical work tasks is measured using the mPPT test: Put on and

- 49 041256 take off the jacket. In another embodiment, the ability of the human patient to perform physical work tasks is measured using mPPT: Pick pennies off the floor. In another embodiment, the ability of a human patient to perform physical work tasks is measured using the mPPT: 360 Degree Rotation test. In another embodiment, the ability of a human patient to perform physical work tasks is measured using the mPPT test: Walk 50 Feet. In another embodiment, the ability of a human patient to perform physical work tasks is measured using the mPPT test: Climbing one flight of stairs. In another embodiment, the ability of the human patient to perform physical work tasks is measured using the mPPT test: Climbing stairs (up and down).

The invention also provides a method for improving or maintaining the quality of life of a human patient, comprising periodically oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidine administered to the patient is 90-225 mg, thereby improving or maintaining the quality of life patient.

In one embodiment, the quality of life of the human patient is improved or maintained for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks. In another embodiment, the quality of life of the human patient is maintained at a constant level. In another embodiment, the human patient's quality of life is measured using the Huntington's Disease Quality of Life (HD-QoL) scale.

The invention further provides a method of reducing the natural deterioration in the general functional ability of a patient with HD, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidine administered to the patient is 90-225 mg, to thereby reduce the natural deterioration in general functional ability in a human patient. In one embodiment, natural deterioration is reduced by 20-70%, 30-60%, or 35-45%. In another embodiment, natural deterioration is reduced by 20%, 30%, 40%, 50%, 60%, or 70%. In one embodiment, natural deterioration is reduced by 0.16-0.56, 0.24-0.48, 0.28-0.36 points per year as measured by UHDRS-TFC. In another embodiment, natural deterioration is reduced by 0.16, 0.24, 0.32, 0.4, 0.48, or 0.56 points per year as measured by UHDRSTFC.

Neurofilament light proteins (NfL) can be used as a biomarker for neurodegeneration in HD patients (Byrne 2017). Plasma concentrations of NfL have been found to increase with the progression of HD disease. Thus, plasma concentrations of NfL in HD patients may provide a means to assess and predict neural damage in HD patients (Byrne 2017). In addition, the results show that blood NfL can provide a reliable estimate of NfL concentration in CSF (Byrne 2017).

The invention further provides a method of maintaining, reducing or reducing the increase in neurofilament light protein concentration in a HD patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the dose is 90-225 mg. Pridopidin is administered to the patient on a daily basis in order to maintain, reduce or reduce the increase in the concentration of neurofilament protein in the human body. In one embodiment, the increase in neurofilament light protein concentration in the human patient is reduced. In another embodiment, the human neurofilament light protein concentration is maintained or decreased.

The invention further provides a method for predicting clinical sensitivity to pridopidine therapy in an HD subject, the method comprising administering an amount of pridopidine and assessing the amount of neurofilament light protein in the subject to thereby predict clinical sensitivity to pridopidine.

In one embodiment, the method further comprises predicting a positive clinical response to pridopidin if the amount of light neurofilament protein decreases in the subject after administration of pridopidin compared to baseline. In one embodiment, the method further comprises predicting a positive clinical response to pridopidin if the amount of neurofilament light protein is maintained in the subject after administration of pridopidine relative to baseline. In another embodiment, the method further comprises predicting positive clinical susceptibility to pridopidine if the amount of light neurofilament protein increases in the subject following administration of pridopidine. Baseline, in this paragraph, is the amount of neurofilament light protein prior to administration of pridopidine.

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

In another embodiment, if the subject is identified as a pridopidin responder, the subject is then administered a pharmaceutical composition containing pridopidin.

In one embodiment, the patient is dosed with 90, 135, 180, or 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 90, 135, or 225 mg of pridopidine daily. In another embodiment, the patient is dosed with 90 mg of pridopidine daily. In another embodiment, the patient is dosed

- 50 041256

135 mg of pridopidine daily. In another embodiment, the patient is dosed with 180 mg of pridopidine daily. In another embodiment, the patient is dosed with 225 mg of pridopidine daily.

In one embodiment, the human patient is afflicted with HD.

In some embodiments, the unit dose of the pharmaceutical composition contains 45, 67.5, 90, or 112.5 mg of pridopidine.

In one embodiment, the pharmaceutical composition is administered twice a day. In another embodiment, an equal amount of the pharmaceutical composition is administered with each administration. In one embodiment, two doses are administered at least 6 hours apart, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours apart. . In some embodiments, the pharmaceutical composition is administered for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

In one embodiment, the patient has a UHDRS-TMS score >25 prior to treatment. In another embodiment, the patient has a UHDRS-IS score (UHDRS scale: independence) below 90% prior to treatment. In another embodiment, the patient has a CAG repeat count in the huntingtin gene greater than or equal to 36. In another embodiment, the human patient has a CAG repeat count in the huntingtin gene of more than 44. In another embodiment, the human patient has less than 44 CAG repeats in the huntingtin gene. . In another embodiment, the human patient is afflicted with early HD. In another embodiment, the human patient has a baseline TFC score that is greater than or equal to 9. In another embodiment, the human patient has a baseline TFC score that is greater than or equal to 7. In another embodiment, the human patient has a baseline TFC score of 11-13. In another embodiment, the human patient has a baseline TFC score of 7-10. In another embodiment, the human patient has a baseline TFC score of 0-6. In another embodiment, the human patient is afflicted with HD and has a baseline TMS score that is the least severe quarter of the total population of HD afflicted patients. In another embodiment, the human patient is afflicted with HD and has a baseline TMS score that is in the two least severe quarters of the general HD patient population. In another embodiment, the human patient is afflicted with HD and has a baseline TMS score that is in the three least severe quarters of the total population of HD afflicted patients. In another embodiment, the human patient is afflicted with HD and has a baseline TMS score that is in the three least severe quarters of the total HD patient population, or a baseline TFC score that is greater than or equal to 9. In another embodiment, the human patient is afflicted with HD and has a baseline TMS score that is in the three least severe quarters of the general HD patient population, or a baseline TFC score that is greater than or equal to 9 or has fewer than 44 CAG repeats in the huntingtin gene. In another embodiment, the human patient is afflicted with HD and has a baseline TMS score that is in the two least severe quarters of the general population of patients afflicted with Huntington's disease. In another embodiment, the human patient is affected by HD and has a baseline TFC score that is greater than or equal to 9 or has more than 44 CAG repeats in the huntingtin gene. In another embodiment, the human patient is HD-affected and has a baseline TMS score that is three of the least severe quarters of the total HD-affected patient population or has less than 44 CAG repeats in the huntingtin gene. In another embodiment, the human patient is afflicted with HD and has a baseline TFC score greater than or equal to 9, or a baseline TMS score that is in the three least severe quarters of the entire HD patient population.

In one embodiment of the invention, pridopidine is pridopidine hydrochloride.

In one embodiment, a titrating dose in an amount other than the intended dose is administered over a period of time at the start of the intermittent administration. In some embodiments, the titration dose is half the amount of the intended dose. In another embodiment, the titrating dose is administered in one daily administration and the intended dose is administered in two daily administrations. In one embodiment, the titration dose is administered 7-21 or 7-14 days prior to the intended dose. In another embodiment, the titration dose is administered 7, 14, or 21 days prior to the intended dose. The titration dose is preferably administered fourteen days prior to the intended dose.

In an embodiment, the method further comprises no worsening of other HD symptoms in the patient from baseline. In one embodiment, the method further comprises no worsening of another symptom of HD compared to a human patient who has not been treated with pridopidine. In another embodiment, the symptoms do not worsen for at least 12 weeks, at least 20 weeks, at least 26 weeks, at least 52 weeks, or at least 78 weeks.

This document provides a pharmaceutical composition containing pridopidin for use in maintaining functional capacity in a human patient, which should be periodically administered orally to the patient so that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, functionality includes ADL.

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament that maintains functional ability in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient in such a way that

- 51 041256 that a dose of 90-225 mg of pridopidine should be administered to the patient daily. In some embodiments, functionality includes ADL.

This document provides a pharmaceutical composition containing pridopidin for use in slowing the clinical progression of HD, as measured by overall functional ability in a human patient, where the pharmaceutical composition is to be administered orally to the patient intermittently such that the daily dose of pridopidin administered to the patient is 90-225 mg .

The present invention relates to the use of an amount of pridopidine in the manufacture of a medicament for slowing the clinical progression of HD as measured by overall functional ability in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document proposes a pharmaceutical composition containing pridopidin for use in maintaining the ability of a human patient to perform basic self-care activities in a human patient, where the pharmaceutical composition should be periodically administered to the patient orally, so that the daily dose of pridopidin administered to the patient is 90-225 mg .

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament for use in maintaining the ability of a human patient to perform basic self-care activities in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in reducing dystonia or maintaining the level of dystonia in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, dystonia includes limb dystonia.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament intended to reduce dystonia or maintain the level of dystonia in a human patient, where the medicament is formulated for intermittent oral administration to the patient so that the daily dose of pridopidine administered to the patient is 90-225 mg. In some embodiments, dystonia includes limb dystonia.

This document provides a pharmaceutical composition containing pridopidin for use in the treatment of dystonia of the extremities in a human patient, where the pharmaceutical composition should be periodically administered to the patient orally so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament for use in the treatment of dystonia of the extremities in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining the same level of gait and balance in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidin administered to the patient is 90-225 mg. In some embodiments, the administration slows down deterioration in the patient's gait and balance.

Provided herein is the use of an amount of pridopidine in the manufacture of a medicament to improve or maintain the gait and balance of a human patient in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90- 225 mg. In some embodiments, the administration slows down deterioration in the patient's gait and balance.

This document provides a pharmaceutical composition containing pridopidin for use in improving, maintaining or slowing the deterioration of gait and balance in a human patient, where the pharmaceutical composition is to be periodically administered to the patient orally, so that the dose of 90 mg of pridopidine is for daily administration to the patient. In some embodiments, the administration slows down deterioration in the patient's gait and balance.

The present document proposes the use of some amount of pridopidine in the manufacture of a medicament to improve, maintain or slow the deterioration of gait and balance in a human patient, where the drug is formulated for intermittent oral administration to the patient, so that the patient should be administered a dose of 90 mg of pridopidine daily. In some embodiments, the administration slows down deterioration in the patient's gait and balance.

This document provides a pharmaceutical composition containing pridopidin for

- 52 041256 applications in improving or maintaining the independence of the human patient, where the pharmaceutical composition should be periodically administered to the patient orally so that the dose of pridopidine administered daily to the patient is 90-225 mg.

The present document proposes the use of an amount of pridopidine in the manufacture of a medicament intended to improve or maintain the autonomy of a human patient, the medicament being formulated for intermittent oral administration to a patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving, maintaining or slowing the deterioration of the independence of a human patient, and the pharmaceutical composition should be periodically administered to the patient orally, so that the dose of pridopidine administered daily to the patient is 90 mg.

The present document proposes the use of an amount of pridopidine in the formulation of a medicament to improve or maintain or slow the deterioration of patient independence when the medicament is formulated for intermittent oral administration to a patient such that the daily dose of pridopidine administered to the patient is 90 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining domains of cognition in a human patient, where the pharmaceutical composition is to be periodically administered orally to the patient so that the daily dose of pridopidin administered to the patient is 90-225 mg.

Provided herein is the use of a certain amount of pridopidine in the manufacture of a medicament for use in improving or maintaining domains of cognition in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90 mg.

Provided herein is a pharmaceutical composition containing pridopidin for use in improving, maintaining, or slowing the deterioration of domains of cognitive function in a human patient, where the pharmaceutical composition is to be administered orally to the patient intermittently, such that the daily dose of pridopidine administered to the patient is 90 mg.

Provided herein is the use of an amount of pridopidine in the manufacture of a medicament for use in improving, maintaining, or retarding deterioration of domains of cognition in a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in reducing the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidine administered to the patient is 90 -225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament to reduce the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient, where the medicament is formulated for intermittent oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90- 225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining a constant level of motor ability in a human patient, where the pharmaceutical composition should be periodically administered to the patient orally, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in improving or maintaining a constant level of motor ability in a human patient, where the drug is formulated for periodic oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90-225 mg .

This document provides a pharmaceutical composition containing pridopidin for use in reducing or maintaining the level of chorea in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in reducing or maintaining the level of chorea in a human patient, where the drug is formulated for intermittent oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90-225 mg.

- 53 041256

This document provides a pharmaceutical composition containing pridopidin for use in reducing or maintaining the same level or slowing down the severity of chorea in a human patient, where the pharmaceutical composition should be periodically administered orally to the patient, so that the dose of pridopidine administered daily to the patient is 90 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament intended to reduce or maintain or slow the severity of chorea in a human patient, where the medicament is formulated for intermittent oral administration to the patient so that the daily dose of pridopidine administered to the patient is 90 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining the behavior and/or psychiatric state of a human patient, where the pharmaceutical composition is to be administered orally to the patient periodically, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

Provided herein is the use of an amount of pridopidine in the manufacture of a medicament for use in improving or maintaining the behavior and/or psychiatric condition of a human patient, wherein the medicament is formulated for intermittent oral administration to the patient such that the daily dose of pridopidine administered to the patient is 90 -225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in reducing or maintaining involuntary movements of a human patient, and the pharmaceutical composition should be periodically administered orally to the patient so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in reducing or maintaining the involuntary movements of a human patient, where the medicament is formulated for intermittent oral administration to the patient so that the daily dose of pridopidine administered to the patient is 90-225 mg.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining a constant level of mobility of a human patient, and the pharmaceutical composition should be periodically administered to the patient orally so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The present document proposes the use of a certain amount of pridopidine for the manufacture of a medicament intended to improve or maintain a constant level of mobility of a human patient, and the drug is intended for periodic oral administration to the patient so that the dose of pridopidine administered daily to the patient is 90-225 mg.

The subject matter of the invention also provides a package including:

a) a pharmaceutical composition containing pridopidine; And

b) instructions for use of the pharmaceutical composition according to the methods of the present invention.

This document provides a pharmaceutical composition containing pridopidin for use in improving or maintaining the ability of a human patient to perform physical work tasks, while the pharmaceutical composition should be periodically administered to the patient orally, so that the daily dose of pridopidine administered to the patient is 90 -225 mg.

The present document proposes the use of a certain amount of pridopidine in the manufacture of a medicament for use in improving or maintaining a constant level of the ability of a human patient to perform physical work tasks, while the drug is designed for periodic oral administration to a patient so that the dose of pridopidine administered daily to the patient is 90-225 mg.

The invention also provides a method of maintaining or improving overall functional ability in a human patient suffering from HD, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine such that the patient is administered a dose of 90 or 180 mg of pridopidine. daily, so as to maintain functional capacity or improve overall functional capacity in a human patient, as measured by UHDRS-TFC, for at least 26 or 52 weeks.

In one embodiment, the patient is dosed with 90 mg of pridopidine daily. In another embodiment, the human patient has a baseline TFC score of 11-13. In another embodiment, the human patient has a baseline TFC score of 7-10. In another embodiment, the human patient has a baseline TMS score that is in the two least severe quarters of the general HD patient population. In another embodiment, the human patient has a baseline TMS score that is three of the least severe quarters of the total HD patient population. In another embodiment, the human patient has

- 54 041256 less than 44 CAG repeats in the huntingtin gene.

The invention also provides a method for maintaining or improving the ability of a human patient to perform elementary self-care activities, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, so that the daily dose of pidopidin administered to the patient is 90 or 180 mg, in order to thereby maintain or improve the patient's ability - a person to perform basic self-care activities, as measured by the UHDRS-TFC domain: Basic Self-Care Activities, for at least 26 or 52 weeks, where the human patient is afflicted with HD.

In one embodiment, the administration further maintains or improves the human patient's ability to manage finances, as measured by the UHDRS-TFC domain: Financial Management, for at least 26 or 52 weeks.

The invention also provides a method of maintaining or improving the ability of a human patient to manage finances, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pidopidin, so that the patient is administered a dose of 90 or 180 mg of pridopidine daily in such a way as to thereby maintain or improve the ability of the human patient to manage finances as measured by the UHDRS-TFC domain: Financial management for at least 26 or 52 weeks where the human patient is afflicted with HD.

In one embodiment, the patient is dosed with 90 mg of pridopidine daily. In another embodiment, the human patient has a baseline UHDRS-TFC score of 11-13. In another embodiment, the human patient has a baseline UHDRS-TFC score of 7-10. In another embodiment, the human patient has a baseline TMS score that is in the two least severe quarters of the general HD patient population. In another embodiment, the human patient has a baseline TMS score that is three of the least severe quarters of the total HD patient population.

The invention also provides a method for maintaining, improving, or reducing the rate of decline in a human patient's ability to perform household chores as measured by the UHDRS-TFC domain: Household chores, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin such that the daily dose of pridopidin administered to the patient is 90 mg, to thereby maintain, improve or reduce the rate of deterioration of a person's ability to perform household chores when a human patient suffers from HD and has a baseline TFC score of 11-13.

The invention also provides a method for maintaining, improving, or reducing the decline in the ability of a human patient to perform household chores, as measured by the Home Affairs domain of the UHDRS TFC, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, so that the daily dose of pridopidine administered to the patient is 90 mg, so as to maintain, improve or reduce the decline in the ability of a person to perform household chores, while the human patient suffers from HD and has a baseline TFC score of 11-13.

The invention also provides a method of maintaining, improving or reducing the rate of deterioration in the level of care of a human patient, as measured by UHDRS TFC: level of care, including periodic oral administration to the patient of a pharmaceutical composition containing pridopidine, so that the dose of pridopidine administered daily to the patient is 90 mg, so that thus maintaining, improving or reducing the rate of deterioration in the level of care of a human patient, wherein the human patient is afflicted with HD and has a baseline TFC score of 11-13.

The invention also provides a method of maintaining, improving or reducing deterioration in the level of care of a human patient, as measured by the Level of care from the UHDRS TFC, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, so that the daily dose of pridopidine administered to the patient is 90 mg, so that such maintain, improve or reduce deterioration in the level of care of a human patient in a manner where the human patient is afflicted with HD and has a baseline TFC score of 11-13.

The invention also relates to a method for improving or maintaining the gait and balance of a human patient, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, such that the patient is administered a daily dose of 90 mg of pridopidine to thereby improve or maintain the gait and balance of the human patient. measured by UHDRS: Gait and balance, for at least 52 weeks, while the human patient is affected by HD and has a baseline TFC score of 11-13.

The invention also provides a method for reducing dystonia or maintaining a level of dystonia in a human patient suffering from HD, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidine, such that the daily dose of pidopidine administered to the patient is 90 or 180 mg, to thereby reduce or maintain the level of dystonia measured by the UHDRS TMS scale: Dystonia, and in a human patient, the initial TFC score is 11-13.

The invention also relates to a method for improving, maintaining or slowing down the deterioration of

- 55 041256 patient dependence, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidine administered to the patient is 90 mg, in order to thereby improve, maintain or slow the deterioration of the independence of the human patient, as measured by the UHDRS scale: Independence, for at least 26 weeks where the human patient is stricken with HD.

The invention also relates to a method for improving, maintaining, or reducing deterioration in a patient's independence, comprising intermittent oral administration to a patient of a pharmaceutical composition containing pridopidin, such that the daily dose of pridopidine administered to the patient is 90 mg, to thereby improve, maintain, or reduce deterioration in the independence of a human patient. measured using the UHDRS scale: Independence, for at least 26 weeks, while the human patient is affected by HD.

In one embodiment, the human patient has a baseline TFC score of 11-13. In another embodiment, the human patient has a baseline TFC score greater than or equal to 7.

The invention also relates to a method for preventing slowdown, decrease in amplitude or deterioration in the ability to perform a finger tapping test in a human patient suffering from HD, comprising intermittent oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90 mg of pridopidin, to thereby prevent slowdown, decrease in amplitude, or impairment of the ability to perform the finger tapping test by the human patient.

In one embodiment, the method further includes preventing slow or irregular performance of the Pronation-Supination test of the arm in a human patient.

The invention also relates to a method for improving or maintaining the behavior and/or psychiatric condition of a human patient, comprising intermittent oral administration to a human patient suffering from HD of a pharmaceutical composition containing pridopidine, so that the daily dose of pridopidine administered to the patient is 90 or 180 mg to thereby improve or maintain the behavior and/or psychiatric condition of the human patient for at least 26 weeks or at least 52 weeks as measured by the Problem Behavior Assessment for irritability or disoriented behavior.

In one embodiment, the human patient has a baseline TFC score of 0-6, the behavior and/or psychiatric status of the human patient is measured by the Problem Behavior Assessment for Annoyance, and the behavior and/or psychiatric status of the human patient is improved or maintained over a period of at least 52 weeks. In another embodiment, the human patient has a baseline TFC score of 11-13, the behavior and/or psychiatric status of the human patient is measured by the Problem Behavior Score for Confused Behavior, and the behavior and/or psychiatric status of the human patient is improved or maintained for at least 26 weeks.

The invention also proposes a method of maintaining:

a) functional capacity in the human patient;

b) the ability of the individual to perform basic self-care activities;

c) the person's ability to manage finances;

d) the person's ability to do household chores;

e) level of care for the human patient;

f) dystonia in a human patient;

g) gait and balance in a human patient;

h) independence in the human patient;

i) cognitive function domains in a human patient;

j) chorea in a human patient;

k) the behavior and/or psychiatric condition of the human patient;

l) motor ability in a human patient;

m) mobility in a human patient; or

n) the ability of the human patient to perform physical work tasks;

including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The invention also proposes a way to improve:

a) functional ability;

b) the ability of the individual to perform basic self-care activities;

c) the person's ability to manage finances;

d) the ability of the human patient to perform household chores;

e) level of care for the human patient;

f) gait and balance in a human patient;

g) independence in the human patient;

- 56 041256

h) cognitive function domains in a human patient;

i) motor ability in a human patient;

j) chorea in a human patient;

k) the behavior and/or psychiatric condition of the human patient;

l) mobility in the human patient; or

m) the ability of the human patient to perform physical work tasks;

including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The invention also proposes a method for reducing:

a) dystonia in a human patient;

b) involuntary movements in a human patient; or

c) the severity of prolonged or periodic muscle contractions associated with dystonia in a human patient, including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the dose of pridopidin administered daily to the patient is 90-225 mg.

The invention also proposes a method for reducing:

a) deterioration in the functional capacity of the human patient;

b) the rate of deterioration in a person's ability to perform basic self-care activities;

c) the rate of deterioration of a person's ability to manage finances;

d) the rate at which a person's ability to perform household chores deteriorates;

e) the rate of deterioration in the level of care in a human patient; or

f) deterioration in the behavior and/or psychiatric condition of the human patient; including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The invention also proposes a method for reducing:

a) deterioration in the functional capacity of the human patient;

b) impairment of the human patient's ability to perform basic self-care activities;

c) deterioration in the ability of the human patient to manage finances;

d) deterioration in the ability of the human patient to perform household chores;

e) deterioration in the level of care of the human patient; or

f) deterioration in the behavior and/or psychiatric condition of the human patient; including periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90-225 mg.

The invention also provides a method for:

a) slowing the deterioration of the gait and balance of the human patient;

b) slowing the decline in the independence of the human patient; or

c) slowing the deterioration of domains of cognitive function in a human patient; comprising periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90 mg.

The invention also provides a method for:

a) reducing deterioration in the gait and balance of the human patient;

b) reducing deterioration in the independence of the human patient; or

c) reducing degradation of domains of cognitive function in a human patient;

comprising periodic oral administration to the patient of a pharmaceutical composition containing pridopidin, so that the daily dose of pridopidin administered to the patient is 90 mg.

The invention also provides a method for:

a) slowing the clinical progression of HD as measured by the overall functional ability of the human patient; or

b) treatment of limb dystonia, preferably, where the treatment includes:

i) preventing a slowdown, decrease in amplitude, or deterioration in the ability to perform a finger tapping test in a human patient, and preventing a slowdown or irregular performance of a pronation-supination test of the hands in a human patient;

ii) preventing slowdown or irregular performance of the hand pronation-supination test in a human patient;

iii) improving the frequency of quantified (Q-motor) motor activity in a finger tapping test in a human patient; or iv) improving the onset interval (IOI) to quantify velocity motor activity;

comprising periodic oral administration to a patient of a pharmaceutical composition,

- 57 041256 including pridopidin, so that the daily dose of pridopidin administered to the patient is 90225 mg.

The invention further provides a pharmaceutical composition containing pridopidine for use in (1) (a) maintaining functional ability, improving functional ability, or reducing impairment of functional ability in a human patient in need thereof, (b) slowing the clinical progression of HD, ( c) alleviate or maintain the level of dystonia in a human patient in need thereof, (d) treat dystonia of a limb in a human patient in need thereof, (e) prevent slowdown, decrease in amplitude or deterioration in the ability to perform a finger tapping test in a human patient and/or preventing slowing or irregular performance of the Pronation-Supination Test, (f) improving or maintaining gait and balance in a human patient in need, (g) improving or maintaining independence in a human patient in need, (h) improving or maintaining the cognitive activity of the human patient in various domains in in a human patient in need, (i) amelioration of prolonged or intermittent muscle contractions associated with dystonia in a human patient in need, (j) improvement or maintenance of motor abilities in a human patient in need, (k) reduction or maintenance of chorea in a human patient in need, (l) improvement, maintenance or reduction of deterioration in behavior and/or psychiatric condition in a human patient in need, (m) reduction or maintenance of an unchanged level of involuntary movements in a human patient in need, (n ) improving or maintaining mobility in a human patient in need, (o) improving or maintaining the ability of the human patient to perform physical work tasks, (p) improving or maintaining the quality of life of the human patient, where the pharmaceutical composition should be periodically orally administered to the patient so that the patient is administered a dose of 90-225 mg pridopid or daily, or (2) (a) improving, maintaining, or reducing the reduction in gait and balance impairment in a human patient in need, (b) improving, maintaining, or reducing the impairment in independence in a human patient in need, (c) improving maintaining or ameliorating cognitive deterioration in a human patient in various domains in a human patient in need thereof, (d) reducing, maintaining or ameliorating chorea in a human patient in need thereof, wherein the pharmaceutical composition is to be periodically orally administered to the patient such that that the patient be administered a daily dose of pridopidine 90 mg.

The invention also contemplates the use of an amount of pridopidine in the formulation of a medicament to (1) (a) maintain functional capacity, improve functional capacity, or reduce impairment of functional capacity in a human patient in need thereof, (b) slow the clinical progression of HD, (c) reduce dystonia or maintaining a level of dystonia in a human patient in need thereof, (d) treating dystonia of a limb in a human patient in need thereof, (e) preventing slowdown, decrease in amplitude, or deterioration in the ability to perform a finger tapping test in a human patient, and/or preventing slowing or irregular performance of the Pronation-Supination test, (f) improving or maintaining gait and balance in a human patient in need, (g) improving or maintaining independence in a human patient in need, (h) improving or maintaining cognitive activities of the human patient different domains in a human patient in need thereof, (i) reducing the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient in need thereof, (j) improving or maintaining motor abilities in a human patient in need thereof, (k ) reducing or maintaining the level of chorea in a human patient in need, (l) improving, maintaining or reducing deterioration in behavior and/or psychiatric condition in a human patient in need, (m) reducing or maintaining involuntary movements in a human patient in need , (n) improve or maintain mobility in a human patient in need, (o) improve or maintain the ability of the human patient to perform physical work tasks, (p) improve or maintain the quality of life of the human patient, where the pharmaceutical composition should be periodically orally administered to the patient so that the patient is administered a dose of 90-225 mg pridop daily, or (2) (a) improving, maintaining or reducing the reduction in gait and balance impairment in a human patient in need, (b) improving, maintaining or reducing the impairment in independence in a human patient in need, (c) improving maintaining or reducing deterioration in the cognitive performance of a human patient in various domains in a human patient in need thereof, (d) reducing, maintaining or reducing the growth of chorea in a human patient in need thereof, wherein the drug is formulated for intermittent oral administration to the patient so that the patient be administered a daily dose of pridopidine 90 mg.

The invention further provides for the use of an amount of pridopidine in (1) (a) maintaining functional ability, improving functional ability, or

- 58 041256 reducing the deterioration of functional ability in a human patient in need, (b) slowing the clinical progression of HD, (c) reducing dystonia or maintaining the level of dystonia in a human patient in need, (d) treating dystonia of a limb in a need thereof of a human patient, (f) preventing slowing, decreasing amplitude, or worsening of the ability to perform a finger tapping test in a human patient and/or preventing slowing or irregular performance of a pronation-supination test of the hands, (f) improving or maintaining gait and balance in a patient in need of this human patient, (g) improving or maintaining independence in a human patient in need, (h) improving or maintaining the human patient's cognitive performance in various domains in a human patient in need, (i) reducing the severity of prolonged or intermittent muscle contractions associated with dystonia in a human patient in need, (j) ul improving or maintaining motor abilities in a human patient in need, (k) reducing or maintaining the level of chorea in a human patient in need, (l) improving, maintaining or reducing deterioration in behavior and / or psychiatric condition in a patient in need - (m) reduce or maintain involuntary movements in a human patient in need, (n) improve or maintain mobility in a human patient in need, (o) improve or maintain the ability of a human patient to perform physical work tasks, (p) improving or maintaining the quality of life of a human patient, wherein the pharmaceutical composition is to be periodically orally administered to the patient such that the patient is administered a dose of 90-225 mg of pridopidine daily, or (2) (a) improving, maintaining, or reducing the reduction in impairment of gait and balance in a human patient in need, (b) improving, maintaining, or lessening the deterioration of the addiction in a human patient in need, (c) improving, maintaining or reducing deterioration in the human patient's cognitive performance in various domains in a human patient in need, (d) reducing, maintaining or reducing the growth of chorea in a human patient in need in this, where the drug is formulated for intermittent oral administration to a patient so that the patient is administered a dose of 90 mg of pridopidine daily.

Each embodiment disclosed herein is construed as applicable to each of the other disclosed embodiments. For example, all combinations of the various elements described herein are within the scope of the invention. In addition, the elements listed in the packaging and pharmaceutical composition embodiments can be used in the method and use embodiments described herein.

Terms.

As used in this document, and unless otherwise noted, each of the following terms shall have the definitions set forth below.

The use of the singular is not restrictive. For example, the method includes the broadest definition of the meaning of the phrase, which can be more than one way.

As used herein, the term effective, as in an amount effective to achieve an end result, means an amount of a component that is sufficient to produce the specified therapeutic response without undesirable side effects (such as toxicity, irritation or allergic response), commensurate with a reasonable ratio of benefit / risk when used in accordance with this disclosure. For example, an amount effective to maintain functional ability or reduce deterioration in functional ability. The specific effective amount will vary depending on such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of treatment, the nature of the concomitant therapy (if any), and the specific formulations used and the structure of the compounds or derivatives thereof.

As used herein, the term treat or treat includes, for example, the reduction of a symptom, the induction of inhibition, regression, or delay of a disorder and/or disease. As used herein, the term inhibiting the progress of a disease or complication of a disease in a subject means preventing or reducing the progress of a disease and/or complication of a disease in a subject.

Administering to an object or administering to a patient (human) means providing, dispensing or administering medicaments, drugs or therapeutic agents to an object/patient to alleviate, cure, or reduce symptoms associated with a condition, such as a pathological condition. The administration may be a periodic administration.

As used herein, the term intermittent administration means repeated/multiple administration separated by a period of time. The period of time between administrations is preferably constant from case to case. Intermittent administration may include administration, for example, once a day, twice a day, three times a day, four times a day, weekly, twice a week, three times a week, four times a week, etc. and so on.

As used herein, the term maintenance of functional capacity in a human patient means that the assessment of functional capacity after a period of administration of pridopidine

- 59 041256 (score after administration) remains unchanged compared with the assessment of the functional ability of the human patient immediately before the period of administration (baseline score). The post-administration score is considered unchanged if the difference between the baseline score and the post-administration score is not statistically significant. The functional ability score can be measured as described herein and includes subsets of the functional ability score.

As used herein, the improvement in functional ability in a human patient means that the functional ability score after a period of pridopidine administration (post-administration score) is improved compared to the functional ability score of a human patient just before the administration period (baseline score).

The functional ability score of a human patient suffering from HD may decrease over time. The rate of such decline may be referred to as the rate of decline in the functional ability score or the rate of deterioration in functional ability or the rate of deterioration in functional ability. For example, on average, the rate of decline in function or decrease in TFC score is faster for patients with early stage HD (TFC score 7-13) than for advanced stage patients (TFC score<7). On average, the decrease is about 0.8-1.2 points per year in patients with early HD, less than 1/2 (about 0.2-0.3) points per year in patients with TFC 3-6; and less than 0.1 for patients with TFC 0-2 (Marder 2000). Therefore, TFC is most sensitive to changes in the early stages of the disease. The overall functional ability score can be measured as described herein and includes subsets of the functional ability score. This deterioration may also be referred to as the natural decline or deterioration in functional capacity in the absence of treatment.

Accordingly, as used herein, reducing the rate of deterioration in functional ability, slowing down the rate of deterioration in functional ability, reducing the rate of functional deterioration, reduced functional deterioration, or slowing the deterioration of functional ability means that the rate of decline in the functional ability score after a period of administration of pridopidine (score after administration) slows down, decreases or decreases compared to the functional ability score of a patient who did not receive the same treatment with pridopidine.

As used herein, reduction in functional impairment or reduction in functional impairment means that the decrease in functional ability score in a patient after a period of pridopidine administration is less than the decrease in functional ability score in a patient who did not receive the same treatment with pridopidine during the same period.

As used herein, maintaining the ability of a human patient to perform basic self-care activities means that the Elementary Self-Care (ADL) score after the period of pridopidine administration (Post-Administered Score) remains unchanged compared to the Human Patient's Elementary Self-Care score immediately before period of administration (baseline score). The post-administration score is considered unchanged if the difference between the baseline score and the post-administration score is not statistically significant. The elementary self-care activity score is a subset of the overall functional ability score and can be measured as described herein.

There are six major ADLs: eating, bathing, dressing, toileting, moving (functional mobility), and the ability to regulate urination and defecation. The ADL is scored as follows: patient requiring general care=0, patient able to perform only simple tasks=1, patient with minimal impairment=2, patient without impairment (normal)=3.

As used herein, the term maintaining a human patient's ability to manage finances means that the financial score after the period of pridopidine administration (post-administration score) remains unchanged compared to the financial score of the human patient immediately before the administration period (Baseline score). The post-administration score is considered unchanged if the difference between the baseline score and the post-administration score is not statistically significant. The Finance score is a subset of the General Functional Ability score and can be measured as described herein.

Financials are scored as follows: patient unable to manage finances=0, patient in need of major assistance=1, patient in need of minor assistance=2, patient, patient in need of no assistance (normal)=3.

As used herein, the term no worsening of other HD symptoms from baseline means that the severity of each of the symptoms of HD in a human patient after the period of pridopidine administration is equal to or less than the severity of the symptom just before the start of the administration period (baseline).

For each baseline score discussed above, in one embodiment, the patient is not administered pridopidine until the baseline score is reached. In another embodiment, some amount of pridopidine

- 60 041256 is administered to the patient until the initial score is reached. In a further embodiment, the amount of pridopidine administered to the patient before baseline is reached is less than or greater than the amount of pidopidine administered to the patient after baseline is reached.

As used herein, the term amount or dose of pridopidin, measured in milligrams, refers to the milligrams of pridopidin present in a formulation, regardless of the form of the formulation. A dose of 90 mg of pridopidine means that the amount of pridopidine in acid form in the formulation is 90 mg, regardless of the form of the formulation. Thus, when pridopidin is in the form of a salt, eg pridopidin hydrochloride, the mass of salt required to provide a 90 mg dose of pridopidin will be greater than 90 mg due to the presence of an additional salt ion.

By any range disclosed herein, it is meant that all hundredths, tenths and integer unit amounts within the range are specifically disclosed as part of the invention. So, for example, from 0.01 to 50 mg means that 0.02, 0.03 .. 0.09; 0.1; 0.2... 0.9; and 1, 2.. 49 mg unit amounts are included as embodiments of this invention.

As used herein, the term pridopidine means a base of pidopidin or a pharmaceutically acceptable salt thereof, as well as derivatives, such as a deuterium-enriched version of pridopidine and a salt thereof. Examples of deuterium-enriched pridopidine and salts thereof and methods for their preparation can be found in US Application Publication Nos. 2013-0197031, 2016-0166559, and 2016-0095847, the entire contents of each of which are incorporated herein by reference. In some embodiments of the invention, pridopidine is a pharmaceutically acceptable salt, such as an HCl salt or a tartrate salt. Preferably, in any embodiments of the invention as described herein, pridopidine is in the form of its hydrochloride salt.

Deuterium-enriched means that the deuterium content at any relevant junction site exceeds the amount of deuterium naturally occurring at that locus in some of the junction. The natural distribution of deuterium is about 0.0156%. Thus, in a deuterium-rich compound, the deuterium content at any of its respective locations is greater than 0.0156% and can vary from greater than 0.0156% to 100%. Deuterium-rich compounds can be prepared by exchanging hydrogen with deuterium or synthesizing the compound using deuterium-rich starting materials.

Pharmaceutically acceptable salts..

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

Examples of pharmaceutically acceptable addition salts include, without limitation, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, L-tartrate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, etc. Such salts can be obtained using procedures well known and described in this field.

pharmaceutical compositions.

Although the compounds for use according to the invention may be administered in the form of a crude compound, it is preferable to administer 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 conventional pharmaceutical excipients. .

In an embodiment, the invention relates to pharmaceutical compositions containing the active compounds or their pharmaceutically acceptable salts or derivatives, together with one or more pharmaceutically acceptable carriers and, therefore, and, optionally, other therapeutic and/or prophylactic ingredients known and used in this field. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient.

The pharmaceutical composition of the invention may be administered by any convenient route that is appropriate for the therapy in question. Preferred routes of administration include oral administration, in particular in tablets, capsules, pills, powder or liquid form, and parenteral administration, in particular dermal, subcutaneous, intramuscular or intravenous injections. The pharmaceutical composition according to the invention can be manufactured by a person skilled in the art using standard methods and conventional methods suitable for the desired composition. If desired, compositions adapted to sustain the release of the active ingredient can be used.

More information on methods of preparation and administration can be found in the latest edition of Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).

- 61 041256

List of abbreviations

The following abbreviations are used throughout the description.

ALT: alanine aminotransferase; ADL: Basic self-service activities; AR: autoregression; AUC: area under the concentration-time curve; bid or bid: twice a day; BL=baseline; CAB: cognitive battery analysis; CAB HVLT-R: Hopkins Verbal Learning Test Redesigned Cognitive Assessment Battery; CGI-C: overall clinical evaluation of changes; CGI-S: overall clinical assessment of disease severity; CI: confidence interval; CIBIC-Plus: assessment of the patient's condition based on the impression of the doctor and caregivers; CIBIS: assessment of the severity of the patient's condition based on the doctor's impression; CIOMS: Council of International Medical Scientific Organizations; C _max : maximum observed plasma drug concentration; CNS: central nervous system; CRF: individual registration card; CRO: contract research organization; CS: complex symmetry; C-SSRS: Columbia University Suicidality Rating Scale; CYP: cytochrome P450; DSM IV TR: Diagnostic and Statistical Manual, Fourth Edition, Revised; EAT: extensive metabolizers; EU: European Union; FA: functional assessment; FAS: complete analysis suite; Freq: click frequency; GCP: Rules for Conducting Quality Clinical Research; GFV-C: static phase cohesive force variability; GGT: gamma-glutamyl transpeptidase; HART: ACR16 Huntington's Disease Randomized Trial; HCG: human chorionic gonadotropin; HD: Huntington's disease; HD-QoL=Quality of life in Huntington's disease; HVLT-R: HAD-CAB revised Hopkins verbal learning test; ICH: International Conference on Harmonization; IEC: Independent Ethics Committee; IOI: interval between pulse starts; IPI: inter-peak interval; IRB: Institute Review Board; IRT: interactive communication technology; IS: Independence Scale; ITI: interval between clicks; ITT: population of all randomized patients according to the prescribed treatment; LSO: local security officer; MAD: multiple incremental dose; MedDRA: Regulatory Medical Dictionary; MermaiHD: multinational European multicentre study of HD ACR16; ML: maximum likelihood; mMS: modified motor function scale; MoCA: Montreal Cognitive Assessment Scale; MS: multiple sclerosis; MTD: maximum tolerated dose; NMDA: Nmethyl-O-aspartate; NOAEL: Level of no observable adverse effects; PBA-s: Problem Behavior Assessment - short form; PD: pharmacodynamics; PDS: physical disability scale; RK: pharmacokinetics; RM: poor metabolizer; PPT: physical performance test; Qd: once a day; Q-Motor: Quantification of motor activity; QoL: quality of life; QTcF: Frederick-corrected QT interval; RBC: erythrocyte; REML: limited maximum likelihood; SAE: serious adverse event; SD: standard deviation; SDMT: character-number matching test; SOC: system organ class; SOP: typical work instruction; SUSAR: suspected unexpected serious adverse reaction; t ¹ / ₂ . half life; TC=phone call; TD: duration of pressing; TF: pressing force; TFC: general functional ability; TMS: General scale of motor activity; TMS: Involuntary movements=combined TMS scores for housework and dystonia. TUG: Stand up and walk time test; UHDRS: Unified Huntington's Disease Rating Scale; ULN: upper limit of normal range; USA: United States; WBC: leukocytes; WHO: World Health Organization; WHO: Drug: World Health Organization (WHO) Directory of Medicines; AHR: change in heart rate from baseline; AQTcF: change in QTcF from baseline; AAHR: placebo-corrected change in heart rate from baseline; placebo-controlled study of Huntington's disease; AAQTcF: placebo-corrected change in QTcF from baseline, week: week; EQ5D-5L European questionnaire for assessing the quality of life on 5 indicators (5 levels).

Clinical researches.

Sixteen (16) clinical studies were completed with pridopidine, including 8 studies in healthy subjects (of which 1 study included patients with schizophrenia), 1 study in patients with Parkinson's disease, 2 studies in patients with schizophrenia (including the study mentioned above) and 6 studies in patients with HD (including 1 open-label extension study). In addition, a charity trial program for the use of pridopidine in patients with HD is ongoing in Europe, and an open long-term safety study is underway in the United States (USA) and Canada. A review of these studies is presented in international publication No. WO 2014/205229, the contents of which are incorporated into the present description by reference.

This invention will be better understood by reference to the experimental details provided below, but those skilled in the art will readily appreciate that the detailed specific experiments are only illustrative of the invention more fully described in the claims that follow.

- 62 041256

Examples

Example 1 Phase II Dosing Randomized Parallel Group Trial Double Blind Placebo Controlled Safety and Efficacy Evaluation of pridopidine 45, 67.5, 90 and 112.5 mg twice daily versus placebo for symptomatic treatment patients with HP (PRIDE-HD).

The present study evaluated the efficacy of pridopidine 45 mg to 112.5 mg twice daily for movement disorders in HD patients for at least 52 weeks of treatment using UHDRS TMS. The study also evaluated the effect of at least 52 weeks of treatment using 45 mg twice daily and 112.5 mg twice daily of the Modified Physical Performance Test (mPPT). The study also evaluated the effect of at least 52 weeks of treatment at a dose of pridopidine 45 mg up to 112.5 mg per dose on UHDRS measures of general functional ability (TFC) and cognitive battery (CAB) analysis. The study also compares data from all patients with data from HD subsets. The study also (i) assessed the safety and tolerability of a range of doses of pridopidine in patients with HD over at least 52 weeks of treatment, (ii) examined the pharmacokinetics (PK) of pridopidine in the study population, and (iii) examined the relationship between exposure to pridopidine and output indicators (for example, parameters of clinical efficacy and toxicity).

Study design.

General design and scheme of the study.

This was a randomized, double-blind, placebo-controlled, parallel-group study comparing the efficacy and safety of pridopidine 45 mg, 67.5 mg, 90 mg, and 112.5 mg twice daily versus placebo in the treatment of movement disorders in HD. . The introduction of pridopidine to patients is given in table. 2. Procedures for research and evaluation are given in Table. 3. A detailed clinical procedure, including screening procedures and other procedures, is given as Example 3 in US Patent Application Publication No. US 2014/0378508 and International Publication No. WO 2014/205229, the contents of which are incorporated herein by reference.

Primary and secondary variables and final evaluation criteria.

The primary efficacy variable and endpoint for this study was the change from baseline UHDRS TMS (defined as the sum of all UHDRS motor domain ratings) at week 26 or week 52. The main measure of motor impairment is the motor function assessment section of the UHDRS, which was performed by a trained assessor. The first part of the motor function assessment consisted of the five TMS sublevels presented below. The sum total of all 31 items is called the Total Movement Scale (TMS). The secondary efficacy variable and end point was change from baseline in mPPT at 26 weeks, or 52 weeks.

mPPT quantifies how well a patient performs physical work tasks (Brown 2000). This is a standardized 9-point test (Standing static balance, Standing up from a chair, Picking up and placing a book on a shelf, Putting on and taking off a jacket, Picking up a penny from the floor, Turning 360 degrees, Walking 50 feet, Climbing one flight of stairs, Walking up stairs (up and down)), which measure the patient's performance in functional tasks. The scoring takes into account the speed and accuracy with which patients perform tasks. The maximum test score is 36, with higher scores indicating better performance. The Multiple Sclerosis Walking Scale (MSWS-12) has been adapted to become a general measure of walking and mobility and has been renamed Walk-12.

Other Efficacy Variables and Endpoints: Other efficacy variables and endpoints for this study are presented below:

Global functional scales: CIBIC-Plus global score compared to baseline; Change from baseline in PDS scale; Change from baseline in UHDRS FA; CGIC compared to baseline; Change from baseline in UHDRS TFC; and Change from baseline in UHDRS IS.

Global/Functional scales.

Change from baseline in HD QoL; and change from baseline in the Walk-12 scale.

Under the TMS scale.

Change from baseline in the Hand Motor Scale (defined as the sum of the UHDRS domains: finger tapping test, hand pronation-supination test, and Luria hand test [fist-rib palm test]); Change from baseline in gait and balance scale (defined as the sum of the UHDRS domains: gait, tandem walking, and retropulsion stability test); Change from baseline in UHDRS mMS (defined as the sum of UHDRS domains: dysarthria, tongue protrusion, finger pressure, hand pronation-supination, Luria hand test, rigidity, bradykinesia, gait, tandem walking, retropulsion stability test); Change from is

- 63 041256 level in UHDRS Chorea; Change from baseline in UHDRS: Dystonia; and responders, defined as patients with UHDRS TMS change from baseline <0.

Other assessments of physical activity.

Change from baseline in the quantitative assessment of motor activity (Qmotor), including digitomotography (accelerated index finger tapping), dysdiadochomotography (pronation/supination hand tapping), manumotography and choreomotography (grip force and chorea analysis), and pedomotography (accelerated foot tapping); and change from baseline in the TUG test.

Cognitive/psychiatric assessments.

Change From Baseline in Brief HD-CAB: SDMT, Emotion Recognition, Path Test, HVLT-R, 3 Hz Tempo Tapping, OTS; and change from baseline to PBA-s.

Variables and final criteria for safety assessment.

Variables and endpoints for safety assessment include the following: AE throughout the study; Changes from baseline in QTcF and other ECG parameters throughout the study; Clinical safety laboratory data (clinical chemistry, hematology and urinalysis) throughout the study; Changes from baseline C-SSRS throughout the study; vital signs throughout the study.

Variables and final criteria for assessing tolerability.

Variables and endpoints for assessing tolerability include the following: number (%) of patients who failed to complete the study; and the number (%) of patients who were unable to complete the study due to AE.

Pharmacokinetic variables and end points.

The main measure of the PK was the determination of the concentration of pridopidine in plasma. Concentrations were also included in a population-based PK model of pridopidine, and individual exposure for study patients (C _max and AUC) was calculated.

Investigational medicinal products and dosage. Pridopidin (as pridopidine hydrochloride) was provided as a size 2 white hard gelatin capsule containing 45 mg of pridopidin and a size 4 white hard gelatin capsule containing 22.5 mg of pridopidine. The placebo was presented as white hard gelatin capsules, corresponding to pridopidin 22.5 or 45 mg capsules, but containing no active ingredient, only excipients (silicified microcrystalline cellulose and magnesium stearate).

table 2

Dose administration (capsules administered twice daily to provide total daily dose)

Treatment Titration period Full dose period Week 1 Week 2 Week 3 Week 4 ^a Weeks 4 ^b to 52 pridopidine 45 mg twice daily 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 22.5 mg pridopidine 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 45 mg Pridopidin 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 90 mg) pridopidine 67.5 mg twice daily 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 22.5 mg pridopidine 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 45 mg Pridopidin 2 x 22.5 mg Placebo (TDD = 90 mg) 1 x 45 mg Pridopidin 2 x 22.5 mg Placebo (TDD = 90 mg) 1 x 22.5 mg Pridopidin 1 x 45 mg Pridopidin 1 x 45 mg Placebo (TDD = 135 mg) pridopidine 90 mg twice daily 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 45 mg Pridopidin 2 x 22.5 mg Placebo (TDD = 90 mg) 1 x 45 mg Pridopidin 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo (TDD = 135 mg) 1 x 45 mg Pridopidin 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo (TDD=135 mg) 2 x 45 mg Pridopidin 1 x 22.5 mg Placebo (TDD = 180 mg) Pridopidin 112.5 mg twice daily 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo 1 x 45 mg Placebo (TDD = 45 mg) 1 x 45 mg Pridopidin 2 x 22.5 mg Placebo (TDD = 90 mg) 1 x 45 mg Pridopidin 1 x 22.5 mg Pridopidin 1 x 22.5 mg Placebo (TDD = 135 mg) 1 x 45 mg Pridopidin 2 x 22.5 mg Pridopidin (TDD=180 mg) 1 x 22.5 mg Pridopidin 2 x 45 mg Pridopidin (TDD = 225 mg) placebo 2 x 22.5 mg Placebo 1 x 45 mg Placebo 2 x 22.5 mg Placebo 1 x 45 mg Placebo 2 x 22.5 mg Placebo 1 x 45 mg Placebo 2 x 22.5 mg Placebo 1 x 45 mg Placebo 1 x 22.5 mg Placebo 2 x 45 mg Placebo

TDD=total daily dose;

^a Excluding day 28;

^b Day 28 only.

- 64 041256

Table 3

Procedures and assessments of the study

Prone 1\ry II Openki Screenshot ntir Period tigression < Obrienka period iio.nioii ,κηοιΊ SH|SH!SL\ First 3b-pellet period ............ ee.che.zhshaya In ιοριΛ 20th yulychιίι Ίοριίο t IC, IC 101MSHTYA 1 kch'eikpis \0 V I HS V2 ts UZ ts V4 V5 ¹ V6' V7* \8 ^J W TS VIC TS TS ts \ II VI? Day Makk ch mum 12 weeks 0 " 1+ 3 20± f 28* F 35* 3' 42 ± S №b '5· 8 I 7 112 with 7 14(1 •4 182 -7 224 .•in 273 "WITH 28ο- 308±10 315 ±10 322- 1357 ±10 3.4±7 378*7 Krone Qpu and Oisnkn Screen shi V L gentle I zero la 2 week shz week la 4 week 5 week F- 6 week 8 week 12; week . .LA' week 20 no, io DYA 2& pele LA 32 week no. week « 44 -'. zhche la L week 52 a week M high visit X X X X X X X X X X X X X 1s yufon thin X X X • X X X informing other interests Lemsh raffia X Msishshinskaya p nsikhschprichs SKSh1 history X -¾ Irsdshsst X Inclusion and exclusion criteria ¹ X X RSHCH1DOMISH1SHCH I X ktiinchsekie .savory thorns e ice you I 1! 0111P1P111Ya) X X X ^e X X X X X AND X X X X Anicic Mil'll! X X \ X X \ X X X X \ X Gesi for pregnant! (zheshshpi I retrotogo iotrayaT * x ^: X X X X X X X X Foil phjMC.il and neurological examination, including "eight I luim.iii f|1M1ChSS and nsnroni shu sksh! oc-,ιυιρ. including M.I.V! (pool U'JM.T) at gkriinsha) X X X X: X X x | >Yu X? V X' ^x1 X ^{11 x1} X' X X ^x1 11 hours of staining "igashl ΙΙΟΚΠΜΙ lOlc'il X X X X X X X .X X X : X X X

- 65 041256 zhzhneleyats > yueti C-SSRS Cheeks hat version) C-SSRS

I Version from guskli's poeipsin) ( ό, her blood for I eueiichekph SH SHLIIC!' THDRS-I\IS ιηΡΡΓ

UHDRS-FA I'HDRS-TFC t'HDRS-lS I'BA-s

shortened RVA-5 X' _x .„ _x " With IBIS X CIBIC-Prui X X X RP-b X X X X X CGI-S X CGI-C X X X X PV-CoE X- X X 1 Q5D-5L X X X Walk-P X X X X X KO YChSch. ί bIΙΗ "|_ openings dti age p.shsh active (Qmotor) ¹¹ X X X X X X X TUG test X X x; X X analysis 0a burnt Yu.INSHSH.NYKH S110№b|YuS1eY X X x _: x; X Lraish ι.ροωι aphids connsngrashsh healer visiting among the wa Xf' χρ x ^q V ¹ X" X'> X X (troii "I") No. • >ιψ to and then mi .'effect-t X: X ,χ X X X X X X X X X X X X X X X >ιψικ o -OH' Go 1 B' 1JIUP ίο card Kenya therapy X X X X X X X X \ \ X X X X X X X X Poll 0 benzo tchantinah and at idepr^ssdidch t Survey about J consumption of drugs Kiir portability to .kimpeiu-Hwnn means before·· escalation (doses of ICCJC apply! X X X X X X X X X gX: X X X Distribution, 5 op of the soul: a healer on foot im X X X X X X X X X ^x1 >review eob nodsipya-nrive rzhennostik therapy X X X X X X X X 1 X X' X V' X it to ici.a{ avg. — — ”— —

Table 3. Legend.

A. The procedures and assessments for these visits (V0 and V4-12) can be completed over several days if they are completed within the specified visit window.

b. Inclusion/exclusion criteria must be met at screening and reviewed on day 0 prior to randomization of the patient.

c. Only electrolytes.

d. Serum pregnancy test at screening (with urinalysis if confirmation required); urine pregnancy test at subsequent time points. Indeterminate Readings

- 66 041256 for a pregnancy test, the serum should be checked twice (urinalysis) and the patient should consult a gynecologist if necessary.

e. Screening will include one ECG. If there is evidence of a prolonged QTcF interval at screening (defined as a QTcF interval > 450 ms), the ECG will be repeated twice and the average of the 3 screening measurements will be used to determine if the patient is eligible for inclusion in the study.

f. At baseline visits, pre-dose QTcF were measured on average by 3 ECGs (within 10-20 minutes of each other), each in three repetitions (total 9 records). A post-dose ECG will be done in triplicate 1-2 hours after the first dose. Samples for PK will be collected before and 1-2 hours after the first dose in situ. In the concomitant ECG, PK samples are collected after the ECG is recorded.

g. One ECG is performed in three repetitions before and 1-2 hours after the daily dose.

h. ECG is optional at 8 weeks unless required by local regulations. This should be done at the discretion of the investigator when there are clinical circumstances that justify an additional ECG, such as in patients with a previous episode of hypokalemia without QT prolongation.

i. At week 52, a triplicate ECG and PK sample will be collected prior to the last study (morning) dose.

j. An ECG is optional at a follow-up visit, but should be done for all patients with pre-existing heart disease and/or QTc change from baseline.

k. Including CAG analysis, cytochrome P450 2D6 status, long QT interval genetic syndrome (assessed only in patients who experience QT interval prolongation following study drug administration leading to study discontinuation), or any other genetic tests associated with a reaction to pridopidine or HD.

l. Assessed as a priority.

m. Safety phone calls will include abbreviated PBA-s (a subset of PBA questions about depressed mood, suicidal thoughts, anxiety, irritability, loss of motivation, and obsessive-compulsive behavior).

n. Including digitomotography (accelerated index finger tapping), dysdiadochomotography (pronation/supination hand tapping), manumotography and choreomotography (grip strength and chorea analysis), and paedomotography (accelerated foot tapping).

O. includes SDMT, emotion recognition, A+B route creation test, HVLT-R; Click test in a given test and OTS.

p. At weeks 2, 12, and 20, PK samples are collected 1-2 hours after the daily dose. In the concomitant ECG, PK samples are collected after the ECG is recorded.

q. At 4, 6 and 16 weeks, PK samples will be collected before and 1-2 hours after the daily dose. In the concomitant ECG, PK samples are collected after the ECG is recorded.

r. On the last day of the study (week 52), study drug administration will take place on site after a predose PK sample has been obtained.

s. At the next visit, 1 sample for PK will be taken. In the case of SAE, an additional PK sample should be targeted for collection in the near future to SAE. In the concomitant ECG, PK samples are collected after the ECG is recorded.

t. This information will be collected as part of a concomitant drug therapy study.

u. Collection only.

v. Compliance with research therapy is reviewed during TC.

w. Each patient took 3 capsules twice a day, i.e. 3 capsules in the morning and 3 capsules in the afternoon (7-10 hours after the morning dose), during the entire study period. Study drug was not administered at the early termination visit. At the field visit, the daily dose was taken locally.

x. Patients who, for safety or tolerability reasons, need to discontinue study medication are encouraged to continue the study and follow the visit schedule as indicated without taking study medication.

Variable and final criterion for assessing primary effectiveness.

UHDRS includes a broad assessment of HD-related features (Huntington Study Group 1996). This is a research tool that has been developed to provide a uniform assessment of the clinical features and course of HD. The TMS component of the UHDRS includes 31 scores out of 15 UHDRS items, with each score scored on a 5-point scale from 0 (normal) to 4 (most abnormal).

Variable and final criterion for evaluating secondary effectiveness.

The secondary performance variable and outcome measure, the Modified Physical Performance Test (mPPT), quantifies a patient's performance in physical

- 67 041256 problems (Brown 2000). This is a standardized 9-item test that measures a patient's performance in functional tasks. Assistive devices are permitted for tasks requiring a standing position (clauses 6-9). Both the speed and accuracy with which patients complete the items are taken into account when scoring. The maximum test score is 36, with higher scores indicating better performance.

Other variables and final criteria for evaluating effectiveness.

Evaluation of the patient's condition based on the impression of the doctor and caregivers.

CIBIC-Plus (a version of ADCS-CGIC) has been developed, validated and widely used in drug research for dementia in Alzheimer's disease (Joffres 2000). An independent rater assessed the overall severity of the patient's disease before starting pridopidine or placebo. This score, known as CIBIS, rates the patient on a 7-point Likert scale from extremely severe HD to asymptomatic HD. At each subsequent evaluation visit, CIBIC-Plus was administered by the same independent rater, but without knowledge of other endpoint scores or AEs experienced by the patient during the study (so as not to confound the CIBIC score as a measure of efficacy or to unmask the study). The independent rater only considers observations of a patient's cognitive, functional, and behavioral performance as obtained from patient and caregiver interviews. The rater then compares these results with the original score. The overall impression of change from baseline (CIBIC-Plus) is rated on a 7-point scale: 1=marked improvement; 2=moderate improvement; 3=minimal improvement; 4=no change; 5=minimum impairment; 6=moderate deterioration; 7=marked deterioration; All scores were relative to baseline. A higher score indicates deterioration in global function. In HD, the inclusion of caregiver data is especially important for the global assessment, as previous studies have shown that patients have limited awareness and recognition of their lesions. The PDS Physical Disability Scale was used during the study as a measure of physical disability. Patients were rated on a scale from 10 (immobility requiring total care - gastrotomy, catheterization) to 100 (Normal; no disease detected) (Myers 1991).

UHDRS Functional Assessments, or UHDRS Overall Functional Assessment The UHDRS TFA scale assesses functionality on 25 tasks of daily activities (eg, Can the patient work in paid work in their usual occupation?). Each question is answered yes or no. The overall clinical assessment of disease severity and CGI-S changes was assessed at baseline, and CGI-C was used at all subsequent time points to assess changes from baseline. The CGI-S scale was originally developed to assess response to treatment in patients with psychiatric disorders (Guy 1976), but is now widely used in a number of conditions. The severity of the disease is assessed by the investigator on a 7-point scale (1=normal, not sick at all, 7=among the most seriously ill). The assessment is based on the judge's judgment, supported by a comprehensive, semi-structured patient/caregiver interview. The CGI-C scale measures the change in a patient's clinical status from a point in time using a 7-point scale ranging from 1 (significantly better) to 7 (significantly worse), with a score of 4 indicating no change.

UHDRS. General functional ability (TFC).

The UHDRS TFC scale is a standardized scale used to rate the 5 disability-related functional domains shown below (employment maintenance, finances, household chores (e.g., laundry, dishwashing), basic self-care activities, and level of care). The TFC score has a range of 0-13 and is the accepted endpoint for disease progression trials. The TFC score was developed and applied by the Huntington Study Group (HSG, 1996) in several studies over 2 decades. The TFC score is accepted by regulatory authorities and is often considered the most widely accepted tool for disease management in HD patients. In addition, TFC is considered the gold standard for measuring the rate of deterioration of HD functional capability. At present, despite numerous attempts, no drug has been shown to delay the decline in TFC. The lower and upper limits make the TFC scores more sensitive to changes in early HD than in late HD.

Functional ability: -.

Keep busy: 0=impossible, 1=non-essential work only, 2=reduced performance for normal work, 3=ok.

Finances: 0=impossible, 1=mostly with help, 2=little help, 3=ok.

Housework: 0=impossible, 1=violated, 2=ok.

Basic Self Care Activities (ADL): 0=general care, 1=simple tasks only, 2=minimal disturbance, 3=normal.

Level of care: 0=skilled nursing full-time, 1=home or systematic care, 2=home.

- 68 041256

UHDRS. Independence scale.

The Independence Scale from the UHDRS is a rating scale in which the degree of patient independence is given as a percentage, from 10% (tube feeding, general hospital care) to 100% (no special care required). Results must end in 0 or 5 (for example, 10%, 15%, 20%, etc.). Patients with a UHDRS-IS score > 90% on examination are not eligible to participate in the study.

Global/Functional scales.

Quality of life in Huntington's disease.

HD-QoL is a standardized tool for measuring health-related quality of life. (Hocaoglu 2012). It is a consensus disease-specific measure for the treatment of HD that can provide an overall assessment of overall health-related quality of life as well as scores on several discrete scales. HD-QoL for people who live with HD; includes people at increased risk of developing HD, people who have tested positive for the huntingtin gene but have no symptoms, and people in the early and advanced stages of the disease. HD-QoL can be used across the entire HD spectrum.

Change from baseline in HD-QoL and in EQ5D-5L was analyzed using an analysis of covariance (ANCOVA) model. The model includes the following fixed effects: treatment, center, antipsychotic use or no use, and baseline HDQoL or EQ5D-5L score. Last Observation Data Transfer (LOCF) was applied to these final evaluation criteria for early exits.

Subscales of the general scale of physical activity.

UHDRS. Hand Motor Scale, or UHDRS TMS. hand motor scale.

The Hand Motor Scale is defined as the sum of the UHDRS domains: finger tapping, hand pronation and supination, and the Luria hand test (fist-rib-palm test).

UHDRS. The Gait and Balance Scale, or UHDRS TMS. Gait and balance scale.

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

UHDRS. Modified Motor Function Scale, or UHDRS. TMS Modified motor function scale.

UHDRS-mMS is defined as the sum of the following domains from UHDRS-TMS: dysarthria, tongue protrusion, finger tapping, hand pronation-supination, Luria hand test, rigidity, bradykinesia, gait, tandem walking, and retropulsion stability test.

UHDRS. Chorea, or UHDRS TMS. Chorea.

In UHDRS, maximal chorea was scored from 0 (absent) to 4 (pronounced/prolonged) for each of the following: face, mouth, trunk, right upper limb, left upper limb, right lower limb, and left lower limb. The maximum chorea is the sum of all scores.

UHDRS. Dystonia or UHDRS TMS. Dystonia.

In UHDRS, maximal dystonia was scored from 0 (none) to 4 (clear/prolonged) for each of the following: trunk, right upper limb, left upper limb, right lower limb, and left lower limb. The maximum dystonia is the sum of all points.

TMS. Share of responders.

Percentage of responders defined as patients with UHDRS-TMS change from baseline <0 at week 26.

Other assessments of physical activity.

Walking scale in multiple sclerosis.

The Multiple Sclerosis Walking Scale (MSWS-12) has been adapted to become a general measure of walking and mobility and has been renamed Walk-12.

European questionnaire for assessing the quality of life on 3 indicators (3 levels).

A 3-level version of the EQ5D (EQ 5D-3L) was introduced in 1990 (EuroQol Group 1990). It consists of the EQ5D Descriptive System and the EQ Visual Analogue Scale (EQ VAS). The EQ 5D-3L descriptive system includes the following 5 dimensions: mobility, self-care, routine activities, pain/discomfort, and anxiety/depression. The development of the 5L retained the five-dimensional structure of the original EQ 5D-3L, but the levels in each dimension were expanded to 5 levels based on qualitative and quantitative research conducted by the EuroQol Group. Labels for each of the dimensions are: No Problem, Minor Problem, Moderate Problem, Serious Problem, and Disability/Extreme Problem. The EQ-VAS is still an integral part of the EQ 5D-5L but has been adapted to make it more user friendly. The respondent is asked to indicate their state of health by selecting the most appropriate statement in each of the 5 dimensions. The EQ VAS records the respondent's self-ratings on a vertical, visual analogue scale, where the final assessment criteria are labeled Best Health and Worst Health. This information can be used to quantify health outcomes.

- 69 041256 according to individual respondents. It should be noted that the numbers 1-3 do not have arithmetic properties and should not be used as a quantitative estimate. EQ5D can be performed by patients with the help of a caregiver/informant if needed.

Quantitative assessments of motor activity (Q-motor).

Motor defects can be objectively assessed using various quantitative measures of motor activity (Q-Motor). All quantification of motor activity (Q-Motor) is based on the use of pre-calibrated temperature controlled force and 3D position sensors with very high sensitivity and retest reliability between sessions and sites in a multicenter clinical study.

Measures of Quantitative Motor Activity Ratings (Q-Motor) thus aim to reduce the limited sensitivity of categorical clinical rating scales, inter- and intra-interviewer variability, and placebo effects seen in scales such as the UHDRS-TMS. In addition, quantitative measures of motor activity (QMotor) allow for objective monitoring of unintended side effects of motor activity in clinical studies. Thus, motor activity quantification (Q-Motor) is an objective, reliable, and sensitive measure of motor function that is not subject to rater bias and limits the impact of the placebo effect. In FIG. 36 shows quantification of motor activity (Q-motor) measurements in a finger tapping test for a normal patient, a mildly impaired patient, and a severely impaired patient. In Track-HD, the largest study on the natural history of asymptomatic and early HD, quantified motor activity (Q-motor) lesions on the digital tapping test correlated with clinical scores as well as regional brain atrophy (Figs. 36 and 37 and Bechtel 2010).

Digitomotography (accelerated index finger tapping) The patient places their hand on the palm rest so that the index finger is over the force transducer. Recordings begin after training. The patient is instructed to tap his finger as quickly as possible between two beeps. The onset of tapping is defined as an increase in force of 0.05 N above the maximum baseline. The tapping ends when the force drops to 0.05 N before the maximum initial level is reached again. Duration and variability in tap duration (TD), onset intervals (IOI), peak-to-peak intervals (IPI), and inter-tap intervals (ITI) are diagnostic outputs for accelerated depression. In addition, the peak tapping force variability (TF) is calculated as a coefficient of variation, and the pressing Freq is determined, i.e. the number of beats between the first and last beat divided by the time between them. Five trials of 10 s duration are carried out with each hand.

Dysdiadochomotography (pronation/supination tapping of the hand) This task assesses the correctness of tapping with the hand while alternating the surface of the palm and the dorsal surface of the hand performing repeated pronation/supination movements. The strength and duration of hand taps are recorded similarly to the task of accelerated tapping. The tone signal prompts the beginning and end of the evaluation. Five trials of 10 s duration are carried out with each hand.

UHDRS: Pronation/supination score.

Assess the ability to rotate the forearm and hand so that the palm is facing down (pronation), and to rotate the forearm and hand so that the palm is facing up (supination) on both sides of the body.

Manumotography and choreomotography (grip force and chorea analysis).

This task allows you to evaluate the coordination of isometric gripping forces with precise clamping between the thumb and forefinger. The grip force is evaluated at the beginning of the grip, during the transport of objects and in the static phase of holding. Patients are instructed to grasp and lift the device equipped with a force sensor and a 3D position sensor by grasping it between thumb and forefinger and holding it stably next to a 10 cm marker. Grip force, 3D position and object orientation are recorded. Mean isometric grip forces and static phase grip force variability (expressed as coefficient of variation=standard deviation [SD]/mean χ100) (GFV-C) are calculated over a 15 second period starting 8 s after the first beep. Five trials of 20 s duration are carried out with each arm. Chorea is evaluated by calculating a position score and an orientation score. The beginning and end of the test is marked with a sound signal.

Pedomotography (accelerated foot tapping).

The patient places the foot on the device so that the ball of the foot is above the force sensor. Recordings begin after training. The patient is told to tap their foot at maximum speed during the period between 2 beeps. The start of pressing is defined as an increase in force of 0.05 N above the maximum initial level. The tapping ends when the force falls again to 0.05 N below the maximum initial level. The duration and variability of TD, IOI, IPI, and ITI are diagnostic outputs for accelerated depression. In addition, the peak TF variability is calculated as a factor

- 70 041256 variations and determine the Freq of pressing, i.e. the number of beats between the first and last beat divided by the time between them. Each leg is subjected to five trials of 10 s duration.

Time test Get up and go.

TUG is a simple test for assessing the mobility of an individual, which requires both static and dynamic balance. This test determines the time it takes a person to get up from a chair, walk 3 meters, turn around, walk back to the chair and sit down. During the test, the person is expected to use their normal footwear and any necessary mobility aids. TUG is often used in the older population because it is easy to perform and most older people can perform it. The test takes little time, requires no special equipment or training, and is easily incorporated into research as part of a routine medical examination (Podsiadlo 1991). The use of the TUG test in combination with UHDRS is recommended for HD clinical trials (Rao, 1991).

The Cognitive Battery (CAB) test for HD CAB can be used to detect symptomatic, procognitive effects (6 months-1 year) and to slow the rate of cognitive decline (>1 year). At 6-12 months after the start of treatment, CAB is especially useful for measuring procognitive effects, and after more than 1 year, CAB is especially useful for detecting a slowdown in the rate of cognitive decline. CAB covers the domains most affected by HD using tests with good psychometric properties. The next six sections describe the tests that are part of the short CAB.

1. Test for matching characters and numbers.

SDMT is a paper and pencil test of psychomotor speed and working memory. Participants need to look at the key at the top of the page, which contains symbols combined with numbers. The rest of the page displays strings of characters and the contestant has 90 seconds to write the number corresponding to each character.

2. Recognition of emotions.

Emotion recognition from facial expressions is tested using computer-generated photographic presentations depicting the 6 basic emotions or a neutral expression. Participants are asked to indicate the emotions expressed in each photo, choosing from the words fear, disgust, happiness, sadness, surprise, anger and neutrality (10 stimuli per emotion).

3. Tests with the construction of the route A and B.

Visual attention and task switching are assessed using a route building test, which consists of 25 circles on a standard sheet of paper. For course A, the participants must connect the circles containing the numbers in ascending order as quickly as possible. For course B, competitors must connect circles containing numbers and letters as quickly as possible, alternating numbers and letters in ascending order (eg 1, A, 2, B, 3, C, etc.). Route A is only used as part of a training session (Bowie 2006). Route A is only used as part of a workout.

4. Revised Hopkins Verbal Learning Test.

The HVLT-R provides a brief analysis of verbal learning and memory (recognition and recall). This test is easy to perform and evaluate, and is well tolerated even by patients with significant impairment. Its use to measure verbal learning and memory has been validated in brain-impaired populations (eg, Alzheimer's disease, HD, amnesic disorder). Each form contains a list of 12 nouns (goals), 4 words taken from each of the 3 semantic categories. Semantic categories differ among the 6 forms, but the forms are very similar in terms of psychometric properties. Preliminary scores are obtained for the ability to recall everything, delayed recall, retention (% of information retained in memory) and recognition discrimination index. The HVLT-R is highly repeat test stable and its constructive, current and discriminant validity is well established. Preliminary scores are derived for training trials 1-3 (ie, ability to recall everything) and trial 4 (eg, delayed recall trials).

5. Tapping test at a given pace.

Psychomotor function is assessed using the Tempo Tapping Test (also known as PTAP). Participants press the left and right mouse buttons, alternating fingers, at a frequency of 3.0 Hz. They first listen to the beeps presented at the desired velocity of tapping, and then start tapping on the beep. After 11 taps on the beep, the repetition of the beep stops and the participants attempt to continue tapping at the same rate until the end of the test (31 taps further).

6. Cambridge Test One Touch Stockings (OTS).

OTS is a spatial planning task that measures the function of the anterior lobe of the brain. OTS is a variant of the Cambridge Stockings task, and places increased demands on working memory as the participant must visualize the solution. As in the Cambridge stockings test, the participant is shown 2 boards with the image of 3 multi-colored sha

- 71 041256 ditch. The displays are presented in such a way that they can be easily perceived as stacks of colored balls held in stockings or socks suspended from a bar. This arrangement makes 3D concepts obvious to the participant and follows verbal instructions. At the bottom of the screen is a row of numbered squares. First, the tester demonstrates to the participant how to use the balls on the lower board to copy their location on the upper board, and solves 1 demonstration problem in which 1 action must be performed. Then the participant must solve 3 more problems, in 2, 3 and 4 actions. After that, the participant is shown several more problems, and he must determine in his mind how many actions are required to solve them, and then touch the square with the corresponding number at the bottom of the screen.

Problem Behavior Analysis - Short Form (PBA-s).

Because of the severity of psychiatric symptoms in HD, it has been recommended that the PBA-s form be used in all HD studies with any need for behavioral assessment as a comprehensive screening for the most common psychiatric symptoms in HD (Craufurd 2001, Kingma 2008). The PBA-s also includes questions regarding suicidal behavior, especially in HD. PBA-s is based on the same set of core behavioral symptoms as the UHDRS behavioral questions previously used as a global psychiatric measure in most HD studies. The PBA-s have more detailed questions and more specific administration and evaluation guidance.

The PBA-s is a short, semi-structured interview covering the most common behavioral and psychiatric manifestations of HD. The interview is not limited to one construct, but covers several broad domains of symptoms related to HD, including 11 items: low mood, suicidal thoughts, anxiety, irritability, anger/aggressive behavior, loss of motivation, perseverative thinking or behavior, obsessive-compulsive behavior, paranoid thinking, hallucinations, behavior suggestive of disorientation. Each symptom is graded according to severity on a 5-point scale according to detailed scoring criteria that roughly correspond to the following: 0=absent; 1=minor; 2=soft; 3=moderate (impairing daily activities) and 4=severe or unbearable. Each symptom is also rated by frequency on a 5-point scale as follows: 0=no symptom; 1=less than once a week; 2=at least once a week; 3=most days (up to and including some of the daily); and 4=all day, every day. The severity and frequency scores are multiplied to obtain a total PVA score for each symptom.

Safety assessment.

In this example, safety was assessed by qualified study personnel by evaluating the following: registered AEs, clinical laboratory test results, vital signs measurements, ECG results, physical and neurological examination results (including body weight), and use of concomitant medications.

Clinical laboratory research.

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

The following serum chemistry analyzes 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 hematological tests were performed: hemoglobin; hematocrit; red blood cell count (RBC); the number of platelets; the number of leukocytes and leukocytes; absolute number of neutrophils; absolute number of lymphocytes; absolute number of eosinophils; absolute number of monocytes; absolute number of basophils; and the absolute number of atypical lymphocytes. Urinalysis includes the following studies: protein; glucose; ketones; blood (hemoglobin); pH; specific gravity; leukocyte esterase; microscopy; bacteria; erythrocytes; leukocytes; cylinders; and crystals.

Basic vital signs.

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

Assessment of pharmacokinetics and pharmacogenomics.

The main measure of the RK is the determination of the concentration of pridopidine in plasma. Concentrations were also included in a population-based PK model of pridopidine, and individual exposure for study patients (C _max and AUC) was calculated.

Taking samples and analyzing blood.

Blood samples (4 ml each) were collected for plasma concentration determination via venipuncture or indwelling catheter on the morning before study drug administration at the following visits:

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Titration period: day 0 (baseline) before and 1-2 hours after the first dose, and day 14 dose 1-2 hours after noon. Full treatment period: Day 28 - dose before noon and 1-2 hours after noon, Day 42 - dose before noon and 1-2 hours after noon, Day 84 - after 1-2 hours after noon, Day 112 - dose before noon and 1-2 hours in the afternoon, 140 days - dose 1-2 hours in the afternoon, day 182 - before the morning dose and at the control visit.

Sample analysis.

Samples were analyzed using the appropriate approved method for the content of pridopidine and its main metabolite TV-45065 (formerly called ACR30). The lower limits of quantification of pridopidine and TV-45065 in plasma are approximately 1.6 to 1.8 ng/mL and 1.5 to 1.9 ng/mL, respectively.

pharmacogenetic variables.

A blood sample (10 ml) was collected in 2 plastic tubes with dipotassium ethylenediaminetetraacetic acid (K2EDTA) at the time of the screening visit for genetic analysis. Analyzes included CAG repeats, CYP2D6 status and genetic long QT syndrome, or any other genetic tests associated with pridopidine or HD response.

Primary efficiency analysis.

Change from baseline in UHDRS-TMS was analyzed using a repeated measurements model (SAS® MIXED procedure with REPEATED subcommand). The model includes the following fixed parameters: study week category by treatment, center, antipsychotic use or no use, and baseline UHDRS-TMS score. In repeated examinations of patients, an unstructured covariance matrix is used. In case the model did not converge, the maximum likelihood (ML) estimation method was used instead of the default restricted ML (REML). If the model still does not converge, use simpler covariance structures with fewer parameters, according to the following order: heterogeneous autoregressive (1) (ARH(1)), heterogeneous with compound symmetry (CSH), autoregressive (1) (AR (1)) and a system with complex symmetry (CS). The estimated mean visit at week 26 of change from baseline in UHDRS-TMS was compared between the active treatment groups) and the placebo group.

Sensitivity analysis.

A sensitivity analysis to assess whether an observed effect in UHDRSTMS is due to the UHDRS-TMS subscale: Chorea, the UHDRS-TMS subscale: Dystonia, or the UHDRSTMS subscale Involuntary movements (chorea+dystonia) is performed as follows:

Three variables were calculated: (1) change from baseline to week 26 and week 52 in total UHDRS-TMS items excluding chorea items, (2) change from baseline to week 26 and week 52 in the sum of UHDRS-TMS items excluding dystonia items, and (3) the change from baseline to week 26 and 52 in the sum of UHDRS-TMS items excluding chorea and dystonia items. These variables were analyzed in the same way as the primary outcome measure of efficacy, except that the variable score at baseline was included in the model instead of baseline UHDRS-TMS.

Pharmacokinetic analysis.

Plasma concentration data for pridopidine and the main metabolite TV-45065 are reported using descriptive statistics in terms of pridopidine dose and CYP2D6 metabolizer status. Concentrations are also used for the population PK model of pridopidin, and to calculate the individual exposure of patients participating in the study (C _max and AUC).

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pridopidin mg twice 67.5 mg twice 90 mg twice 112.5 mg twice

Analysis group, η (%) Placebo daily once daily once daily once daily All Total

Stopped treatment during 1st period 12(15) 22 (27) 17(21) 14(17) 20 (24) 73 (22) 85* (21) Death 0 0 0 0 0 0 0 By-effect 5(6) 6(7) 11(13) 11(14) 14(17) 42(13) 47 (12) Terminated by object 3(4) 9(H) 3(4) 0 3(4) 15(5) 18(4) non-compliance 2(2) 1(1) 1(1) 0 0 2 (<1) 4 (<1) protocol violation 1(1) 1(1) 1(1) 1(1) 0 h (<1) 4 (<1) Pregnancy 0 0 0 0 0 0 0 Lost to follow up 0 0 0 0 0 0 0 Loss of efficiency 0 0 1(1) 0 0 1 (<1) 1 (<1) Other 1(1) 5(6) 0 2(2) 3(4) 10(3) 11(3) Stopped treatment during 1st period but continued until FU 1(1) 0 2(2) 2(2) 2(2) 6(2) 7(2) Completion of 26 weeks of study 70 (85) 61 (75) 66 (80) 67 (83) 66 (80) 260 (80) 330 (81) Amendment to signed protocol 4 59 (72) 55 (68) 60 (73) 62 (77) 57 (70) 234 (72) 293 (72) Included in the 2nd period 57 (70) 49 (60) 54 (66) 56 (69) 46 (56) 205 (63) 262 (64) Those who started processing in the 2nd period 57 (70) 49 (60) 52 (63) 56 (69) 46 (56) 203 (62) 260 (64) ITT population for analysis 52 weeks (ITT2) 82 (100) 81 (100) 82 (100) 81(100) 82 (100) 326 (YuO) 408 (YuO) population study for safety analysis at 52 weeks (SP2) 82 (100) 81 (100) 82 (100) 81(100) 82 (100) 326 (YuO) 408 (YuO) population study PK for analysis 52 weeks 0 0 0 0 0 0 0

(RK2)

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Complete assay kit for analysis at 52 81 (99) weeks (FAS2) 75 (93) 79 (96) 81 (100) 81 (99) 316 (97) 397 (97) Complete treatment at 52 weeks 52 (63) 43 (53) 44 (54) 53 (65) 44 (54) 184 (56) 236 (58) Stopped treatment during 2nd period 5(6) 6(7) 8(10) 3(4) 2(2) 19(6) 24(6) Death 0 0 0 1(1) 0 1 (<1) 1 (<1) By-effect 1(1) 4(5) 5(6) 0 1(1) Yu(3) 11(3) Terminated by object 2(2) 1(1) 2(2) 0 0 3(<1) 5(1) non-compliance KD 0 0 0 0 0 1 (<D protocol violation 0 0 0 0 0 0 0 Pregnancy 0 0 0 0 0 0 0 Lost to follow up 0 0 0 0 0 0 0 Loss of efficiency 1(1) 0 0 1(1) 1(1) 2(<1) h (<1) Other 0 1(1) 1(1) 1(1) 0 3 (<1) h (<1) Stopped treatment during 2nd period but continued to FU 0 1(1) 2(2) 0 1(1) 4(1) 4 (<1) Completion of 52 weeks of study 52 (63) 43 (53) 46 (56) 52 (64) 44 (54) 185 237

(57) (58)

Stages of Huntington's disease.

Many clinicians and diagnosticians use the Shoulson and Fan grading scale based on TFC scores to track the progression of HD. This rating scale groups total TFC scores into five disease stages, with lower stages indicating more intact functioning. In the table below. Figure 4 presents TFC rates, mean years after diagnosis, and general recommendations for typical levels of care for each stage of the disease (Johnson 2014). Tab. 5 shows the number of patients at each stage of TFC participating in the study.

Table 4

Stage TFC score years after motor activity diagnostics Typical abilities and level of care 1 11-13 0-8 Able to work at least partially working day, may be required a little help in one of the number Finance, Household or Basic ADL functions 2 7-10 3-13 Unable to work, needs some help with some basic functions 3 3-6 5-16 Inability to work, requires major assistance with most basic functions 4 1-2 9-21 Requires significant assistance in all major functions, and although perception may be intact, assistance in action is required. 5 0 11-26 Needs serious help with all major functions and complete care

Stage 1 or 2 patients have the highest rate of natural deterioration and are most sensitive to the clinical indicator described in this application. The TFC and HD-CAB scores are designed specifically for patients with stage 1 or 2 and earlier. Patients in stages 3, 4, or 5 often have difficulty making assessments, the lower and upper limits of their ability to track changes, and very significant loss of brain tissue.

Early stage HD, as used herein, means stage 1 or 2 HD (BL TFC>7) as defined in Table 1. 4 above.

Table 5

Stages of HD patients in the study

N % years since HD diagnosis Stage 1 (TFC = 1113) 78 19 3 Stage 2 (TFC = 7-10) 218 53 5 Stage 3 (TFC = 3-6) 101 25 5-8 Stage 4 (TFC = 1-2) 10 2 >8 Stage 5 (TFC = 0) 1 <1

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Results.

The results of this example are shown in FIG. 1-47 and in table. 6 below.

Table 6

Respondent Analysis Questions Analysis of observed data 45 mg twice a day N=37 placebo N=41 What proportion of early stage subjects did not have TFC deterioration (score >0) at 52 weeks? 30(81%) 20 (49%) p-value (chi-square) 0.003 What proportion of early stage subjects had >1 point improvement on TFC at 52 weeks? 10 (27%) 5 (12%) p-value (chi-square) 0.099

Between patients receiving 45 mg twice daily and patients receiving placebo, there was a significant difference in the proportion of subjects who did not experience a decrease in TFC over 52 weeks.

Review of the preliminary analysis of functional, diagnostic end-point evaluation criteria and safety.

Endpoints that are independent of rater bias were less susceptible to placebo effect, such as motor activity quantification (Qmotor). The detected signals are indicative of the biological effects of pridopidine. Total functional capacity (TFC) showed trends in favor of pridopidine after 26 weeks of treatment. Despite high doses, no important data related to the safety of use have been obtained.

Preliminary results on TFC scales - considerations.

An expected deterioration of approximately 0.5 points was observed in the placebo group after 6 months. Medical history data indicate that in patients with HD, TFC worsens by about 1 point per year. TFC starts showing a divergence from placebo at 12-20 weeks and the divergence becomes a strong trend at 26 weeks. The TFC data support the conclusion that pridopidine causes a delay in the progress of deterioration in functional capacity. Fig. 42 shows a graphical representation of the deterioration of TFC at different stages of the disease.

Regardless of the particular theory, the treatment effects shown in the figures were more pronounced in the treatment of patients in the early stages (including stages 1 and 2), especially in early stages with a baseline TFC level greater than or equal to 7, and especially in stage 1 (BL TFC=11-13). Regardless of the specific theory, this is especially true for TFC: Finance and ADL, TFC: Housework, Dystonia, Involuntary movements (dystonia and chorea), Gait and balance. An HD patient with a baseline TFC score of 11-13 is considered a stage 1 HD patient.

Potential placebo factors in this example.

The following elements may explain the placebo effect observed in this example: rater bias, lack of hope in HD coupled with high expectations of effective treatment and desire for recovery in patients, overall positive data with pridopidine treatment results in high expectations, patients have 80 % chance of receiving active treatment, large number of pills may result in expected duration, protocol changes during the study, and number of grades per visit.

Dystonia.

The general treatment of dystonia illustrated in this application is a typical treatment for the following types of dystonia: early-onset generalized dystonia (DYT1 and non-DYT1), focal dystonia, musicians' dystonia, DOPA-responsive dystonia, myoclonic dystonia, paroxysmal dystonia and dyskinesia, X-linked dystonia-parkinsonism, rapidly developing dystonia-parkinsonism, secondary dystonia, dystonia in patients with HD, and psychogenic dystonia. In particular, the present invention relates to the treatment of dystonia in a patient with HD, for example, in a patient with an early stage (stage 1 or stage 2).

Discussion.

The efficacy of pridopidine.

Pridopidine has previously shown beneficial effects on motor function in 2 large, double-blind, placebo-controlled trials in patients with HD (HART and MermaiHD). The primary endpoint for both studies was mMS. Both studies provided evidence of a positive effect on the UHDRS-Total Movement Scale (TMS), demonstrating a difference in favor of pridopidine 45 mg twice daily compared to placebo. In a pooled analysis of 2 studies, pridopidine 45 mg significantly improved TMS compared to placebo at weeks 12 and 26 (Landwehrmeyer 2011). The PRIDE-HD study used change in TMS from baseline to week 26 as the primary endpoint to further evaluate the effects of pridopidine at doses ranging from 45 mg to 112.5 mg twice daily.

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The PRIDE-HD study included patients at all stages of the disease (i.e., early and late stages), and 72% of patients treated with pridopidine were in the early stages of the disease (stages 1 and 2 HD; baseline TFCs from 7 to 13). (HD1 and HD2)). In the early stages of HD, many HD clinical scales and assessment tools are most sensitive to time-dependent changes. PRIDE-HD did not meet the primary endpoint compared to placebo due to the large placebo effect. However, an analysis of data from the PRIDE-HD trial demonstrated a smaller reduction in UHDRS-TFC score in patients treated with pridopidine 45 mg twice daily compared to patients treated with placebo (type I error correction for multiple comparisons was not applied). This effect was most evident in patients with early HD.

Fig. 1 and 2 are graphs showing measurements of pridopidin concentration (ng/ml) in the blood of patients up to week 20 of treatment.

Fig. 3-5 are graphs showing the change in UHDRS TMS over time. A lower number represents an improvement. In FIG. 3 shows the dose comparison in the PRIDE-HD study. In FIG. 4 shows the placebo effect in UHDRS TMS, which was higher in the PRIDE-HD study than in the MermaiHD or HART studies. In FIG. 5a shows improvement in UHDRS TMS for both pridopidine 45 mg and pridopidine 90 mg in the PRIDE-HD study compared to placebo in the MermaiHD and HART studies. In FIG. 5b shows overall improvement in UHDRS-TMS for pridopidine 45 mg twice daily.

UHDRS: general functional capability (UHDRS TFC).

The data in this application demonstrates that pridopidine has an effect on the progression of HD as measured by total functional capacity (TFC). This effect on TFC was statistically significant in the full assay set and even more pronounced in patients with early HD. Patients with early HD are defined as patients with a baseline (BL) TFC score greater than or equal to 7 (stage 1 and stage 2).

There was a significant reduction in UHDRS TFC between patients treated with pridopidine at some doses compared with patients treated with placebo at 52 weeks in both the full assay set (FAS) and the early stage HD subset. Patients with early-stage HD (baseline 7-13) receiving pridopidine have more positive TFC results than patients with late-stage HD (baseline 0-6) receiving pridopidine. The effect on TFC observed after 26 weeks reached significance in the early stage subpopulation (FIGS. 10b and 20b). The effect on TFC observed after 52 weeks reached significance in the early stage subpopulation (FIGS. 10d, 11d, 21j, 31b).

The annual decrease in TFC in the placebo group, shown for example in FIG. 10c, 21j and 31a was comparable to the annual decline in TFC reported in the literature and seen in historical placebo groups. As shown, for example, in FIG. 10b, 10d, 21b, 21j, 21n, and 31b, worsening of TFC in placebo patients was higher in patients with early HD. These data show a slowdown in HD clinical progress as measured by TFC and is the first clinical study to be done among eleven (11) other clinical trials. Significance was observed in UHDRS TFC at 26 weeks (Fig. 21b) TFC: Finance at 26 weeks (Fig. 12b, 21d, 21f), TFC: Finance and ADL at 26 weeks (Fig. 11b, 21d), TFC: ADL at 26 weeks (Fig. 21h) and UHDRS: TFC at 52 weeks (Fig. 21j) TFC: Finance at 52 weeks (Fig. 21n), TFC: Finance and ADL: at 52 weeks (Fig. 11e, 21l), TFC: ADL after 52 weeks (Fig. 21p).

UHDRS scale: independence (UHDRS IS).

UHDRS-IS is part of the functional evaluation of UHDRS (Huntington Study Group 1996). This is a rating scale in which the degree of independence of the patient is indicated as a percentage, from 10% (tube feeding, general hospital care) to 100% (no special care required). Results must end in 0 or 5 (for example, 10%, 15%, 20%, etc.). Scale scores were collected at screening, baseline, 4, 12, 20, 26 weeks/early termination, 28 and 52 weeks/early termination.

Change from baseline score at week 52 UHDRS-IS is shown in FIG. 9e. The change from baseline in UHDRS-IS assessed at week 52 decreased across treatment groups but was not statistically significant in any treatment group. For the placebo group, there was a decrease (indicating a downward trend) in IS at week 52. Positive trends in the desired direction were observed in patients with HD in the early stages (baseline TFC score>7) at 52 weeks (see Fig. 20d). There were no clinically significant changes in patients with baseline TFC<7. The independence scale supports the TFC effect, which ensures the convergence of the final assessment criteria.

UHDRS TMS and final criteria for assessing physical activity.

The effects of locomotor activity were statistically significant in the stage 1 subpopulations. For example, statistically significant changes are observed in subgroups of patients with stage 1 HD for general TMS, Involuntary movements (dystonia, chorea),

Ability to move (TMS: Gait and balance, Stand and walk time test, Walk test 12). An improvement in the ability to move may contribute to the TFC data.

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The large placebo response masked motor effects in the full assay set. However, in the early stages of HD, there was a statistically significant effect on TMS at 26 weeks (Fig. 8b) and 52 weeks (Fig. 8d) due to the lower placebo effect. Involuntary movements (chorea and dystonia) measured by TMS improved in stage 1 HD patients at 26 weeks (Fig. 8n). The effect persisted at week 52 (Fig. 8p).

Effects were seen primarily with 45 mg twice daily and 90 mg twice daily, indicating a non-linear dose response.

In addition, positive effects on locomotion (such as gait, stand-up-and-go time test, and climbing stairs) were observed in early stage patients treated with pridopidine 45 mg (see, for example, Figs. 18b, 18d, 19b, 19d ).

PBA-s.

The PBA-s is a short, semi-structured interview covering the most common behavioral and psychiatric manifestations of HD. The interview is not limited to one construct, but covers several broad symptom domains relevant to HD, including 11 items: low mood (depression), suicidal thoughts, anxiety, irritability, anger/aggression, loss of motivation (apathy), perseverative thinking or behavior, obsessive-compulsive behavior, paranoid thinking, hallucinations, behavior suggestive of disorientation. Each symptom is graded according to severity on a 5-point scale according to detailed scoring criteria that roughly correspond to the following: 0=absent; 1=minor; 2=soft; 3=moderate (impairing daily activities) and 4=severe or unbearable. Each symptom is also rated by frequency on a 5-point scale as follows: 0=no symptom; 1=less than once a week; 2=at least once a week; 3=most days (up to some part of each day); and 4=all day, every day.

The severity and frequency scales are multiplied (after all values outside the range 0 to 4 are omitted) to obtain an overall PBA-s score for each symptom. The total PVA score is calculated as the sum of all symptom/domain PVA scores.

PVA scores were collected at baseline, 4, 12, 26, and 52 weeks.

The change from baseline score at week 26 in PBA-s domains and total scores showed no significant results (FIGS. 17a-d, 17i). However, the change from baseline to week 52 in total PBA-s score as well as several PBA-s domains showed a trend towards improvement or significant improvement (FIGS. 17d-17h). In the full assay set, the pridopidine 45 mg group showed a trend towards improvement in PVA: Overall Scale at 52 weeks compared with the placebo group (Δ3.98 placebo points, p=0.0603, n=75) (see FIG. 17e-17f)). Fig. 17j and 17l show a trend towards improvement in PVA: Apathy in early stage patients at 26 weeks and 52 weeks, respectively. Fig. 17r shows significant improvement in PVA: Confusion in early stage patients at 26 weeks for 45 mg twice daily, respectively.

HD Cognitive Battery Analysis Test.

The PRIDE-HD study was the first major study to include the HD Cognitive Battery Test (HD-CAB) (Stout et al., 2014). HD-CAB was designed to detect symptomatic, procognitive effects (6 months-1 year) and slow the rate of cognitive decline (>1 year) in patients with late asymptomatic, HD1 and HD2. HD-CAB covers the cognitive domains most affected in HD with tests with good psychometric properties. The battery includes the following tests: Symbol-Number Matching Test, Emotion Recognition Test, Path Building Test B, Revised Hopkins Verbal Learning Test, 3 Hz Tempo Tapping Test, and Cambridge One-Touch Stockings Test.

For the 6 domains of HD-CAB, there was no consistent pattern of improvement or decline as evidenced by mean changes from baseline for the pridopidine or placebo groups.

Positive results indicating a potential improvement from baseline in tapping at a given pace at 3 Hz (a measure of psychomotor function) were observed in the full analysis performed at week 52 for the 45 mg twice daily treatment group (see FIG. 41d).

Example 2. Effect of pridopidine on the functional capacity of patients with Huntington's disease.

Goal of the work.

To study deterioration in functional capacity as measured by the Total Functional Capacity (TFC) scale in patients treated with pridopidine 90 mg/day without placebo for 36 months (OPEN-HART) and compare results with historical cohorts of patients treated with placebo, enrolled in HSG sponsored studies (CARE-HD and 2CARE).

prior art.

Patients with HD experience motor, cognitive, and behavioral symptoms that lead to severe, long-term disability. TFC (range 0-13, high scores indicate greater

- 78 041256 higher ability) assesses the ability of patients to work, manage finances and household chores, perform basic self-care activities and live independently, and is most sensitive to early changes in disability. TFC was used in the OPEN-HART and Coenzyme Q10, CARE-HD and 2CARE studies.

Ways.

This analysis compared the OPEN-HART cohort (n=50) treated with pridopidine 90 mg/day and the placebo CARE-HD (n=80) and 2CARE (n=213) cohorts, without matching baseline characteristics. For this analysis, TFC scores at baseline, 12, 24, and 36 months from OPEN-HART and 2CARE, and TFC scores at baseline, 12, 25, and 30 months from CARE were used.

Results.

At baseline, the OPEN-HART cohort had the lowest absolute mean (SD) TFC score compared to the CARE-HD and 2CARE cohorts [9.14 (2.78), 10.3 (1.7), and 11.05 (1 .47), respectively].

Mean change from baseline in TFC at 12 months for OPEN-HART was: -0.49 (1.60), CARE: -1.00 (1.48) and 2CARE: -1.11 (1.62 ); after 24 months (OPEN-HART and 2CARE) and 25 months (CaRE) were: -1.00 (1.92), -1.80 (2.06) and -2.24 (1.91), respectively; after 36 months (OPEN-HART and 2CARE) were: -1.68 (2.22) and -2.54 (2.53), respectively; and after 30 months (CARE) was: -2.80 (2.27).

The results show that the decrease in TFC over time was slower in patients who received pridopidine in OPEN-HART compared to those who received placebo in CARE-HD and 2CARE. A slower decline in TFC levels was observed, suggesting that pridopidine has neuroprotective and/or disease-modifying properties.

Example 3 Phase 3 study.

The proposed phase 3 study is a 78-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of pridopidine 45 mg twice daily in adult patients with early HD.

The study consists of a screening period (up to 8 weeks); 2-week titration period; 76 weeks double-blind full dose treatment period; and the follow-up period (consisting of an end-of-study visit 3-4 weeks after the end-of-treatment visit).

During the screening period, patients provide informed consent and are subsequently assessed to determine eligibility for the study. The HD stage is set on the UHDRS TFC scale. TMS and UHDRS-IS are evaluated. The TMS score was conducted by trained raters on site and also videotaped for central rating by an independent blind third party (Independent Judgment Committee (IAC)). The IAC minimizes rater bias and errors during screening by reviewing all information collected at screening, including the patient's medical history, before any patient is approved for randomization.

Eligible patients are encouraged to return for baseline visits and baseline assessments. Those patients who were still eligible for the study were randomly assigned (in a 1:1 ratio) to 1 of 2 treatment groups: 45 mg twice daily - pridopidine or placebo. For patients treated with pridopidine, the dose is titrated over the first 2 weeks from 45 mg daily to a final dose of 45 mg twice daily of pridopidine.

During titration (days 0 to 14), patients receive 1 scheduled telephone call (TC) during the second week. Patients visit on-site clinics at 26, 52, and 78 weeks to evaluate safety and efficacy, and to collect blood to evaluate pharmacokinetics. At 3, 6, 12, 39, and 65 weeks, there are safety visits either by a visiting nurse at home or in the clinic. Patients will receive 1 scheduled TS approximately 6-7 weeks after each home visit or local clinic visit. During these TSs, patients are asked about the following: adverse events, concomitant medications, alcohol/drug use, study drug tolerance, benzodiazepine and antidepressant use, and adherence to therapy. The C-SSRS (starting with the last visit version) and the abbreviated PBA-s (a subset of the PBA-s questions on depressive mood, suicidal ideation, anxiety, irritability, loss of motivation, and obsessive-compulsive behavior) are assessed.

Patients who complete all scheduled visits have final procedures and evaluations conducted at the end of treatment visit (week 78). Patients who withdraw from the study prior to the completion of the evaluation period will have week 78 procedures and evaluations performed at their last visit, which is considered their early termination visit.

Approximately 3-4 weeks after the last dose of study drug, an end-of-study exit visit is performed to evaluate efficacy, safety (including one ECG), pharmacokinetics, recovery, and dependence.

Primary final evaluation criterion.

The primary end point of efficacy to be assessed is the change from baseline in TFC at week 78 in patients treated with pridopidine 45 mg twice

- 79 041256 times a day, compared with patients receiving placebo. The primary efficacy analysis is performed using a linear, mixed, repeated measures model with change from baseline in the primary outcome measure (TFC) as the dependent variable in the modified treatment population (randomized patients with at least 1 TFC score after baseline). level). The model includes visit (4 levels: 12, 26, 52 and 78 weeks), treatment group, treatment group interaction visit, country, HD stage (HD1 or HD2), and antipsychotic use (yes or no) as fixed factors, and includes the corresponding baseline score as a covariate. An unstructured covariance matrix is used for repeated observations on patients, and the Kenward-Roger method is used to calculate the degrees of freedom in the denominator. The primary analysis for TFC will compare the change from baseline to week 78 between pridopidine 45 mg twice daily and placebo. Lower scores indicate more severe functional impairment than higher scores.

Secondary final evaluation criteria.

Two secondary endpoints are selected based on evidence-based trends observed in PRIDE-HD.

1. Change from baseline to week 78 in UHDRS TMS in patients treated with pridopidine 45 mg twice daily compared with patients receiving placebo.

TMS is the standard and accepted clinical tool for tracking the progress of motor symptoms in patients with HD (Huntington Study Group 1996). The motor function section of the UHDRS assesses motor function signs in HD using standardized assessments of oculomotor function, dysarthria, chorea, dystonia, gait, and postural stability. TMS is the sum of 31 individual motor function ratings, with each rating given on a 5-point scale from 0 (normal) to 4 (most abnormal). Higher scores indicate more severe motor impairment than lower scores.

Results from the HART and MermaiHD studies have suggested a potential benefit of pridopidine in improving motor symptoms in HD (de Yebenes 2011; Huntington Study Group HART Investigators 2013). In the PRIDE-HD study, TMS showed improvement at all doses at week 26, but did not reach statistical significance, probably due to the high and persistent placebo effect, thus obscuring the ability to assess the potential benefit of pridopidine's motor function. The study currently proposed includes several measures to minimize the placebo effect and allow an accurate assessment of the ability of pridopidine to provide motor function benefits.

2. Change from baseline to Week 78 in the Apathy Evaluation Scale (AES) in patients treated with pridopidine 45 mg twice daily compared with patients receiving placebo.

Apathy is one of the most common neurobehavioral symptoms in HD, occurring in approximately 50-70% of the symptomatic HD population and increasing as the disease progresses. Symptoms include lack of interest and motivation, inability to initiate activities, social withdrawal, and emotional lethargy. Apathy scores in HD patients are highly correlated with disease duration, suggesting that apathy is an inevitable consequence of progressive disease. Although less distressing than symptoms such as depression and less disruptive than irritability or aggression, apathy has a significant adverse effect on HD sufferers as it leads to a deterioration in goal-directed behavior that greatly contributes to the quality of life from day to day. day (Krishnamoorthy 2011; Martinez-Horta 1 2016).

An exploratory analysis in the PRIDE-HD study showed that the Problem Behavior Score Apathy subscale was improved in early HD patients treated with 45 mg twice daily compared with placebo at week 52. Apathy Improvement provides convergent evidence of clinical utility with the primary endpoint, TFC. The AES was designed to measure deviations in goal-directed behavior, goal-related thought content, and emotional indifference (Marin et al., 1991). This more comprehensive scale was chosen as the secondary endpoint, while RBA remains the exploratory endpoint.

The Bonferroni-Holmes method to control for type 1 error will be used as follows: if the primary end-evaluation criterion is reached, both secondary end-evaluation criteria will be tested simultaneously at α=0.025. If one of these secondary endpoints is achieved, the other can be subsequently tested at α=0.05.

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Bibliography

Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357-81.

Bechtel, N. et al., Tapping linked to function and structure in premanifest and symptomatic Huntington disease. Neurology. 2010 Dec 14;75(24):2150-60.

Bezdicek O, Majerova V, Novak M, Nikolai T, Ruzicka E, Roth J. Validity of the Montreal Cognitive Assessment in the detection of cognitive dysfunction in Huntington's disease. Appl Neuropsychol Adult. 2013;20(l):33-40.

Bowie CR, Harvey PD. Administration and interpretation of the Trail Making Test. Nat Protocol. 2006;l(5):2277-81.

Brown M, Sinacore DR, Binder EF, Kohrt WM. Physical and performance measures for the identification of mild to moderate frailty. J Gerontol A Biol Sci Med Sci. 2000 Jun;55A(6):M350-5.

Byrne, LM et al., Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: a retrospective cohort analysis, Lancet Neurol published June 7, 2017,

Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 1963;20:140-4.

Cepeda C, Cummings DM, Andre VM, Holley SM, Levine MS. Genetic mouse models of Huntington's disease: focus on electrophysiological mechanisms. A.S.N. Neuro. 2010 Apr 7;2(2):e00033.

Coenzyme Q10 in Huntington's Disease (HD) (2CARE), ClinicalTrials.gov Identifier: NCT00608881, clinicaltrials.gov/ct2/show/NCT00608881?term=2CARE%20+Huntington&rank=l, accessed September 13, 2016.

Craufiird D, Thompson JC, Snowden JS. Behavioral changes in Huntington Disease. Neuropsychiatry Neuropsychol Behav Neurol. 2001 Oct-Dec; 14(4):219-26.

Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch Gen Psychiatry. 2007 Mar;64(3):327-37.

Dyhring T, Nielsen E0, Sonesson C, Pettersson F, Karlsson J, Svensson P, Christophersen P, Waters N. The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties . Eur J Pharmacol. 2010 Feb 25;628(l-3): 19-26.

Exploratory Population Pharmacokinetic Modeling and Simulations With Pridopidine (Report

- 81 041256

Number: CPD13D013). Pharsight Consulting Services, 10 July 2013.

Guy W. Clinical Global Impression: ECDEU assessment manual for psychopharmacology. Publication ADM-76-338, US Department of Health, Education, and Welfare Washington DC: US Government Printing Office. 1976: 217-22.

Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ. Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). Neurology. 2003 Jan 14;60(l):316.

Hocaoglu MB, Gaffan EA, Ho AK. The Huntington's Disease health-related Quality of Life questionnaire (HDQoL): a disease-specific measure of health-related quality of life. Clin Genet. 2012 Feb;81(2): 117-22.

Huntington Study Group TREND-HD Investigators. Randomized controlled trial of ethyleicosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol. 2008 Dec;65(12): 1582-9.

Huntington Study Group. Unified Huntington's Disease Rating Scale: Reliablility and Consistency, Movement Disorders, 1996,11(2):136-142.

Huntington Study Group. Dosage effects of riluzole in Huntington's disease: a multicenter placebo-controlled study. Neurology. 2003 Dec 9;61(ll):1551-6.

Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006 Feb 14;66(3):366-72.

Huot P, Levesque M, Parent A. The fate of striatal dopaminergic neurons in Parkinson's disease and Huntington's chorea. brain. 2007 Jan;130(Pt 1):222-32.

Joffres C, Graham J, Rockwood K. Qualitative analysis of the clinician interview-based impression of change (Plus): methodological issues and implications for clinical research. Int Psychogeriatr. 2000 Sep;12(3):403-13.

Johnson AC and Paulsen JS. Huntington's Disease: A Guide for Professionals. D. Lovecky and K. Tarapata eds. 2014.Huntington's Disease Society of Americas (HDSA)

Kieburtz K, Koroshetz W, McDermott M, et al. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurol. 2001 Aug 14; 57(3):397-404.

Kingma EM, van Duijn E, Timman R, van der Mast RC, Roos RA. Behavioral problems in Huntington's disease using the Problem Behaviours Assessment. Gen Hosp Psychiatry. 2008 Mar-Apr;30(2):155-6

Krishnamoorthy, A. and Craufurd, D. Treatment of Apathy in Huntington's Disease and Other Movement Disorders. Current Treatment Options in Neurology, 2011, 13(5):508-19

Kung VW, Hassam R, Morton AJ, Jones S. Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington's disease. neuroscience. 2007

- 82 041256

Jun 8;146(4): 1571-80.

Landwehrmeyer B, Marder K, Biilmann Ronn B, Haglund M on behalf of the MermaiHD and HART study investigators. Effects of the dopaminergic stabilizer pridopidine on motor symptoms in Huntington's disease: a meta-analysis. Presented at the World Congress on Huntington's Disease, 11-14 September 2011, Melbourne (Australia).

Mahant N, McCusker EA, Byth K, Graham S; Huntington Study Group. Huntington's disease: clinical correlates of disability and progression. Neurology. 2003 Oct 28;61(8): 1085-92.

Marder K, Zhao H, Myers RH, Cudkowicz M, Kayson E, Kieburtz K, Orme C, Paulsen J, Penney JB Jr, Siemers E, Shoulson I. Rate of functional decline in Huntington's disease. Huntington Study Group. Neurology 2000;54:452-58

Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res 1991;38(2): 143-62.

Martinez-Horta S, Perez-Perez J, van Duijn E, Fernandez-Bobadilla R, Carceller M, Pagonabarraga J, et al. Neuropsychiatric symptoms are very common in premanifest and early stage Huntington's Disease. Parkinsonism Relat Disord 2016;25:58-64.

Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for disease progression in Huntington's disease. Cochrane Database Syst Rev. 2009 Jul 8;(3).

Mestre T, Ferreira J, Coelho MM, Rosa M, Sampaio C. Therapeutic interventions for symptomatic treatment in Huntington's disease. Cochrane Database Syst Rev. 2009 Jul 8;(3).

Myers RH, Sax DS, Koroshetz WJ, Mastromauro C, Cuppies LA, Kiely DK, Pettengill FK, Bird ED. Factors associated with slow progression in Huntington's disease. Arch Neurol. 1991 Aug48(8):800-4.

Natesan S, Svensson KA, Reckless GE, Nobrega JN, Barlow KB, Johansson AM, Kapur S. The dopamine stabilizers (S)-(-)-(3-methanesulfonyl-phenyl)-l-propyl-piperidine [(-)- OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat. J Pharmacol Exp Ther. 2006 Aug;318(2):810-8.

Nieoullon A, Coquerel A. Dopamine: a key regulator to adapt action, emotion, motivation and cognition. Curr Opin Neurol. 2003 Dec;16 Suppl 2:S3-9.

Open-label Extension Study of Pridopidine (ACR16) in the Symptomatic Treatment of Huntington Disease (OPEN-HART), ClinicalTrials.gov Identifier: NCT01306929, clinicaltrials.gov/ct2/show/NCT01306929, accessed September 13, 2016.

Podsiadlo D, Richardson S. The timed Up & Go: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991 Feb;39(2): 142-8.

Ponten H, Kullingsjo J, Lagerkvist S, Martin P, Pettersson F, Sonesson C, Waters S, Waters N.

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Claims (9)

In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol. 2010 Oct 10;644(l-3):88-95. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12): 1266-77. Rao AK, Muratori L, Louis ED, Moskowitz CB, Marder KS. Clinical measurement of mobility and balance impairments in Huntington's disease: validity and responsiveness. Gait posture. 2009 Apr;29(3):433-6. Reuben DB, Siu AL. An objective measure of physical function of elderly outpatients. The Physical Performance Test. J Am Geriatr Soc. 1990 Oct;38(10): 1105-12. Stout JC, Queller S, Baker KN, Cowlishaw S, Sampaio C, Fitzer-Attas C, Borowsky B; HDCAB Investigators. HD-CAB: a cognitive assessment battery for clinical trials in Huntington's disease. Mov Disord 2014;29(10): 1281-8. Stroop J.R. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:643-62. The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 1990;16:199-208. Waters S, Pettersson F, Dyhring T, Sonesson C, Tedroff J, Waters N et al. Pharmacology of the dopaminergic stabilizer pridopidine (ACR16). Clin Genet 2009;76(Sl):74 (Abstract D10). Zhan L, Kerr JR, Lafuente MJ, Maclean A, Chibalina MV, Liu B, Burke B, Bevan S, Nasir J. Altered expression and coregulation of dopamine signaling genes in schizophrenia and bipolar disorder. Neuropathol Appl Neurobiol. 2011 Feb;37(2):206-19. CLAIM 1. Use of an oral pharmaceutical composition containing pridopidine or a pharmaceutically acceptable salt thereof in the early stages of Huntington's disease (HD1 and HD2, TFC 7-13) to maintain functional capacity, improve functional capacity, or reduce deterioration in functional capacity in a human patient, as measured using the UHDRS Total Functional Ability Scale (TFC), and where the early stages of the disease are defined as HD1 (TFC 11-13 points) and HD2 (TFC 7-10 points) on this scale and where the human patient has a baseline TFC score of 7-13 on this scale. 2. Use according to claim 1, wherein the deterioration in functional ability is reduced by at least 20%, at least 30%, at least 40%, at least 50%, or at least 80%. 3. Use according to claim 1 or 2, wherein the human patient is administered a dose of 90 to 225 mg of pridopidine or a pharmaceutically acceptable salt thereof daily. 4. Use according to claim 1 or 2, where the overall functional ability is: (a) maintaining a professional activity, (b) the ability to manage finances, (c) the ability to perform household chores, the ability to perform basic self-care activities, and/or (d) the need for a negligible level of care for a human patient. 5. Use according to claim 4, wherein the functional ability is the ability to perform elementary self-care activities as measured by the Elementary self-care activities domain of the UHDRS-TFC, which is maintained or improved, wherein the human patient is administered a daily dose of pridopidine from 90 to 225 mg. 6. Use according to any one of claims 1-5, further comprising improving or maintaining the ability to manage finances as measured by the Financial Management domain of the UHDRS-TFC. 7. Use according to any one of claims 1 to 6, wherein a dose of 90 or 180 mg of pridopidine is administered to a human patient on a daily basis. 8. Use according to claim 4, wherein the functional ability is the ability to perform household chores as measured by the household chores domain of the UHDRS TFC, which is maintained, improved, or degraded, and the human patient has a baseline TFC score of 713. 9. Use according to claim 4, where the functional ability is the level of care, measured by the Level of care from the UHDRS TFC, which is maintained, improved. -